Clinical trial NCT02386839
Conditions: Retinopathy of Prematurity (ROP)
Sponsor: Shire
Start date: 2015-03-26; Completion date: 2021-09-28
Enrollment: 76 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the long-term efficacy and safety outcomes following short-term exposure to rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (NCT01096784).

Detailed description:
Long-term Safety and Efficacy Outcome Study Comparing Children Previously Enrolled in Study ROPP-2008-01 for the Prevention of Retinopathy of Prematurity (ROP)

Arms: arm 1: Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784) were enrolled in this group for assessment of rhIGF-1/rhIGFBP-3 long-term efficacy and safety outcomes. arm 2: Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784) were enrolled in this group for assessment of rhIGF-1/rhIGFBP-3 long-term efficacy and safety outcomes.
Interventions: intervention 1: rhIGF-1/rhIGFBP-3
Intervention descriptions: intervention 1: Participants who received "rhIGF-1/rhIGFBP-3" in study ROPP-2008-01 (NCT01096784) will be enrolled to this study. No investigational product will be administered in this study.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:  
NCT02386839 
 
Study Title: 
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 
Previously Treated with rhIGF-1/rhIGFBP-3 for the Prevention of 
Retinopathy of Prematurity (ROP) or Who Received Standard Neonatal 
Care 
 
 
Study Number: 
SHP607-201 
 
Protocol Version and Date: 
Original Protocol: 
27 Aug 2014 
Amendment 1: 
19 Feb 2016 
Amendment 2: 
21 Feb 2017 
Amendment 3: 
11 May 2017 
Amendment 4: 
09 Apr 2018 
 


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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3
Clinical Trial Protocol:  SHP-607-201
27 August 14
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
Visual acuity as assessed by an age appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
The secondary efficacy endpoints of this study are:

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition 
(WPPSI-IV)

Physical development as assessed by standardized, age appropriate tools including 
physical exam, neurological examination for assessment of cerebral palsy, and hearing 
assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention Deficit/Hyperactivity Disorder Rating Scale-fourth edition (ADHD 
RS-IV) for the assessment of symptoms of attention deficit/hyperactivity 
disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism 
Spectrum Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
The health economic outcome research endpoints of this study are:

Health-related quality of life (HRQoL) 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, respectively)

Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS) 

Resource use associated with inpatient visits, outpatient visits, medical utilization and  
pharmacy utilization will be assessed 
The safety endpoints of this study are:

Physical examination including tonsil examination
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Clinical Trial Protocol:  SHP-607-201
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Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or 
standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
Date of Original Protocol:  27 August 2014
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Clinical Trial Protocol:  SHP-607-201
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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ..................................................................................................10
LIST OF IN-TEXT FIGURES.................................................................................................10
LIST OF ABBREVIATIONS..................................................................................................11
1
INTRODUCTION ...........................................................................................................13
2
STUDY OBJECTIVES....................................................................................................15
2.1
Primary Objectives.................................................................................................15
2.2
Secondary Objectives.............................................................................................15
2.3
Exploratory Objective............................................................................................15
3
STUDY ENDPOINTS.....................................................................................................16
3.1
Efficacy Endpoints.................................................................................................16
3.1.1
Primary Efficacy Endpoints.........................................................................16
3.1.2
Secondary Efficacy Endpoints.....................................................................16
3.2
Health Economic Outcome Research Endpoints...................................................17
3.3
Safety Endpoints....................................................................................................17
3.4
Exploratory Endpoints ...........................................................................................17
4
INVESTIGATIONAL PLAN..........................................................................................18
4.1
Overall Study Design and Plan..............................................................................18
4.2
Rationale for Study Design....................................................................................19
4.3
Study Duration.......................................................................................................20
5
STUDY POPULATION SELECTION ...........................................................................21
5.1
Study Population....................................................................................................21
5.2
Inclusion Criteria ...................................................................................................21
5.3
Exclusion Criteria ..................................................................................................21
6
STUDY TREATMENT...................................................................................................22
6.1
Description of Treatment .......................................................................................22
6.2
Treatments Administered.......................................................................................22
6.3
Selection and Timing of Dose for Each Subject....................................................22
6.4
Method of Assigning Subjects to Treatment Groups.............................................22
6.5
Masking..................................................................................................................22
6.6
Medications............................................................................................................22
6.7
Restrictions ............................................................................................................22
6.7.1
Prior Therapy ...............................................................................................22
6.7.2
Other Restrictions ........................................................................................22
6.7.3
Treatment Compliance.................................................................................22
6.7.4
Packaging and Labeling...............................................................................22
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6.8
Storage and Accountability....................................................................................23
7
STUDY PROCEDURES .................................................................................................24
7.1
Informed Consent...................................................................................................24
7.2
Study Entrance Criteria and Eligibility..................................................................24
7.3
Study Enrollment ...................................................................................................24
7.4
Demographics ........................................................................................................24
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference.....24
7.5.1
Length and Height........................................................................................24
7.5.2
Body Weight ................................................................................................25
7.5.3
Head Circumference ....................................................................................25
7.6
Efficacy Assessments.............................................................................................25
7.6.1
Visual Assessments......................................................................................25
7.6.1.1
Visual Acuity .....................................................................................25
7.6.1.2
Corrective Lens Determination..........................................................26
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility) .............26
7.6.1.4
Refraction with Cycloplegia ..............................................................27
7.6.1.5
Stereoacuity........................................................................................27
7.6.1.6
7.6.2
Hearing Assessment History........................................................................28
7.6.3
Behavioral Assessments...............................................................................28
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition....28
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence, Fourth 
Edition (WPPSI-IV)...........................................................................28
7.6.3.3
Child Behavior Checklist (CBCL).....................................................29
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition........................29
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale-Fourth 
Edition................................................................................................29
7.6.3.6
Social Communication Questionnaire – Lifetime Form....................30
7.6.4
Cerebral Palsy Assessment ..........................................................................30
7.6.5
Pulmonary Morbidity Assessment...............................................................30
7.6.6
Survival Assessment....................................................................................30
7.6.7
Health Economic Outcome Research Assessments.....................................30
7.6.7.1
Health Related Quality of Life...........................................................30
7.6.8
Health Care Resource Use ...........................................................................31
7.6.8.1
Health Status Classification System-Preschool .................................31
7.7
Safety Assessments................................................................................................32
7.7.1
Abdominal ultrasound..................................................................................32
7.7.2
Echocardiogram ...........................................................................................32
7.7.3
Physical Examination...................................................................................32
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7.8
Medication Assessment .........................................................................................33
7.9
Adverse Events Assessments.................................................................................33
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions ......................................................33
7.9.1.1
Adverse Event....................................................................................33
7.9.1.2
Serious Adverse Event.......................................................................34
7.9.1.3
Suspected Unexpected Serious Adverse Reaction.............................35
7.9.1.4
Targeted Medical Events ...................................................................35
7.9.2
Classification of Adverse Events and Serious Adverse Events...................35
7.9.3
Clarification between Serious and Severe ...................................................35
7.9.4
Relatedness of Adverse Events and Serious Adverse Events......................36
7.9.5
Procedures for Recording and Reporting Adverse Events ..........................36
7.9.5.1
Adverse Event Monitoring and Period of Observation......................36
7.9.5.2
Reporting Serious Adverse Events ....................................................37
7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting..............................................................................38
7.10
Removal of Subjects from the Trial.......................................................................38
7.11
Other Study Procedures .........................................................................................39
7.11.1
Participation in Other Clinical Studies ........................................................39
7.12
Appropriateness of Measurements.........................................................................39
8
STUDY ACTIVITIES .....................................................................................................40
8.1
Initial Study Visit (40 weeks CA [term equivalent]).............................................40
8.2
Study Visits............................................................................................................40
8.2.1
Outcome Assessment Visits Conducted by Telephone ...............................40
8.2.2
Clinical Site Visits .......................................................................................41
8.2.2.1
Outcome Assessment Site Visits .......................................................41
8.2.2.2
Visits Dedicated to Corrective Lens Determination ..........................44
8.3
Assessments upon Discontinuation .......................................................................44
9
QUALITY CONTROL AND ASSURANCE .................................................................45
10
STATISTICAL ANALYSES ..........................................................................................46
10.1
General Methodology ............................................................................................46
10.2
Determination of Sample Size ...............................................................................46
10.3
Method of Assigning Study Subjects to Treatment Groups ..................................46
10.4
Population Description...........................................................................................46
10.4.1
Analysis Populations....................................................................................46
10.4.2
Subject Disposition......................................................................................46
10.4.3
Protocol Violations and Deviations .............................................................47
10.4.4
Demographics and Baseline Characteristics................................................47
10.5
Efficacy Analysis...................................................................................................47
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10.5.1
Primary Efficacy Analysis...........................................................................47
10.5.2
Secondary Efficacy Analysis .......................................................................48
10.5.3
Subset Analyses ...........................................................................................49
10.5.4
Exploratory Analyses...................................................................................49
10.6
Health Economics and Outcomes Research Analyses...........................................49
10.7
Analysis of Safety..................................................................................................49
10.8
Statistical/Analytical Issues ...................................................................................50
10.8.1
Adjustment for Covariates...........................................................................50
10.8.2
Handling of Dropouts or Missing Data........................................................50
10.8.3
Interim Analyses and Data Monitoring........................................................50
10.8.4
Multiple Comparisons/Multiplicity .............................................................50
10.8.5
Sensitivity Analyses.....................................................................................50
11
ADMINISTRATIVE CONSIDERATIONS....................................................................51
11.1
Investigators and Study Administrative Structure.................................................51
11.2
Institutional Review Board or Independent Ethics Committee Approval .............51
11.3
Ethical Conduct of the Study.................................................................................51
11.4
Subject Information and Consent...........................................................................51
11.5
Subject Confidentiality ..........................................................................................52
11.6
Study Monitoring...................................................................................................52
11.7
Case Report Forms and Study Records .................................................................53
11.7.1
Case Report Forms.......................................................................................53
11.7.2
Critical Documents ......................................................................................53
11.8
Data Monitoring Committee..................................................................................54
11.9
Protocol Violations/Deviations..............................................................................54
11.10 Premature Closure of the Study.............................................................................54
11.11 Access to Source Documentation ..........................................................................55
11.12 Data Generation and Analysis ...............................................................................55
11.13 Retention of Data...................................................................................................55
11.14 Financial Disclosure...............................................................................................55
11.15 Publication and Disclosure Policy .........................................................................55
12
LIST OF REFERENCES.................................................................................................57
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LIST OF IN-TEXT TABLES
Table 7-1
Summary of Visual Acuity Assessments ...................................................26
Table 7-2
Assessments for Physical Examinations ....................................................33
Table 7-3
Adverse Event Severity..............................................................................35
Table 12-1
Summary of Visual Acuity Assessments ...................................................62
LIST OF IN-TEXT FIGURES
Figure 4-1
Overview of Study Design, Study SHP-607-201.......................................19
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AAO
American Academy of Ophthalmology
ADHD
attention-deficit hyperactivity disorder
ADHD-RS-IV
Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition
AE
adverse event
ASD
Autism Spectrum Disorder
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CBCL
Child Behavior Checklist (1 ½ to 5)
CFR
Code of Federal Regulations
CA
corrected age
CI
confidence interval
CRF
case report form (electronic)
CRO
contract research organization
DMC
data monitoring committee
eCRF
electronic case report form
EOS
end of study
ETDRS
Early Treatment of Diabetic Retinopathy Study
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GH
growth hormone
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IND
Investigational New Drug application
IRB
institutional review board
LV
left ventricle
MedDRA
Medical Dictionary for Regulatory Activities 
OD
right eye
OS
left eye
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Abbreviation
Definition
OU
both eyes
PedsQL
Pediatric Quality of Life Inventory 
REB
research ethics board
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SCQ
Social Communication Questionnaire
SD
standard deviation
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
UK
United Kingdom
US
United States
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
VLBW
very low birth weight
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition
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1
INTRODUCTION
Retinopathy of prematurity (ROP) is a rare disorder of the developing retinal blood vessels and 
retinal neurons of the preterm infant and is one of the leading causes of preventable blindness in 
children.1
Visual acuity is decreased in infants with a history of ROP.2 In addition to acuity, other aspects 
of eye health are also significantly impacted by ROP. Strabismus and myopia are clearly 
increased in patients with a history of ROP.3-6  Additionally, more than half of patients at 6 to 
10 years of age with a history of Stage 1 and Stage 2 ROP were reported to have ongoing visual 
issues.7
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. During fetal life, IGF-1 is available through placental 
absorption and ingestion from amniotic fluid.8 Deprivation of such factors is likely to cause 
inhibition or improper stimulation of important pathways, which in the eye may cause abnormal 
retinal vascular development, the hallmark of ROP.
The finding in both a mouse model of ROP and preterm infants that development of ROP is 
associated with low levels of IGF-1 after premature birth, indicates a possible role for 
replacement of IGF-1 to levels found in utero as a strategy to potentially decrease abnormal 
retinal vascularization and abnormal retinal neural development, and ultimately, ROP. 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) is the human recombinant form of the naturally 
occurring protein complex of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was developed to enhance the systemic exposure of administered rhIGF-1 
and to improve the safety profile of rhIGF-1 therapy. rhIGF-1/rhIGFBP-3 was approved by the 
Food and Drug Administration (FDA) in 2005 for the treatment of growth failure in children 
with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have 
developed neutralizing antibodies to GH. 
The pharmacokinetics and safety of rhIGF-1/rhIGFBP-3 have been evaluated in a Phase I study 
(ROPP-2005-01) and pharmacokinetics, safety, and efficacy are being evaluated in the ongoing 
phase II study (ROPP-2008-01). Sections A-C of the ROPP-2008-01 study are complete. 
Section D of the ROPP-2008-01 study is currently being conducted to assess pharmacokinetics, 
safety and efficacy of rhIGF-1/rhIGFBP-3 for the prevention of ROP in premature infants (up to 
a corrected age [CA] of 40 weeks [± 4 days]). Subjects in Study ROPP-2008-01are randomly 
assigned to receive rhIGF-1/rhIGFBP-3 or standard neonatal care. The target dose of 
rhIGF-1/rhIGFBP-3 for Study Section D is 250 μg/kg/24 hours to be administered via 
continuous infusion starting on Study Day 0 (day of birth) and continuing through postmenstrual 
age (gestational age + time elapsed from birth) 29 weeks + 6 days.
Although the rhIGF-1/rhIGFBP-3 therapy in Section D of the Phase II study (Study 
ROPP-2008-01) represents a short-term exposure (< 2 months for each subject), 
rhIGF-1/rhIGFBP-3 may have long-lasting effects on visual outcomes as well as other potential 
outcomes related to complications of prematurity such as neurodevelopment, pulmonary 
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Clinical Trial Protocol:  SHP-607-201
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function, and growth. In addition, it is critical to understand any long term safety effects from 
short term exposure to rhIGF-1/rhIGFBP-3. 
The long-term outcomes assessed in this study will require utilization of different assessment 
tools than are utilized in the Phase II study, ROPP-2008-01 Section D, given the changes in 
physical and cognitive development that will occur in the subjects as they age during their 
participation in this study. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of rhIGF-1/rhIGFBP-3.
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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints

Visual acuity as assessed by an age-appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
3.1.2
Secondary Efficacy Endpoints

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition 
(WPPSI-IV)

Physical development as assessed by standardized, age appropriate tools including 
physical examination, neurological examination for assessment of cerebral palsy, and 
hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition 
(ADHD-RS-IV) for the assessment of symptoms of 
attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3
(treated) or standard neonatal care (control). Enrolled subjects in this study will be followed 
through age 5 years CA. This study will enroll both subjects who were in the treated (received 
rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of Study 
ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term efficacy and 
safety outcomes versus standard neonatal care. No investigational product will be administered 
in this study. 
In this study, the Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon 
discontinuation from Study ROPP-2008-01 or may occur any time up to the visit at 3 months 
CA. Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age of 
23 weeks + 0 days to 27 weeks + 6 days.
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. Both 
telephone and clinical site visits are included to help maintain contact with subjects throughout 
the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required. 
See Appendix 1 for the Study Schedule of Events table.
The overall study design is outlined in Figure 4-1.
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Insulin-like growth factor-1 (IGF-1) mediates its primary actions by binding to its specific 
receptor, the insulin-like growth factor 1 receptor (IGF-1R), which is present on many cell types 
in many tissues. Binding to its receptor initiates intracellular signaling including via the AKT 
signaling pathway. This pathway is involved in stimulation of cell division, growth and 
differentiation and inhibits programmed cell death. Specifically regarding premature infants, 
IGF-1 is an important mediator of fetal growth and has been shown to play a role in early 
postnatal growth following pre-term delivery.9, 10
Insulin-like growth factor-1 (IGF-1) has also been shown to play a role in pulmonary 
development11 and neural development.12, 13 Given the potential role for IGF-1 in the 
development of multiple systems, this study has been designed to evaluate the long-term effects 
of rhIGF-1/rhIGFBP-3, both from a safety and efficacy perspective, on the development of the 
premature infant.
4.3
Study Duration
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years CA.
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5
STUDY POPULATION SELECTION
5.1
Study Population
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks + 0 days to 27 weeks + 6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. Up to 
120 subjects are planned to be randomized in Study ROPP-2008-01 Section D.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject was randomized in Study ROPP-2008-01, Section D
2. Subject’s parent or legally authorized representative(s) must provide written informed 
consent prior to performing any study-related activities. Study-related activities are any 
procedures that would not have been performed during normal management of the subject.
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. Any other condition or therapy that, in the Investigator’s opinion, may pose a risk to the 
subject or interfere with the subject’s ability to be compliant with this protocol or interfere 
with the interpretation of results
2. The subject or subject’s parent or legally authorized representative(s) is unable to comply 
with the protocol as determined by the Investigator
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6
STUDY TREATMENT
6.1
Description of Treatment
No investigational product will be administered in this study.
6.2
Treatments Administered
Not applicable.
6.3
Selection and Timing of Dose for Each Subject
Not applicable.
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable.
6.5
Masking
Not applicable.
6.6
Medications
Any medications administered to the subjects will be collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued). Any 
investigational product received by subjects will be recorded separately as part of an assessment 
of subjects’ participation in other clinical studies (Section 7.11.1).
6.7
Restrictions 
6.7.1
Prior Therapy
There are no restrictions related to prior therapy.
6.7.2
Other Restrictions
There are no restrictions related to fluid or food intake, or subject activity.
6.7.3
Treatment Compliance
Not applicable.
6.7.4
Packaging and Labeling
Not applicable.
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6.8
Storage and Accountability
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7
STUDY PROCEDURES
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events in Appendix 1). 
All data collected are to be recorded on the subject’s appropriate eCRF. 
Details for study procedures are described in the Operations Manual for this study.
7.1
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).
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 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria and Eligibility
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.
7.3
Study Enrollment
Subjects will be considered enrolled in the study once written informed consent has been 
obtained from the subject’s parent(s) or legally authorized representative(s).
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be recorded.
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference
7.5.1
Length and Height
Body length (supine measurement) will be collected when subjects are 24-months CA or 
younger. 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.
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Height (standing measure) will be collected when subjects are older than 24-months CA. 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). 
7.5.2
Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures 
(type of scale will depend upon subject’s age). Care should be taken to remove any extraneous 
clothing prior to measures and shoes should be removed.
The measure should be recorded to the nearest 0.1 kg.
7.5.3
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.
7.6
Efficacy Assessments
7.6.1
Visual Assessments
After corrective lens determination has occurred (Section 7.6.1.2), all visual assessments should 
be conducted with best-corrected vision, ie, with corrective lenses in place (if required); this 
applies to 24-month and 5-year visits.
7.6.1.1
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. It will be assessed by 
the methods summarized in Table 7-1; the method employed will be selected based on the 
subject’s age (CA) at the time of the study visit. Visual acuity measurements will be measured 
and recorded for the left (OS), right (OD) eye, and both eyes (OU).
At ages 6 months and 12 months CA, visual acuity will be assessed with Teller acuity cards. At 
ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner 
determines that it will not be possible to perform an accurate assessment with the relevant LEA 
tool, visual acuity should be assessed with the Teller acuity cards. 
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The visual acuity assessments should be performed by an optometrist or ophthalmologist trained 
in pediatrics. 
Table 7-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
7.6.1.2
Corrective Lens Determination
An assessment to determine if the subject requires vision correction with corrective lenses will 
be performed. This is being performed to ensure the accuracy of subjects’ subsequent visual 
acuity assessments (at the 24-month and 5-year visits). The corrective lens determination will be 
performed according to the guidelines published by the American Academy of Ophthalmology 
(AAO).14
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)
Ocular alignment will be assessed in primary gaze by comparing the position of the corneal light 
reflection in OS and OD (corneal light reflection assessment). Presence or absence of strabismus 
will be recorded in primary gaze and in as many of the 9 positions of gaze as feasible with the 
cover test assessment of refixation movement. Extraocular muscle over-action or deficiency will 
be recorded. The assessment will be performed according to the AAO guidelines.14
Presence or absence of nystagmus as observed during the ocular alignment assessments will also 
be recorded.
The assessment will be performed by a pediatric ophthalmologist or an ophthalmologist trained 
in the care of pediatric subjects with a history of premature birth. Degree of adherence to the 
AAO guidelines will be at the discretion of the examining physician in consideration of the need 
for patient cooperation. 
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7.6.2
Hearing Assessment History
Results of previously completed hearing assessments will be recorded; hearing tests are not 
being performed as part of this study. 
7.6.3
Behavioral Assessments
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition
The BSID-III will be used to assess cognitive, motor, and language skills, and is applicable to 
children aged 1 to 42 months. 
The BSID-III is an assessment tool designed to measure a young child's skills in the 3 core areas 
of development:  cognitive, language, and motor. There are 5 subscales, the cognitive subscale 
stands alone while 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 examiner's manual.
The BSID-III 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.
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition 
(WPPSI-IV)
The WPPSI-IV is a measure of general cognitive development in children that has components 
of both verbal and nonverbal tasks.19  It is applicable to preschoolers and young children aged 
2 years + 6 months to 7 years + 7 months, and is a direct assessment of a child’s cognitive skills.
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 standardization20 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.
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The WPPSI-IV will be administered to the subject by a trained professional. Scores to be 
recorded are detailed in the Study Operations Manual.
7.6.3.3
Child Behavior Checklist (CBCL)
The CBCL (1 ½ to 5) is a parent-reported outcome measure used to assess behavioral, emotional, 
and social functioning of toddlers and preschool children aged 18 to 60 months.21 It is composed 
of 99 items that are rated on a Likert scale and includes the following 7 syndrome scales 
arranged under 2 domains (ie, Internalizing and Externalizing Problems):22

Internalizing Problems

Emotionally Reactive

Anxious/Depressed

Somatic Complaints

Withdrawn

Sleep Problems

Attention Problems

Aggressive Behavior
The questionnaire is widely used and has been employed to assess long-term behavioral 
outcomes in children born prematurely, aged similarly to the subjects expected in this study 
population.22 - 24 It is associated with well-established normative data;25 norms may be selected 
to aid in interpretation of the scale scores.
The CBCL (1 ½ to 5) is a questionnaire that will be administered to 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.
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition
The VABS-II Expanded Interview Form will be used to measure the personal and social skills of 
subjects serially over time; these scales are organized within a 3-domain structure:  
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what he or she is able to do. 
The VABS-II Expanded Interview Form will be administered to 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.
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale-Fourth Edition
The ADHD-RS-IV was developed to measure the behaviors of children with ADHD. The 
ADHD-RS-IV consists of 18 items designed to reflect current symptomatology of ADHD based 
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on DSM-IV 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-IV, 26 will be completed by the subject’s parent(s) or legally authorized 
representative(s). Scores to be recorded are detailed in the Study Operations Manual.
7.6.3.6
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children27 that can be used for screening for autism or autism spectrum disorders in the general 
population.28
The SCQ will be completed by the subject’s parent(s) or legally authorized representative(s). 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.
7.6.4
Cerebral Palsy Assessment
Comprehensive neurological examination for the diagnosis of cerebral palsy (CP) will be 
conducted. The Amiel-Tison neurological examination framework29 will be utilized for this 
assessment and conducted by trained medical professionals.
7.6.5
Pulmonary Morbidity Assessment
Pulmonary morbidity will be assessed with questions related to family history and smoking 
status as well as diagnosis of select pulmonary symptoms, conditions and related 
hospitalizations. The questionnaire will be administered to the subject’s parent(s) or legally 
authorized representative(s). 
7.6.6
Survival Assessment
Survival status will be assessed and recorded.
7.6.7
Health Economic Outcome Research Assessments
7.6.7.1
Health Related Quality of Life
Health-related quality of life (HRQoL) is an important outcome towards improving the health 
care of pediatric patients as it is that part of a person’s overall quality of life that is determined 
primarily by their health status and which can be influenced by clinical interventions. It is an 
important concept, which is also used in determining the value of health care services in this 
population.30, 31   It is a multidimensional construct whose content is guided by the World Health 
Organization32; minimally it includes physical, psychological (including emotional and 
cognitive), and social health dimensions.
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In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL™) Scales appropriate for the child’s age of development.33 - 35 The development of the 
PedsQL was based on the delineations of the World Health Organization (WHO) and is a 
modular approach to assessing HRQoL in the pediatric population. Initially, the PedsQL Generic 
Scales were developed and continue to be used in children aged 2 to 18 years. More recently 
Infant Scales have been developed that apply to ages 1 to 24 months.34
The following scales will be used in this study:

Infant Scale for ages 1-12 months (36 Items)

Infant Scale for ages 13–24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent and may be conducted via telephone 
through a call center. The scale(s) to be administered at each visit will be specified in the Study 
Operations Manual.
7.6.8
Health Care Resource Use
To understand the value of the investigational product administered in Study ROPP-2008-01 
(Section D), the resource use associated with inpatient visits, outpatient visits, and medical and 
pharmacy utilization in this study will be recorded. 
This assessment may be conducted via telephone through a call center.
7.6.8.1
Health Status Classification System-Preschool
Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS), which is a validated instrument adapted for use via parent proxy 
within the pediatric population age 2.5 to 5 (adapted from the validated Health Utilities Index 
Mark 2 and 3 [HUI 2/3]).36 Validity of the HSCS-PS concepts has not been established for ages 
younger than 2.5 years.
The HSCS-PS was developed to provide a consistent measure of health status in preschool-aged 
children who had been born prematurely.36 The system is applicable to children with special 
needs as may be included in this study; validation cohorts for the system included children with 
very low birth weight (VLBW), which is congruent with this study population.
The instrument is composed of 12 dimensions (Vision, Hearing, Speech, Mobility, Dexterity, 
Self-care, Emotion, Learn/remember, Think/problem solve, Pain, General Health, and Behavior) 
intended to provide a comprehensive assessment of a child’s health status as it pertains to 
health-related quality of life. The individual domains of the instrument will be scored as a mean 
score, representing the overall state for each concept individually. The global score will be 
recorded as well as the scores for each of the dimensions.
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The HSCS-PS is a questionnaire that will be administered to the subject’s parent(s) or legally 
authorized representative(s) and may be conducted via telephone through a call center.
7.7
Safety Assessments
7.7.1
Abdominal ultrasound
An abdominal ultrasound will be performed to assess the size of the spleen and kidneys. The 
spleen will be measured in the coronal longitudinal plane and the longest longitudinal length will 
be measured for each kidney (left and right).37 Ultrasound results will be assessed by a central 
reader.
Organ size will be interpreted in the context of reference values established for children.37, 38
7.7.2
Echocardiogram
Echocardiographic examination (conventional M-mode recording of the left ventricle [LV] 
parasternal long axis view) will be performed for the evaluation of cardiac size, assessed by 
measuring the following:

interventricular septal thickness (during end diastole)

LV posterior wall thickness

LV intracavity volume (both in end diastole and end systole)
Echocardiogram results will be assessed by a central reader.
7.7.3
Physical Examination
Physical examinations will include a review of the subject’s general appearance, neurological 
examination, as well as a tonsillar examination (Table 7-2). Any abnormal change in findings 
will be recorded as an AE. 
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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Tonsils
7.8
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 7.11.1).
7.9
Adverse Events Assessments
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions
7.9.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
In this long-term outcome study in follow-up to Study ROPP-2008-01 (Section D), no 
investigational product is being administered. However, the relationship to the investigational 
product (rhIGF-1/rhIGFBP-3) as administered in Study ROPP-2008-01 (Section D) will be 
assessed. 
Adverse events collected in this study will be the following:  

those considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP -2008-01, Section D)

those considered related to procedures performed in this study (Study SHP-607-201)

specified targeted medical events (Section 7.9.1.3) regardless of causality

fatal SAEs regardless of causality
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Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset 
of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record AEs on the AE electronic case report form 
(eCRF), regardless of the severity. The Investigator should treat subjects with AEs appropriately 
and observe them at suitable intervals until the events stabilize or resolve. Adverse events may 
be discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given are regarded as AEs and 
will be documented on the appropriate pages of the eCRF. Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as 
AEs and must be documented as such in the eCRF.
7.9.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
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 one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
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(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
7.9.1.3
Suspected Unexpected Serious Adverse Reaction
Suspected unexpected serious adverse reactions (SUSAR) are suspected adverse reactions related 
to an investigational product (investigational products and comparators [if applicable]), which 
occur in the concerned study, and that are both serious and unexpected according to the current 
Investigator’s Brochure.
7.9.1.4
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, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D):

intracranial hypertension

any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and 
diabetes)

tonsillar hypertrophy (based on tonsil exam [part of the physical exam])

increased kidney size 

increased cardiac size

increased spleen size
7.9.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.9.3
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
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functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.9.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product (rhIGF-1/rhIGFBP-3 as administered in 
Study ROPP-2008-01, Section D) is to be determined by the Investigator based on the following 
definitions (See Table 7-4).
Table 7-4
Adverse Event Relatedness
Relationship to Product
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, follows a known or suspected response 
pattern to the investigational product, is confirmed by improvement 
upon stopping the investigational product (de-challenge), and 
reappears upon repeated exposure (re-challenge). Note that this is not 
to be construed as requiring re-exposure of the subject to 
investigational product; however, the determination of definitely 
related can only be used when recurrence of event is observed.
7.9.5
Procedures for Recording and Reporting Adverse Events
7.9.5.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored throughout the study. 
For the purposes of this study, the period of observation extends from the time at which the 
subject’s parent(s) or legally authorized representative(s) gives informed consent until the 
subject’s final evaluation of the study. For safety purposes, the final evaluation will be defined as 
the last study visit when the subject is 5 years-old in CA.
If the Investigator considers it necessary to report an AE in a study subject after the end of the 
safety observation period, he or she should contact the Sponsor to determine how the AE should 
be documented and reported.
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7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The Sponsor and the CRO are responsible for notifying the relevant regulatory authorities/US 
central IRBs/European Union (EU) central ECs of related, unexpected SAEs.
For some European regulatory authorities, these reports are submitted directly to Eudravigilance. 
In case of deaths or life-threatening SUSARs, these must be reported to the relevant regulatory 
authorities before 7 days have elapsed from that the initial SAE report has reached the Sponsor 
or its representatives. A full report has to be submitted within another 8 days. For other SUSARs 
the timelines for reporting are 15 days.
In addition, the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the rhIGF-1/rhIGFBP-3 program at Shire.
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.
7.10
Removal of Subjects from the Trial
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a subject 
from the study:

Non-compliance, including failure to appear at one or more study visits

The subject was erroneously included in the study

The subject develops an exclusion criterion 

The study is terminated by the Sponsor
The subject, the subject’s parent(s), or the subject’s legally authorized representative acting on 
behalf of the subject is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a subject or the subject’s parent(s) or the subject’s legally authorized representative(s) acting 
on behalf of the subject, discontinues participation in the study, or the subject is discontinued by 
the Investigator, reasonable efforts will be made to follow the subject through the end of study 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the subject withdraws from the study, the subject will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
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7.11
Other Study Procedures
7.11.1
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in another 
clinical study that involves 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 being evaluated in the study, and the subject’s treatment assignment 
in the study (if possible). 
7.12
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. These are the pulmonary 
morbidity assessment and the cerebral palsy assessment. In these cases, the tools are either based 
on validated tools or the current state of knowledge in the literature. For example, the cerebral 
palsy assessment is based on the Amiel-Tison neurological examination framework29 and the 
pulmonary assessment is based on published research in a similar pediatric population.39, 40
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8
STUDY ACTIVITIES
The timing of the visits in this study is based on subjects’ corrected age (CA). 
8.1
Initial Study Visit (40 weeks CA [term equivalent])
The Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon discontinuation from 
Study ROPP-2008-01, Section D or any time up to the visit at 3 months CA. 
At the Initial Visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data.
The following AE data, collected as part of Study ROPP-2008-01 (Section D) will also be 
recorded:

Ongoing targeted medical events regardless of causality

Ongoing study drug-related AEs, including SAEs
8.2
Study Visits
Study visits for follow-up outcome assessments will take place at the following time points in 
CA:

3 months (±2 weeks) – conducted by telephone

6 months (±1 month) – clinical site visit

12 months (±3 months) – clinical site visit

24 months (±3 months) – clinical site visit

3 years (±3 months) – conducted by telephone

4 years (±3 month) – conducted by telephone

5 years (+6 months) – clinical site visit
In addition, there will be 2 visits that must occur at least 1 month prior to the 24-month and 
5-year CA study visits to assess the need for corrective lenses. The timing of these 2 visits 
(20 months [-1 month] and 4.75 years [-1 month]) was set to ensure that any prescribed 
corrective lenses would be worn for at least 1 month prior to the visual assessments at the 
24-month and 5-year study visits CA.
The activities at the study visits are described in Sections 8.2.1 and 8.2.2.
8.2.1
Outcome Assessment Visits Conducted by Telephone
Visits at 3 months, 3 years, and 4 years CA will be conducted by telephone. The following 
outcome assessments will be conducted at each of these 3 visits, unless otherwise indicated:
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
HRQoL 

HCRU

HSCS-PS (3-year and 4-year visits only)

Medications

Survival assessment

Assessment of participation in other clinical studies

Adverse events (including targeted medical events)
8.2.2
Clinical Site Visits
8.2.2.1
Outcome Assessment Site Visits
The following clinical site visits (in CA) to capture follow-up outcome data will occur at the 
clinical site:

6 months (±1 month)

12 months (±3 months) 

24 months (±3 months)

5 years (+6 months)
The following assessments will be performed at the 6-month visit:

Visual acuity

Refraction with cycloplegia

Length

Weight

Head circumference

VABS-II

Physical examination (including tonsil examination)

Hearing Assessment History (Historical hearing test data may be recorded at any time prior 
to the 6-month visit) 

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this clinical site 
visit)
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
HCRU (may be performed by telephone if there are time constraints during this clinical site 
visit)

Abdominal ultrasound

Echocardiogram

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 12-month visit:

Visual acuity

Corrective lens determination

Ocular alignment and motility

Refraction with cycloplegia

Length

Weight

Head circumference

BSID-III

VABS-II

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this clinical site 
visit)

HCRU (may be performed by telephone if there are time constraints during this clinical site 
visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 24-month visit:

Visual acuity

Ocular alignment and motility
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
Refraction with cycloplegia

Length

Weight

Head circumference

BSID-III

CBCL

VABS-II

Physical examination (including tonsil examination)

Cerebral Palsy assessment

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this clinical site 
visit)

HCRU (may be performed by telephone if there are time constraints during this clinical site 
visit)

HSCS-PS (may be performed by telephone if there are time constraints during this clinical 
site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 5-year visit:

Visual acuity

Ocular alignment and motility

Refraction with cycloplegia

Stereoacuity

Height

Weight

WPPSI-IV

CBCL

VABS-II

ADHD-RS-IV
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
SCQ

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment


HRQoL (may be performed by telephone if there are time constraints during this clinical site 
visit)

HCRU (may be performed by telephone if there are time constraints during this clinical site 
visit)

HSCS-PS (may be performed by telephone if there are time constraints during this clinical 
site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
8.2.2.2
Visits Dedicated to Corrective Lens Determination
The following clinical site visits are dedicated solely to corrective lens determination in 
preparation for the outcome assessment visits at 24-months and 5-years CA:

20 months (-1 month) 

4.75 years (-1 month) 
At these visits, the following will be performed:

Visual acuity

Refraction with cycloplegia

Corrective lens determination
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior 
to the 24-month and 5-year visits, respectively. Any prescribed corrective lenses must be worn 
for at least 1 month prior to the 24 month and 5 year assessments.
8.3
Assessments upon Discontinuation
If a subject discontinues prior to the 5-year CA visit, every attempt will be made to complete the 
assessments scheduled for the subject’s next visit. 
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 Code of Federal Regulations (CFR) Part 
11 Guidance. The clinical trial database will include an audit trail to document any evidence of 
data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses 
will be performed by the Biometrics department at Shire. Statistical analyses will be performed 
using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3
or standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
10.2
Determination of Sample Size
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study.
10.3
Method of Assigning Study Subjects to Treatment Groups
Not applicable.
10.4
Population Description
10.4.1
Analysis Populations

Enrolled Population- the Enrolled Population will consist of all subjects for whom written 
informed consent has been provided for this study. 

Safety Population- the Safety Population will consist of the subjects in the Enrolled 
Population who have safety follow-up data in this long-term outcome study.
10.4.2
Subject Disposition
Subjects who complete the study and subjects who prematurely discontinue from the study will 
be summarized by treatment group using descriptive statistics. In addition, for subjects who 
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prematurely discontinue from the study, the reasons for discontinuation will be summarized by 
treatment group.
10.4.3
Protocol Violations and Deviations
Protocol violations and deviations will be listed. Details of the criteria for deviations and 
violations will be provided in the SAP.
10.4.4
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for the Enrolled Population. 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. Continuous variables such as age (including corrected age), weight, and 
length/height will be summarized using number of observations, mean, standard deviation, 
median, minimum and maximum values. Categorical variables, like gender and race, will be 
summarized using number of observations and percentages.
Medical history, including maternal and perinatal history, (as obtained from the antecedent 
study, ROPP-2008-01) will be summarized by treatment group using the number of observations 
and percentages of subjects reporting each category.
10.5
Efficacy Analysis
All efficacy analyses will be performed using the Enrolled Population.
10.5.1
Primary Efficacy Analysis
The primary efficacy endpoints consist of the following:

Visual Acuity:  Visual acuity will be categorized as the following: 
o
normal (measurable acuity ≥20/40), 
o
below normal (20/200≤measurable acuity <20/40), 
o
poor (measurable acuity ≤20/200)
o
blind/low vision (only the ability to detect the 2.2 cm wide stripes on the low-
vision Teller acuity card and at any location in the visual field). 
The number and proportion of patients within each category listed above will be 
summarized by treatment group and visit. In addition, acuity results in the normal and 
below normal categories will be classified as favorable outcomes, and acuity results in 
the poor and blind/low-vision categories will be classified as unfavorable outcomes. 
Tabular summaries by treatment group and visit will include the frequency and the 
percentage for each visual acuity category. In addition, shift tables of favorable 
outcomes from baseline (first assessment during this study) to each of the subsequent 
assessments, including the last assessment, will be presented by treatment group.
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
Ocular Alignment and Oculomotor Exam (Motility):  Findings from the ocular 
motility assessment will be either presence or absence of strabismus (esotropia, 
exotropia, hypertropia, or hypotropia). Tabular summaries by treatment group and 
visit will include the frequency and the percentage in each category. In addition, shift 
tables from baseline (first assessment during this study) to the last assessment will be 
provided by treatment group.

Nystagmus:  Presence or absence of nystagmus will be summarized by treatment 
group and visit

Refraction with Cycloplegia:  Findings from the refraction with cycloplegia will be 
summarized by treatment group and visit

Stereoacuity:  Presence or absence of stereopsis will be summarized by treatment 
group and visit
10.5.2
Secondary Efficacy Analysis

Growth Parameters (body weight, body length [and height], and head circumference):  
A standard Z-score, utilizing WHO child growth standards, will be calculated for each 
assessment by adjusting age- and sex- matched means and standard deviations (norm). 
The descriptive statistics of the Z-score for each of these parameters will be 
summarized at each assessment and the corresponding change from baseline. When 
appropriate, a 95% CI for the corresponding mean change within each group and the 
difference in the mean change between the 2 treatment groups and the corresponding 
95% CI will be presented as appropriate. If the parametric assumption for the 
distribution of the above endpoints cannot be justified, a non-parametric approach will 
be utilized to estimate the treatment difference (ie, median difference or 
Hodges-Lehmann estimator and the corresponding confidence intervals)

BSID-III and WPPSI-IV:  The raw score for each domain within each questionnaire 
will be summarized by treatment group and visit using descriptive statistics.

ADHD-RS-IV:  ADHD-RS-IV total score and subscales (Hyperactivity/Impulsivity 
and Inattentiveness) will be summarized by treatment group and visit using descriptive 
statistics.

SCQ:  The SCQ subscales (communication and social) will be summarized by 
treatment group and visit using descriptive statistics

VABS-II:  The raw score for each domain of the scale will be summarized by 
treatment group and visit using descriptive statistics.

CBCL:  The raw score and change from baseline for each domain of the scale will be 
summarized by treatment group and visit using descriptive statistics.

Pulmonary morbidity questionnaire:  The binary response of each question will be by 
treatment group and visit using descriptive statistics.

Survival:  For subjects who have an event (ie, death), the event time will be calculated 
as the length of time from the subject’s date of birth to death during the study due to 
any cause. Subjects who do not have an event (ie, death) during the study will be 
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censored at the end of the study. The survival endpoint will be analyzed by treatment 
group using Kaplan-Meier methods.
10.5.3
Subset Analyses
Subgroup analyses may be explored based on factors that may have influence on the efficacy or 
safety endpoints. Subgroup analyses will be specified in the SAP.
10.5.4
Exploratory Analyses
10.6
Health Economics and Outcomes Research Analyses
For PedsQL, descriptive statistics will be provided for summary scores by treatment group 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 and at each time point.
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.
10.7
Analysis of Safety
Safety summaries will be based on all assessments post-baseline. The safety data will be 
assessed by AE monitoring, change in cardiac size, and kidney and spleen size over time. 
Adverse events will be summarized by system organ class and preferred term for each treatment 
group and overall, the number and percentage of subjects having any AE, having an AE in each 
body system and having each individual AE. In addition, those events which resulted in death, or 
were otherwise classified as serious will be presented in a separate listing. In addition, the 
summary of AEs will be presented by severity and relationship to trial medication. 
The change in cardiac size, and size of kidney and spleen will be assessed at the 6-month CA 
visit via echocardiogram and abdominal ultrasound, respectively.  These data will be analyzed as 
a binary response (ie, normal/abnormal) and summarized using frequency count.  The number 
and proportion of patients with each category (ie, normal/abnormal) for each of these safety 
endpoints will be summarized by treatment group.  In addition, the 2-sided 95% CI for the 
proportion of patients with a normal status for each of the endpoints will be estimated by 
treatment group.
Physical examinations findings will be summarized descriptively. 
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10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
If any baseline data are imbalanced and are considered to be clinically relevant, between-group 
comparisons for efficacy outcomes will be adjusted for covariates and detailed in the SAP. 
10.8.2
Handling of Dropouts or Missing Data
Handling of missing data rules will be described in the SAP.
10.8.3
Interim Analyses and Data Monitoring
An interim analysis will be performed after all data from all enrolled subjects in this study have 
either completed 2-year follow-up (24-month visit) assessments or have prematurely withdrawn 
from the study (before completing 2 years of follow-up) has been entered into the database, 
queried and discrepancies resolved. A full 2-year study report based on these data, including 
efficacy and safety endpoint analyses, will be completed.
Additionally, descriptive analyses of the data at other time points before study completion may 
be performed for safety monitoring, regulatory reporting or general planning purposes.
10.8.4
Multiple Comparisons/Multiplicity
Not applicable.
10.8.5
Sensitivity Analyses
Sensitivity analyses for the efficacy outcomes will be detailed in the SAP, as necessary.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 and Investigator Agreement. Curriculum vitae must be provided for the Investigators 
and sub-investigators listed on Form FDA 1572 or Investigator Agreement. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, and their study related duties and functions. 
The Investigator must maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form. This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study. Within 3 months of study completion or termination, 
a final report must be provided to the IRB/IECREB. A copy of these reports will be sent to the 
study clinical monitor. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are reported to the US (FDA or other Regulatory agencies (Safety Reports) must be 
submitted promptly to the IRB/IEC/REB.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent) form must be in a language understandable to the subject or the subject’s 
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parent(s) or legally authorized representative(s) and must specify who informed the subject, the 
subject’s parent(s), or the subject’s legally authorized representative(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the subject, the subject’s parent(s) or the subject’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the eCRF, and if the subject name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The subjects will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed.
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The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Electronic case report forms (eCRFs) are provided for each subject. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the Investigator to ensure that the following documents are available to Sponsor 
or their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed 
within 12 months of study initiation)

Copy of Investigator and sub-investigator(s) current medical license (indicating 
license number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC/REB clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written 
information to be provided regarding subject recruitment procedures

Copy of IRB/IEC/REB approved Subject Information/Informed Consent Form/any 
other written information/advertisement (with IRB approval stamp and date of 
approval)

Current list of IRB/IEC/REB Committee members/constitution (dated within 
12 months prior to study initiation)

Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
Given that any long-term safety signal observed in this study could impact the safety profile of 
rhIGF-1/rhIGFBP-3 as administered in premature neonates being enrolled in the antecedent 
study (ROPP-2008-01, Section D), the Data Monitoring Committee (DMC) for Study 
ROPP-2008-01 will review safety data from this long-term outcome study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities, where applicable, 
have given approval/favorable opinion. Modifications to the protocol will not be made without 
agreement of the Sponsor. Changes to the protocol will require written IRB/IEC/REB 
approval/favorable opinion prior to implementation, except when the modification is needed to
eliminate an immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable 
regulatory authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The 
Sponsor will submit all protocol modifications to the regulatory authorities, where applicable, in 
accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC/REB.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to the FDA or other applicable international regulatory authority 
before initiation, if applicable.
11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study
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27 August 14
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
Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC/REB, or the Sponsor may request access to all source 
documents, eCRFs, and other study documentation for onsite audit or inspection. Direct access to 
these documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. The Sponsor or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-Drug Dictionary (WHO-DD). Central reads 
will be employed as described in the study manual to aid in consistent measurement of 
abdominal ultrasound and echocardiogram parameters. 
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
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Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with the Sponsor, 
provided the Sponsor a copy of the draft document intended for publication, and obtained the 
Sponsor’s written consent for such publication. All information obtained during the conduct of 
this study will be regarded as confidential. 
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33. Varni JW, Limbers CA. The pediatric quality of life inventory:  measuring pediatric health-
related quality of life from the perspective of children and their parents. Pediatr Clin North 
Am 2009;56:843-63.
34. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL Infant Scales:  feasibility, internal 
consistency reliability, and validity in healthy and ill infants. Quality of life research :  an 
international journal of quality of life aspects of treatment, care and rehabilitation 
2011;20:45-55.
35. Varni JW, Seid M, Kurtin PS. PedsQL 4.0:  reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical 
care 2001;39:800-12.
36. Saigal S, Rosenbaum P, Stoskopf B, et al. Development, reliability and validity of a new 
measure of overall health for pre-school children. Quality of life research :  an international 
journal of quality of life aspects of treatment, care and rehabilitation 2005;14:243-57.
37. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal 
children. Am J Roentgenol 1984;142:467-9.
38. Rosenberg HK, Markowitz RI, Kolberg H, Park C, Hubbard A, Bellah RD. Normal splenic 
size in infants and children:  sonographic measurements. Am J Roentgenol 1991;157:119-21.
39. Stevens TP, Finer NN, Carlo WA, et al. Respiratory Outcomes of the Surfactant Positive 
Pressure and Oximetry Randomized Trial (SUPPORT). J Pediatr 2014;165:240-9.e4.
40. Zivanovic S, Peacock J, Alcazar-Paris M, et al. Late outcomes of a randomized trial of high-
frequency oscillation in neonates. N Engl J Med 2014;370:1121-30.
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Appendix 1
Study Schedule of Events
Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 wks
6 
± 1 mth
12
± 3 mths
20 
-1 mthg
24
± 3 mth
3f
± 3 mths
4f
± 3 mths
4.75
-1 mthg
5
+ 6 mths
Informed Consent
•
Eligibility Criteria
•
Demographics
•
Visual acuitya
•
•
•
•
•
•
Corrective lens determination
•
•g
•g
Ocular alignment and motility
•
•
•
Refraction with cycloplegia
•
•
•
•
•
•
Stereoacuity
•
Length
•
•
•
Height
•
Weight
•
•
•
•
Head Circumference
•
•
•
BSID-III
•
•
WPPSI-IV
•
CBCL
•
•
VABS-II
•
•
•
•
ADHD-RS-IV
•
SCQ
•
Physical Examination including tonsil 
examination 
•
•
•
•
Cerebral Palsy Assessment
•
Hearing Assessment Historyb
•
Pulmonary Morbidity Assessment
•
•
•
•
Survival assessment
•
•
•
•
•
•
•
HRQoLc
•
• h
• h
•h
•
•
• h
HCRU
•
• h
• h
•h
•
•
• h
HSCS-PS
•h
•
•
• h
Abdominal Ultrasound
•
Echocardiogram
•
Assessment of Participation in Other Clinical 
Studies
•
•
•
•
•
•
•
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Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 wks
6 
± 1 mth
12
± 3 mths
20 
-1 mthg
24
± 3 mth
3f
± 3 mths
4f
± 3 mths
4.75
-1 mthg
5
+ 6 mths
Medications
•
•
•
•
•
•
•
Adverse eventsd
•i
•
•
•
•
•
•
•
Abbreviations:  ADHD-RS-IV = Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition; BSID-III = Bayley Scales of Infant and Toddler 
Development-Third Edition, CBCL = Child Behavior Checklist; CA = corrected age; HCRU = health care resource use; HRQoL = health-related quality of life; 
HSCS-PS = Health Status Classification System; mth(s) = months; 
; PedsQL = Pediatric Quality of Life Inventory; 
SCQ = Social Communication Questionnaire; VABS-II = Vineland Adaptive Behavior Scales, Second Edition; wks = weeks; WPPSI-IV = Wechsler Preschool 
and Primary Scale of Intelligence, Fourth Edition
a
The tools used to assess visual acuity will change as the subject ages during their participation in the study. The tools that will be used in this study and are 
summarized by applicable study visit in Table 12-1.
b
Historical hearing test data may be recorded at any time during the study prior to the 6-month visit.
c
HRQoL will be assessed via the validated PedsQL™  scales appropriate for the child’s age of development as specified in the Study Operations Manual
d
Adverse event collection will include an assessment of the specified targeted medical events 
e
The Initial Visit  may be performed prior to 40 weeks CA for any subject who discontinued from Study ROPP-2008-01 and, for all subjects,  any time after 
40 weeks CA, up to the study visit to occur at 3 months CA.
f
Visits at 3 months, 3 years, and 4 years CA will be conducted by telephone.
g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments.
h
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through a call center if there are 
time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through a call center and may be 
performed at any time within the visit window.
i
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201):  any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
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Table 12-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
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SYNOPSIS
Sponsor:
Premacure AB, A Member of the Shire Group of Companies
Name of Finished Product:
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
Study Title:
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated with 
rhIGF-1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or Who Received 
Standard Neonatal Care
Study Number:
SHP-607-201
Study Phase:  II
Investigational Product, Dose, and Mode of Administration:
Not applicable.
Primary Objectives
The primary objectives of this study are:

To evaluate the long-term efficacy outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) 
as assessed by ROP associated visual outcomes

To evaluate the long-term safety outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D)
Secondary Objectives
The secondary objectives of this study are to evaluate the effect following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) on:

Growth parameters

Cognitive development

Physical development

Child behavior

Pulmonary morbidity

Survival

Health-related quality of life (HRQoL)

Health utility

Health care resource use (HCRU)
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Efficacy Assessments:
Efficacy will be assessed by visual outcomes, growth parameters, cognitive development, physical 
development, child behavior, pulmonary morbidity, and survival.
Safety Assessments:
Safety will be assessed by physical examination (including tonsil examination), AEs (as
specified), echocardiogram, and abdominal ultrasound.
Statistical Methods
Details regarding the statistical methods and definitions will be provided in the Statistical Analysis 
Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses will be 
performed by the sponsor or CRO after the database is locked. Statistical analyses will be 
performed using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or 
standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
Date of Original Protocol:  27 August 2014
Date of Amendment 1: 19 February 2016
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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ..................................................................................................10
LIST OF IN-TEXT FIGURES.................................................................................................10
LIST OF ABBREVIATIONS..................................................................................................11
1
INTRODUCTION ...........................................................................................................13
2
STUDY OBJECTIVES....................................................................................................15
2.1
Primary Objectives.................................................................................................15
2.2
Secondary Objectives.............................................................................................15
2.3
Exploratory Objective............................................................................................15
3
STUDY ENDPOINTS.....................................................................................................16
3.1
Efficacy Endpoints.................................................................................................16
3.1.1
Primary Efficacy Endpoints.........................................................................16
3.1.2
Secondary Efficacy Endpoints.....................................................................16
3.2
Health Economic Outcome Research Endpoints...................................................17
3.3
Safety Endpoints....................................................................................................17
3.4
Exploratory Endpoints ...........................................................................................17
4
INVESTIGATIONAL PLAN..........................................................................................18
4.1
Overall Study Design and Plan..............................................................................18
4.2
Rationale for Study Design....................................................................................19
4.3
Study Duration.......................................................................................................20
5
STUDY POPULATION SELECTION ...........................................................................21
5.1
Study Population....................................................................................................21
5.2
Inclusion Criteria ...................................................................................................21
5.3
Exclusion Criteria ..................................................................................................21
6
STUDY TREATMENT...................................................................................................22
6.1
Description of Treatment .......................................................................................22
6.2
Treatments Administered.......................................................................................22
6.3
Selection and Timing of Dose for Each Subject....................................................22
6.4
Method of Assigning Subjects to Treatment Groups.............................................22
6.5
Masking..................................................................................................................22
6.6
Medications............................................................................................................22
6.7
Restrictions ............................................................................................................22
6.7.1
Prior Therapy ...............................................................................................22
6.7.2
Other Restrictions ........................................................................................22
6.7.3
Treatment Compliance.................................................................................22
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6.7.4
Packaging and Labeling...............................................................................22
6.8
Storage and Accountability....................................................................................23
7
STUDY PROCEDURES .................................................................................................24
7.1
Informed Consent...................................................................................................24
7.2
Study Entrance Criteria and Eligibility..................................................................24
7.3
Study Enrollment ...................................................................................................24
7.4
Demographics ........................................................................................................24
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference.....24
7.5.1
Length and Height........................................................................................24
7.5.2
Body Weight ................................................................................................25
7.5.3
Head Circumference ....................................................................................25
7.6
Efficacy Assessments.............................................................................................25
7.6.1
Visual Assessments......................................................................................25
7.6.1.1
Visual Acuity .....................................................................................25
7.6.1.2
Corrective Lens Determination..........................................................26
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility) .............26
7.6.1.4
Refraction with Cycloplegia ..............................................................27
7.6.1.5
Stereoacuity........................................................................................27
7.6.1.6
7.6.2
Hearing Assessment History........................................................................28
7.6.3
Behavioral Assessments...............................................................................28
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition....28
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence, Fourth 
Edition (WPPSI-IV)...........................................................................28
7.6.3.3
Child Behavior Checklist (CBCL).....................................................29
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition........................29
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale-Fourth 
Edition................................................................................................30
7.6.3.6
Social Communication Questionnaire – Lifetime Form....................30
7.6.4
Cerebral Palsy Assessment ..........................................................................30
7.6.5
Pulmonary Morbidity Assessment...............................................................30
7.6.6
Survival Assessment....................................................................................30
7.6.7
Health Economic Outcome Research Assessments.....................................31
7.6.7.1
Health Related Quality of Life...........................................................31
7.6.8
Health Care Resource Use ...........................................................................31
7.6.8.1
Health Status Classification System-Preschool .................................31
7.7
Safety Assessments................................................................................................32
7.7.1
Abdominal ultrasound..................................................................................32
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7.7.2
Echocardiogram ...........................................................................................32
7.7.3
Physical Examination...................................................................................32
7.8
Medication Assessment .........................................................................................33
7.9
Adverse Events Assessments.................................................................................33
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions ......................................................33
7.9.1.1
Adverse Event....................................................................................33
7.9.1.2
Serious Adverse Event.......................................................................34
7.9.1.3
Suspected Unexpected Serious Adverse Reaction.............................35
7.9.1.4
Targeted Medical Events ...................................................................35
7.9.2
Classification of Adverse Events and Serious Adverse Events...................35
7.9.3
Clarification between Serious and Severe ...................................................36
7.9.4
Relatedness of Adverse Events and Serious Adverse Events......................36
7.9.5
Procedures for Recording and Reporting Adverse Events ..........................37
7.9.5.1
Adverse Event Monitoring and Period of Observation......................37
7.9.5.2
Reporting Serious Adverse Events ....................................................37
7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting..............................................................................38
7.10
Removal of Subjects from the Trial.......................................................................39
7.11
Other Study Procedures .........................................................................................39
7.11.1
Participation in Other Clinical Studies ........................................................39
7.12
Appropriateness of Measurements.........................................................................39
8
STUDY ACTIVITIES .....................................................................................................41
8.1
Initial Study Visit (40 weeks CA [term equivalent]).............................................41
8.2
Study Visits............................................................................................................41
8.2.1
Outcome Assessment Visits Conducted by Telephone ...............................42
8.2.2
Clinical Site Visits .......................................................................................42
8.2.2.1
Outcome Assessment Site Visits .......................................................42
8.2.2.2
Visits Dedicated to Corrective Lens Determination ..........................45
8.3
Assessments upon Discontinuation .......................................................................46
9
QUALITY CONTROL AND ASSURANCE .................................................................47
10
STATISTICAL ANALYSES ..........................................................................................48
10.1
General Methodology ............................................................................................48
10.2
Determination of Sample Size ...............................................................................48
10.3
Method of Assigning Study Subjects to Treatment Groups ..................................48
10.4
Population Description...........................................................................................48
10.4.1
Analysis Populations....................................................................................48
10.4.2
Subject Disposition......................................................................................48
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10.4.3
Protocol Violations and Deviations .............................................................49
10.4.4
Demographics and Baseline Characteristics................................................49
10.5
Efficacy Analysis...................................................................................................49
10.5.1
Primary Efficacy Analysis...........................................................................49
10.5.2
Secondary Efficacy Analysis .......................................................................50
10.5.3
Subset Analyses ...........................................................................................51
10.5.4
Exploratory Analyses...................................................................................51
10.6
Health Economics and Outcomes Research Analyses...........................................51
10.7
Analysis of Safety..................................................................................................51
10.8
Statistical/Analytical Issues ...................................................................................52
10.8.1
Adjustment for Covariates...........................................................................52
10.8.2
Handling of Dropouts or Missing Data........................................................52
10.8.3
Interim Analyses and Data Monitoring........................................................52
10.8.4
Multiple Comparisons/Multiplicity .............................................................52
10.8.5
Sensitivity Analyses.....................................................................................52
11
ADMINISTRATIVE CONSIDERATIONS....................................................................53
11.1
Investigators and Study Administrative Structure.................................................53
11.2
Institutional Review Board or Independent Ethics Committee Approval .............53
11.3
Ethical Conduct of the Study.................................................................................53
11.4
Subject Information and Consent...........................................................................53
11.5
Subject Confidentiality ..........................................................................................54
11.6
Study Monitoring...................................................................................................54
11.7
Case Report Forms and Study Records .................................................................55
11.7.1
Case Report Forms.......................................................................................55
11.7.2
Critical Documents ......................................................................................55
11.8
Data Monitoring Committee..................................................................................56
11.9
Protocol Violations/Deviations..............................................................................56
11.10 Premature Closure of the Study.............................................................................56
11.11 Access to Source Documentation ..........................................................................57
11.12 Data Generation and Analysis ...............................................................................57
11.13 Retention of Data...................................................................................................57
11.14 Financial Disclosure...............................................................................................57
11.15 Publication and Disclosure Policy .........................................................................58
12
LIST OF REFERENCES.................................................................................................59
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LIST OF IN-TEXT TABLES
Table 7-1
Summary of Visual Acuity Assessments ...................................................26
Table 7-2
Assessments for Physical Examinations ....................................................33
Table 7-3
Adverse Event Severity..............................................................................35
Table 12-1
Summary of Visual Acuity Assessments ...................................................64
LIST OF IN-TEXT FIGURES
Figure 4-1
Overview of Study Design, Study SHP-607-201.......................................19
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AAO
American Academy of Ophthalmology
ADHD
attention-deficit hyperactivity disorder
ADHD-RS-IV
Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition
AE
adverse event
ASD
Autism Spectrum Disorder
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CBCL
Child Behavior Checklist (1 ½ to 5)
CFR
Code of Federal Regulations
CA
corrected age
CI
confidence interval
CRF
case report form (electronic)
CRO
contract research organization
DMC
data monitoring committee
eCRF
electronic case report form
EOS
end of study
ETDRS
Early Treatment of Diabetic Retinopathy Study
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GH
growth hormone
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IND
Investigational New Drug application
IRB
institutional review board
LV
left ventricle
MedDRA
Medical Dictionary for Regulatory Activities 
OD
right eye
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Abbreviation
Definition
OS
left eye
OU
both eyes
PedsQL
Pediatric Quality of Life Inventory 
REB
research ethics board
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SCQ
Social Communication Questionnaire
SD
standard deviation
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
UK
United Kingdom
US
United States
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
VLBW
very low birth weight
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI-IV
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition
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1
INTRODUCTION
Retinopathy of prematurity (ROP) is a rare disorder of the developing retinal blood vessels and 
retinal neurons of the preterm infant and is one of the leading causes of preventable blindness in 
children.1
Visual acuity is decreased in infants with a history of ROP.2 In addition to acuity, other aspects 
of eye health are also significantly impacted by ROP. Strabismus and myopia are clearly 
increased in patients with a history of ROP.3-6  Additionally, more than half of patients at 6 to 
10 years of age with a history of Stage 1 and Stage 2 ROP were reported to have ongoing visual 
issues.7
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. During fetal life, IGF-1 is available through placental 
absorption and ingestion from amniotic fluid.8 Deprivation of such factors is likely to cause 
inhibition or improper stimulation of important pathways, which in the eye may cause abnormal 
retinal vascular development, the hallmark of ROP.
The finding in both a mouse model of ROP and preterm infants that development of ROP is 
associated with low levels of IGF-1 after premature birth, indicates a possible role for 
replacement of IGF-1 to levels found in utero as a strategy to potentially decrease abnormal 
retinal vascularization and abnormal retinal neural development, and ultimately, ROP. 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) is the human recombinant form of the naturally 
occurring protein complex of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was developed to enhance the systemic exposure of administered rhIGF-1 
and to improve the safety profile of rhIGF-1 therapy. rhIGF-1/rhIGFBP-3 was approved by the 
Food and Drug Administration (FDA) in 2005 for the treatment of growth failure in children 
with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have 
developed neutralizing antibodies to GH. 
The pharmacokinetics and safety of rhIGF-1/rhIGFBP-3 have been evaluated in a Phase I study 
(ROPP-2005-01) and pharmacokinetics, safety, and efficacy are being evaluated in the ongoing 
phase II study (ROPP-2008-01). Sections A-C of the ROPP-2008-01 study are complete. 
Section D of the ROPP-2008-01 study is currently being conducted to assess pharmacokinetics, 
safety and efficacy of rhIGF-1/rhIGFBP-3 for the prevention of ROP in premature infants (up to 
a corrected age [CA] of 40 weeks [± 4 days]). Subjects in Study ROPP-2008-01are randomly 
assigned to receive rhIGF-1/rhIGFBP-3 or standard neonatal care. The target dose of 
rhIGF-1/rhIGFBP-3 for Study Section D is 250 μg/kg/24 hours to be administered via 
continuous infusion starting on Study Day 0 (day of birth) and continuing through postmenstrual 
age (gestational age + time elapsed from birth) 29 weeks + 6 days.
Although the rhIGF-1/rhIGFBP-3 therapy in Section D of the Phase II study (Study 
ROPP-2008-01) represents a short-term exposure (< 2 months for each subject), 
rhIGF-1/rhIGFBP-3 may have long-lasting effects on visual outcomes as well as other potential 
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outcomes related to complications of prematurity such as neurodevelopment, pulmonary 
function, and growth. In addition, it is critical to understand any long term safety effects from 
short term exposure to rhIGF-1/rhIGFBP-3. 
The long-term outcomes assessed in this study will require utilization of different assessment 
tools than are utilized in the Phase II study, ROPP-2008-01 Section D, given the changes in 
physical and cognitive development that will occur in the subjects as they age during their 
participation in this study. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of rhIGF-1/rhIGFBP-3.
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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints

Visual acuity as assessed by an age-appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
3.1.2
Secondary Efficacy Endpoints

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition 
(WPPSI-IV)

Physical development as assessed by standardized, age appropriate tools including 
physical examination, neurological examination for assessment of cerebral palsy, and 
hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition 
(ADHD-RS-IV) for the assessment of symptoms of 
attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3
(treated) or standard neonatal care (control). Enrolled subjects in this study will be followed 
through age 5 years CA. This study will enroll both subjects who were in the treated (received 
rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of Study 
ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term efficacy and 
safety outcomes versus standard neonatal care. No investigational product will be administered 
in this study. 
In this study, the Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon 
discontinuation from Study ROPP-2008-01 or may occur any time up to the visit at 3 months 
CA. Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age of 
23 weeks + 0 days to 27 weeks + 6 days.
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. Both 
telephone and clinical site visits are included to help maintain contact with subjects throughout 
the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required. 
See Appendix 1 for the Study Schedule of Events table.
The overall study design is outlined in Figure 4-1.
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Insulin-like growth factor-1 (IGF-1) mediates its primary actions by binding to its specific 
receptor, the insulin-like growth factor 1 receptor (IGF-1R), which is present on many cell types 
in many tissues. Binding to its receptor initiates intracellular signaling including via the AKT 
signaling pathway. This pathway is involved in stimulation of cell division, growth and 
differentiation and inhibits programmed cell death. Specifically regarding premature infants, 
IGF-1 is an important mediator of fetal growth and has been shown to play a role in early 
postnatal growth following pre-term delivery.9,10
Insulin-like growth factor-1 (IGF-1) has also been shown to play a role in pulmonary 
development11 and neural development.12,13 Given the potential role for IGF-1 in the 
development of multiple systems, this study has been designed to evaluate the long-term effects 
of rhIGF-1/rhIGFBP-3, both from a safety and efficacy perspective, on the development of the 
premature infant.
4.3
Study Duration
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years CA.
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5
STUDY POPULATION SELECTION
5.1
Study Population
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks + 0 days to 27 weeks + 6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. Up to 
120 subjects are planned to be randomized in Study ROPP-2008-01 Section D.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject was randomized in Study ROPP-2008-01, Section D
2. Subject’s parent or legally authorized representative(s) must provide written informed 
consent prior to performing any study-related activities. Study-related activities are any 
procedures that would not have been performed during normal management of the subject.
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. Any other condition or therapy that, in the Investigator’s opinion, may pose a risk to the 
subject or interfere with the subject’s ability to be compliant with this protocol or interfere 
with the interpretation of results
2. The subject or subject’s parent or legally authorized representative(s) is unable to comply 
with the protocol as determined by the Investigator
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6
STUDY TREATMENT
6.1
Description of Treatment
No investigational product will be administered in this study.
6.2
Treatments Administered
Not applicable.
6.3
Selection and Timing of Dose for Each Subject
Not applicable.
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable.
6.5
Masking
Not applicable.
6.6
Medications
Any medications administered to the subjects will be collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued). Any 
investigational product received by subjects will be recorded separately as part of an assessment 
of subjects’ participation in other clinical studies (Section 7.11.1).
6.7
Restrictions 
6.7.1
Prior Therapy
There are no restrictions related to prior therapy.
6.7.2
Other Restrictions
There are no restrictions related to fluid or food intake, or subject activity.
6.7.3
Treatment Compliance
Not applicable.
6.7.4
Packaging and Labeling
Not applicable.
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6.8
Storage and Accountability
Not applicable
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7
STUDY PROCEDURES
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events in Appendix 1). 
All data collected are to be recorded on the subject’s appropriate eCRF. 
Details for study procedures are described in the Operations Manual for this study.
7.1
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).
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 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria and Eligibility
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.
7.3
Study Enrollment
Subjects will be considered enrolled in the study once written informed consent has been 
obtained from the subject’s parent(s) or legally authorized representative(s).
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be recorded.
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference
7.5.1
Length and Height
Body length (supine measurement) will be collected when subjects are 24-months CA or 
younger. 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 
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extended and the toes should be pointing upward with feet perpendicular to the measuring 
surface.
Height (standing measure) will be collected when subjects are older than 24-months CA. 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). 
7.5.2
Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures 
(type of scale will depend upon subject’s age). Care should be taken to remove any extraneous 
clothing prior to measures and shoes should be removed.
The measure should be recorded to the nearest 0.1 kg.
7.5.3
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.
7.6
Efficacy Assessments
7.6.1
Visual Assessments
After corrective lens determination has occurred (Section 7.6.1.2), all visual assessments should 
be conducted with best-corrected vision, ie, with corrective lenses in place (if required); this 
applies to 24-month and 5-year visits.
7.6.1.1
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. It will be assessed by 
the methods summarized in Table 7-1; the method employed will be selected based on the 
subject’s age (CA) at the time of the study visit. Visual acuity measurements will be measured 
and recorded for the left (OS), right (OD) eye, and both eyes (OU).
At ages 6 months and 12 months CA, visual acuity will be assessed with Teller acuity cards. At 
ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
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Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner 
determines that it will not be possible to perform an accurate assessment with the relevant LEA 
tool, visual acuity should be assessed with the Teller acuity cards. 
The visual acuity assessments should be performed by an optometrist or ophthalmologist trained 
in pediatrics. 
Table 7-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
7.6.1.2
Corrective Lens Determination
An assessment to determine if the subject requires vision correction with corrective lenses will 
be performed. This is being performed to ensure the accuracy of subjects’ subsequent visual 
acuity assessments (at the 24-month and 5-year visits). The corrective lens determination will be 
performed according to the guidelines published by the American Academy of Ophthalmology 
(AAO).14
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)
Ocular alignment will be assessed in primary gaze by comparing the position of the corneal light 
reflection in OS and OD (corneal light reflection assessment). Presence or absence of strabismus 
will be recorded in primary gaze and in as many of the 9 positions of gaze as feasible with the 
cover test assessment of refixation movement. Extraocular muscle over-action or deficiency will 
be recorded. The assessment will be performed according to the AAO guidelines.14
Presence or absence of nystagmus as observed during the ocular alignment assessments will also 
be recorded.
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It not only applies to healthy children, but in the course of the scale’s standardization20 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-IV will be administered to the subject by a trained professional. Scores to be 
recorded are detailed in the Study Operations Manual.
7.6.3.3
Child Behavior Checklist (CBCL)
The CBCL (1 ½ to 5) is a parent-reported outcome measure used to assess behavioral, emotional, 
and social functioning of toddlers and preschool children aged 18 to 60 months.21 It is composed 
of 99 items that are rated on a Likert scale and includes the following 7 syndrome scales 
arranged under 2 domains (ie, Internalizing and Externalizing Problems):22

Internalizing Problems

Emotionally Reactive

Anxious/Depressed

Somatic Complaints

Withdrawn

Sleep Problems

Attention Problems

Aggressive Behavior
The questionnaire is widely used and has been employed to assess long-term behavioral 
outcomes in children born prematurely, aged similarly to the subjects expected in this study 
population.22-24 It is associated with well-established normative data;25 norms may be selected to 
aid in interpretation of the scale scores.
The CBCL (1 ½ to 5) is a questionnaire that will be administered to 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.
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition
The VABS-II Expanded Interview Form will be used to measure the personal and social skills of 
subjects serially over time; these scales are organized within a 3-domain structure:  
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what he or she is able to do. 
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The VABS-II Expanded Interview Form will be administered to 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.
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale-Fourth Edition
The ADHD-RS-IV was developed to measure the behaviors of children with ADHD. The 
ADHD-RS-IV consists of 18 items designed to reflect current symptomatology of ADHD based 
on DSM-IV 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-IV,26 will be completed by the subject’s parent(s) or legally authorized 
representative(s). Scores to be recorded are detailed in the Study Operations Manual.
7.6.3.6
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children27 that can be used for screening for autism or autism spectrum disorders in the general 
population.28
The SCQ will be completed by the subject’s parent(s) or legally authorized representative(s). 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.
7.6.4
Cerebral Palsy Assessment
Comprehensive neurological examination for the diagnosis of cerebral palsy (CP) will be 
conducted. The Amiel-Tison neurological examination framework29 will be utilized for this 
assessment and conducted by trained medical professionals.
7.6.5
Pulmonary Morbidity Assessment
Pulmonary morbidity will be assessed with questions related to family history and smoking 
status as well as diagnosis of select pulmonary symptoms, conditions and related 
hospitalizations. The assessment will be administered to the subject’s parent(s) or legally 
authorized representative(s). 
7.6.6
Survival Assessment
Survival status will be assessed and recorded.
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7.6.7
Health Economic Outcome Research Assessments
7.6.7.1
Health Related Quality of Life
Health-related quality of life (HRQoL) is an important outcome towards improving the health 
care of pediatric patients as it is that part of a person’s overall quality of life that is determined 
primarily by their health status and which can be influenced by clinical interventions. It is an 
important concept, which is also used in determining the value of health care services in this 
population.30,31 It is a multidimensional construct whose content is guided by the World Health 
Organization;32 minimally it includes physical, psychological (including emotional and 
cognitive), and social health dimensions.
In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL™) Scales appropriate for the child’s age of development.33-35  The development of the 
PedsQL was based on the delineations of the World Health Organization (WHO) and is a 
modular approach to assessing HRQoL in the pediatric population. Initially, the PedsQL Generic 
Scales were developed and continue to be used in children aged 2 to 18 years. More recently 
Infant Scales have been developed that apply to ages 1 to 24 months.34
The following scales will be used in this study:

Infant Scale for ages 1-12 months (36 Items)

Infant Scale for ages 13–24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent and may be conducted via telephone by 
clinical site staff. The scale(s) to be administered at each visit will be specified in the Study 
Operations Manual.
7.6.8
Health Care Resource Use
To understand the value of the investigational product administered in Study ROPP-2008-01 
(Section D), the resource use associated with inpatient visits, outpatient visits, and medical and 
pharmacy utilization in this study will be recorded. 
This assessment may be conducted via telephone by clinical site staff.
7.6.8.1
Health Status Classification System-Preschool
Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS), which is a validated instrument adapted for use via parent proxy 
within the pediatric population age 2.5 to 5 (adapted from the validated Health Utilities Index 
Mark 2 and 3 [HUI 2/3]).36  Validity of the HSCS-PS concepts has not been established for ages 
younger than 2.5 years.
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The HSCS-PS was developed to provide a consistent measure of health status in preschool-aged 
children who had been born prematurely.36 The system is applicable to children with special 
needs as may be included in this study; validation cohorts for the system included children with 
very low birth weight (VLBW), which is congruent with this study population.
The instrument is composed of 12 dimensions (Vision, Hearing, Speech, Mobility, Dexterity, 
Self-care, Emotion, Learn/remember, Think/problem solve, Pain, General Health, and Behavior) 
intended to provide a comprehensive assessment of a child’s health status as it pertains to 
health-related quality of life. The individual domains of the instrument will be scored as a mean 
score, representing the overall state for each concept individually. The global score will be 
recorded as well as the scores for each of the dimensions.
The HSCS-PS is a questionnaire that will be administered to the subject’s parent(s) or legally 
authorized representative(s) and may be conducted via telephone by clinical site staff.
7.7
Safety Assessments
7.7.1
Abdominal ultrasound
An abdominal ultrasound will be performed to assess the size of the spleen and kidneys. The 
spleen will be measured in the coronal longitudinal plane and the longest longitudinal length will 
be measured for each kidney (left and right).37 Ultrasound results will be assessed by a central 
reader.
Organ size will be interpreted in the context of reference values established for children.37,38
7.7.2
Echocardiogram
Echocardiographic examination (conventional M-mode recording of the left ventricle [LV] 
parasternal long axis view) will be performed for the evaluation of cardiac size, assessed by 
measuring the following:

interventricular septal thickness (during end diastole)

LV posterior wall thickness

LV intracavity volume (both in end diastole and end systole)
Echocardiogram results will be assessed by a central reader.
7.7.3
Physical Examination
Physical examinations will include a review of the subject’s general appearance, neurological 
examination, as well as a tonsillar examination (Table 7-2). Any abnormal change in findings 
will be recorded as an AE. 
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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Tonsils
7.8
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 7.11.1).
7.9
Adverse Events Assessments
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions
7.9.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset 
of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
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In this long-term outcome study in follow-up to Study ROPP-2008-01 (Section D), no 
investigational product is being administered. However, the relationship to the investigational 
product (rhIGF-1/rhIGFBP-3) as administered in Study ROPP-2008-01 (Section D) will be 
assessed. 
For the purposes of this study only the following adverse events will be collected:  

those considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP -2008-01, Section D)

those considered related to procedures performed in this study (Study SHP-607-201)

specified targeted medical events (Section 7.9.1.3) regardless of causality
Throughout the study, the Investigator must record AEs on the AE electronic case report form 
(eCRF), regardless of the severity. The Investigator should treat subjects with AEs appropriately 
and observe them at suitable intervals until the events stabilize or resolve. Adverse events may 
be discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given are regarded as AEs and 
will be documented on the appropriate pages of the eCRF. Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as 
AEs and must be documented as such in the eCRF.
7.9.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
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 one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
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subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
For the purposes of this study only SAE listed in the following will be collected:

fatal SAEs regardless of causality

SAEs related to ROP

SAEs related to congenital malformations not identified at birth which may impact 
neurocognitive development 
7.9.1.3
Suspected Unexpected Serious Adverse Reaction
Suspected unexpected serious adverse reactions (SUSAR) are suspected adverse reactions related 
to an investigational product (investigational products and comparators [if applicable]), which 
occur in the concerned study, and that are both serious and unexpected according to the current 
Investigator’s Brochure.
7.9.1.4
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, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D):

intracranial hypertension

any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and 
diabetes)

tonsillar hypertrophy (based on tonsil exam [part of the physical exam])

increased kidney size 

increased cardiac size

increased spleen size
7.9.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
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Table 7-3
Adverse Event Severity
Severity
Definition
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.9.3
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.9.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product (rhIGF-1/rhIGFBP-3 as administered in 
Study ROPP-2008-01, Section D) is to be determined by the Investigator based on the following 
definitions (See Table 7-4).
Table 7-4
Adverse Event Relatedness
Relationship to Product
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, follows a known or suspected response 
pattern to the investigational product, is confirmed by improvement 
upon stopping the investigational product (de-challenge), and 
reappears upon repeated exposure (re-challenge). Note that this is not 
to be construed as requiring re-exposure of the subject to 
investigational product; however, the determination of definitely 
related can only be used when recurrence of event is observed.
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7.10
Removal of Subjects from the Trial
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a subject 
from the study:

Non-compliance, including failure to appear at one or more study visits

The subject was erroneously included in the study

The subject develops an exclusion criterion 

The study is terminated by the Sponsor
The subject, the subject’s parent(s), or the subject’s legally authorized representative acting on 
behalf of the subject is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a subject or the subject’s parent(s) or the subject’s legally authorized representative(s) acting 
on behalf of the subject, discontinues participation in the study, or the subject is discontinued by 
the Investigator, reasonable efforts will be made to follow the subject through the end of study 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the subject withdraws from the study, the subject will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.11
Other Study Procedures
7.11.1
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in another 
clinical study that involves 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 being evaluated in the study, and the subject’s treatment assignment 
in the study (if possible). 
7.12
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. These are the pulmonary 
morbidity assessment and the cerebral palsy assessment. In these cases, the tools are either based 
on validated tools or the current state of knowledge in the literature. For example, the cerebral 
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palsy assessment is based on the Amiel-Tison neurological examination framework29 and the 
pulmonary assessment is based on published research in a similar pediatric population39,40.
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8
STUDY ACTIVITIES
The timing of the visits in this study is based on subjects’ corrected age (CA). 
8.1
Initial Study Visit (40 weeks CA [term equivalent])
The Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon discontinuation from 
Study ROPP-2008-01, Section D or any time up to the visit at 3 months CA. 
At the Initial Visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data.
The following AE data, collected as part of Study ROPP-2008-01 (Section D) will be recorded:

Ongoing targeted medical events regardless of causality

Ongoing study drug-related AEs, including SAEs
SAEs, as outlined in Section 7.9.1.1 and Section 7.9.1.2, that the subject experiences between the 
ROPP-2008-01 end-of-study visit and the time of informed consent for the SHIP-607-201 study 
will be reported by the Investigator, pending permission for subject’s parent or legally authorized 
representative(s), as documented on the informed consent form.
8.2
Study Visits
Study visits for follow-up outcome assessments will take place at the following time points in 
CA:

3 months (±2 weeks) – conducted by telephone

6 months (±1 month) – clinical site visit

12 months (±3 months) – clinical site visit

20 month (-1 months) – clinical site visit

24 months (±3 months) – clinical site visit

3 years (±3 months) – conducted by telephone

4 years (±3 month) – conducted by telephone

4.75 years (-1 months) – clinical site visit

5 years (+6 months) – clinical site visit
In addition, there will be 2 visits that must occur at least 1 month prior to the 24-month and 
5-year CA study visits to assess the need for corrective lenses. The timing of these 2 visits 
(20 months [-1 month] and 4.75 years [-1 month]) was set to ensure that any prescribed 
corrective lenses would be worn for at least 1 month prior to the visual assessments at the 
24-month and 5-year study visits CA.
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The activities at the study visits are described in Sections 8.2.1 and 8.2.2.
8.2.1
Outcome Assessment Visits Conducted by Telephone
Visits at 3 months, 3 years, and 4 years CA will be conducted by telephone. The following 
outcome assessments will be conducted at each of these 3 visits, unless otherwise indicated:

HRQoL 

HCRU

HSCS-PS (3-year and 4-year visits only)

Medications

Survival assessment

Assessment of participation in other clinical studies

Adverse events (including targeted medical events)
8.2.2
Clinical Site Visits
8.2.2.1
Outcome Assessment Site Visits
The following clinical site visits (in CA) to capture follow-up outcome data will occur at the 
clinical site:

6 months (±1 month)

12 months (±3 months) 

20 months (-1 month)

24 months (±3 months)

4.75 years (-1 months)

5 years (+6 months)
The following assessments will be performed at the 6-month visit:

Visual acuity

Refraction with cycloplegia

Length

Weight

Head circumference

VABS-II

Physical examination (including tonsil examination)
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
Hearing Assessment History (Historical hearing test data may be recorded at any time 
prior to the 6-month visit) 

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Abdominal ultrasound

Echocardiogram

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 12-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

VABS-II

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
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The following assessments will be performed at the 20-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Assessment of participation in other clinical studies
The following assessments will be performed at the 24-month visit:

Visual acuity

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

CBCL

VABS-II

Physical examination (including tonsil examination)

Cerebral Palsy assessment

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at 4.75-year visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)
The following assessments will be performed at the 5-year visit:
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
Visual acuity

Ocular alignment and motility

Stereoacuity

Height

Weight

WPPSI-IV

CBCL

VABS-II

ADHD-RS-IV

SCQ

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment


HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
8.2.2.2
Visits Dedicated to Corrective Lens Determination
The following clinical site visits are dedicated solely to corrective lens determination in 
preparation for the outcome assessment visits at 24-months and 5-years CA:

20 months (-1 month) 

4.75 years (-1 month) 
At these visits, the following will be performed:

Visual acuity

Corrective lens determination (includes refraction with cycloplegia)
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The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior 
to the 24-month and 5-year visits, respectively. Any prescribed corrective lenses must be worn 
for at least 1 month prior to the 24 month and 5 year assessments.
8.3
Assessments upon Discontinuation
If a subject discontinues prior to the 5-year CA visit, every attempt will be made to complete the 
assessments scheduled for the subject’s next visit. 
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 Code of Federal Regulations (CFR) Part 
11 Guidance. The clinical trial database will include an audit trail to document any evidence of 
data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses 
will be performed by the Biometrics department at Shire. Statistical analyses will be performed 
using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3
or standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
10.2
Determination of Sample Size
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study.
10.3
Method of Assigning Study Subjects to Treatment Groups
Not applicable.
10.4
Population Description
10.4.1
Analysis Populations
Enrolled Population- the Enrolled Population will consist of all subjects for whom written 
informed consent has been provided for this study. 
Safety Population- the Safety Population will consist of the subjects in the Enrolled Population
who have safety follow-up data in this long-term outcome study.
10.4.2
Subject Disposition
Subjects who complete the study and subjects who prematurely discontinue from the study will 
be summarized by treatment group using descriptive statistics. In addition, for subjects who 
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prematurely discontinue from the study, the reasons for discontinuation will be summarized by 
treatment group.
10.4.3
Protocol Violations and Deviations
Protocol violations and deviations will be listed. Details of the criteria for deviations and 
violations will be provided in the SAP.
10.4.4
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for the Enrolled Population. 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. Continuous variables such as age (including corrected age), weight, and 
length/height will be summarized using number of observations, mean, standard deviation, 
median, minimum and maximum values. Categorical variables, like gender and race, will be 
summarized using number of observations and percentages.
Medical history, including maternal and perinatal history, (as obtained from the antecedent 
study, ROPP-2008-01) will be summarized by treatment group using the number of observations 
and percentages of subjects reporting each category.
10.5
Efficacy Analysis
All efficacy analyses will be performed using the Enrolled Population.
10.5.1
Primary Efficacy Analysis
The primary efficacy endpoints consist of the following:

Visual Acuity:  Visual acuity will be categorized as the following: 
o
normal (measurable acuity ≥20/40), 
o
below normal (20/200≤measurable acuity <20/40), 
o
poor (measurable acuity ≤20/200)
o
blind/low vision (only the ability to detect the 2.2 cm wide stripes on the low-
vision Teller acuity card and at any location in the visual field). 
The number and proportion of patients within each category listed above will be 
summarized by treatment group and visit. In addition, acuity results in the normal and 
below normal categories will be classified as favorable outcomes, and acuity results in 
the poor and blind/low-vision categories will be classified as unfavorable outcomes. 
Tabular summaries by treatment group and visit will include the frequency and the 
percentage for each visual acuity category. In addition, shift tables of favorable 
outcomes from baseline (first assessment during this study) to each of the subsequent 
assessments, including the last assessment, will be presented by treatment group.
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
Ocular Alignment and Oculomotor Exam (Motility):  Findings from the ocular 
motility assessment will be either presence or absence of strabismus (esotropia, 
exotropia, hypertropia, or hypotropia). Tabular summaries by treatment group and 
visit will include the frequency and the percentage in each category. In addition, shift 
tables from baseline (first assessment during this study) to the last assessment will be 
provided by treatment group.

Nystagmus:  Presence or absence of nystagmus will be summarized by treatment 
group and visit

Refraction with Cycloplegia:  Findings from the refraction with cycloplegia will be 
summarized by treatment group and visit

Stereoacuity:  Presence or absence of stereopsis will be summarized by treatment 
group and visit
10.5.2
Secondary Efficacy Analysis

Growth Parameters (body weight, body length [and height], and head circumference):  
A standard Z-score, utilizing WHO child growth standards, will be calculated for each 
assessment by adjusting age- and sex- matched means and standard deviations (norm). 
The descriptive statistics of the Z-score for each of these parameters will be 
summarized at each assessment and the corresponding change from baseline. When 
appropriate, a 95% CI for the corresponding mean change within each group and the 
difference in the mean change between the 2 treatment groups and the corresponding 
95% CI will be presented as appropriate. If the parametric assumption for the 
distribution of the above endpoints cannot be justified, a non-parametric approach will 
be utilized to estimate the treatment difference (ie, median difference or 
Hodges-Lehmann estimator and the corresponding confidence intervals)

BSID-III and WPPSI-IV:  The raw score for each domain within each questionnaire 
will be summarized by treatment group and visit using descriptive statistics.

ADHD-RS-IV:  ADHD-RS-IV total score and subscales (Hyperactivity/Impulsivity 
and Inattentiveness) will be summarized by treatment group and visit using descriptive 
statistics.

SCQ:  The SCQ subscales (communication and social) will be summarized by 
treatment group and visit using descriptive statistics

VABS-II:  The raw score for each domain of the scale will be summarized by 
treatment group and visit using descriptive statistics.

CBCL:  The raw score and change from baseline for each domain of the scale will be 
summarized by treatment group and visit using descriptive statistics.

Pulmonary morbidity assessment:  The binary response of each question will be by 
treatment group and visit using descriptive statistics.

Survival:  For subjects who have an event (ie, death), the event time will be calculated 
as the length of time from the subject’s date of birth to death during the study due to 
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any cause. Subjects who do not have an event (ie, death) during the study will be 
censored at the end of the study. The survival endpoint will be analyzed by treatment 
group using Kaplan-Meier methods.
10.5.3
Subset Analyses
Subgroup analyses may be explored based on factors that may have influence on the efficacy or 
safety endpoints. Subgroup analyses will be specified in the SAP.
10.5.4
Exploratory Analyses
10.6
Health Economics and Outcomes Research Analyses
For PedsQL, descriptive statistics will be provided for summary scores by treatment group 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 and at each time point.
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.
10.7
Analysis of Safety
Safety summaries will be based on all assessments post-baseline. The safety data will be 
assessed by AE monitoring, change in cardiac size, and kidney and spleen size over time. 
Adverse events will be summarized by system organ class and preferred term for each treatment 
group and overall, the number and percentage of subjects having any AE, having an AE in each 
body system and having each individual AE. In addition, those events which resulted in death, or 
were otherwise classified as serious will be presented in a separate listing. In addition, the 
summary of AEs will be presented by severity and relationship to trial medication. 
The change in cardiac size, and size of kidney and spleen will be assessed at the 6-month CA 
visit via echocardiogram and abdominal ultrasound, respectively.  These data will be analyzed as 
a binary response (ie, normal/abnormal) and summarized using frequency count.  The number 
and proportion of patients with each category (ie, normal/abnormal) for each of these safety 
endpoints will be summarized by treatment group.  In addition, the 2-sided 95% CI for the 
proportion of patients with a normal status for each of the endpoints will be estimated by 
treatment group.
Physical examinations findings will be summarized descriptively. 
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10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
If any baseline data are imbalanced and are considered to be clinically relevant, between-group 
comparisons for efficacy outcomes will be adjusted for covariates and detailed in the SAP. 
10.8.2
Handling of Dropouts or Missing Data
Handling of missing data rules will be described in the SAP.
10.8.3
Interim Analyses and Data Monitoring
An interim analysis will be performed after all data from all enrolled subjects in this study have 
either completed 2-year follow-up (24-month visit) assessments or have prematurely withdrawn 
from the study (before completing 2 years of follow-up) has been entered into the database, 
queried and discrepancies resolved. A full 2-year study report based on these data, including 
efficacy and safety endpoint analyses, will be completed.
Additionally, descriptive analyses of the data at other time points before study completion may 
be performed for safety monitoring, regulatory reporting or general planning purposes.
10.8.4
Multiple Comparisons/Multiplicity
Not applicable.
10.8.5
Sensitivity Analyses
Sensitivity analyses for the efficacy outcomes will be detailed in the SAP, as necessary.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 and Investigator Agreement. Curriculum vitae must be provided for the Investigators 
and sub-investigators listed on Form FDA 1572 or Investigator Agreement. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, and their study related duties and functions. 
The Investigator must maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form. This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study. Within 3 months of study completion or termination, 
a final report must be provided to the IRB/IECREB. A copy of these reports will be sent to the 
study clinical monitor. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are reported to the US (FDA or other Regulatory agencies (Safety Reports) must be 
submitted promptly to the IRB/IEC/REB.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent) form must be in a language understandable to the subject or the subject’s 
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parent(s) or legally authorized representative(s) and must specify who informed the subject, the 
subject’s parent(s), or the subject’s legally authorized representative(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the subject, the subject’s parent(s) or the subject’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the Sponsor. Only the subject number - will be recorded in 
the eCRF, and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The subjects will be told that 
representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed.
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The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Electronic case report forms (eCRFs) are provided for each subject. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the Investigator to ensure that the following documents are available to Sponsor 
or their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed 
within 12 months of study initiation)

Copy of Investigator and sub-investigator(s) current medical license (indicating 
license number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC/REB clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written 
information to be provided regarding subject recruitment procedures

Copy of IRB/IEC/REB approved Subject Information/Informed Consent Form/any 
other written information/advertisement (with IRB approval stamp and date of 
approval)

Current list of IRB/IEC/REB Committee members/constitution (dated within 
12 months prior to study initiation)

Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
Given that any long-term safety signal observed in this study could impact the safety profile of 
rhIGF-1/rhIGFBP-3 as administered in premature neonates being enrolled in the antecedent 
study (ROPP-2008-01, Section D), the Data Monitoring Committee (DMC) for Study 
ROPP-2008-01 will review safety data from this long-term outcome study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities, where applicable, 
have given approval/favorable opinion. Modifications to the protocol will not be made without 
agreement of the Sponsor. Changes to the protocol will require written IRB/IEC/REB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable 
regulatory authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The 
Sponsor will submit all protocol modifications to the regulatory authorities, where applicable, in 
accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC/REB.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to the FDA or other applicable international regulatory authority 
before initiation, if applicable.
11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:
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
The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC/REB, or the Sponsor may request access to all source 
documents, eCRFs, and other study documentation for onsite audit or inspection. Direct access to 
these documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. The Sponsor or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-Drug Dictionary (WHO-DD). Central reads 
will be employed as described in the study manual to aid in consistent measurement of 
abdominal ultrasound and echocardiogram parameters. 
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
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11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with the Sponsor, 
provided the Sponsor a copy of the draft document intended for publication, and obtained the 
Sponsor’s written consent for such publication. All information obtained during the conduct of 
this study will be regarded as confidential. 
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32. Constitution of the World Health Organization:  basic document. Geneva, Switzerland:  
World Health Organization; 1948.
33. Varni JW, Limbers CA. The pediatric quality of life inventory:  measuring pediatric health-
related quality of life from the perspective of children and their parents. Pediatr Clin North 
Am 2009;56:843-63.
34. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL Infant Scales:  feasibility, internal 
consistency reliability, and validity in healthy and ill infants. Quality of life research :  an 
international journal of quality of life aspects of treatment, care and rehabilitation 
2011;20:45-55.
35. Varni JW, Seid M, Kurtin PS. PedsQL 4.0:  reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical 
care 2001;39:800-12.
36. Saigal S, Rosenbaum P, Stoskopf B, et al. Development, reliability and validity of a new 
measure of overall health for pre-school children. Quality of life research : an international 
journal of quality of life aspects of treatment, care and rehabilitation 2005;14:243-57.
37. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal 
children. Am J Roentgenol 1984;142:467-9.
38. Rosenberg HK, Markowitz RI, Kolberg H, Park C, Hubbard A, Bellah RD. Normal splenic 
size in infants and children:  sonographic measurements. Am J Roentgenol 1991;157:119-21.
39. Stevens TP, Finer NN, Carlo WA, et al. Respiratory Outcomes of the Surfactant Positive 
Pressure and Oximetry Randomized Trial (SUPPORT). J Pediatr 2014;165:240-9.e4.
40. Zivanovic S, Peacock J, Alcazar-Paris M, et al. Late outcomes of a randomized trial of high-
frequency oscillation in neonates. N Engl J Med 2014;370:1121-30.
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Appendix 1
Study Schedule of Events
Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 wks
6 
± 1 mth
12
± 3 mths
20 
-1 mthg
24
± 3 mth
3f
± 3 mths
4f
± 3 mths
4.75
-1 mthg
5
+ 6 mths
Informed Consent
•
Eligibility Criteria
•
Demographics
•
Visual acuitya
•
•
•
•
•
•
Corrective lens determinationh
•
•g
•g
Ocular alignment and motility
•
•
•
Refraction with cycloplegiah
•
Stereoacuity
•
Length
•
•
•
Height
•
Weight
•
•
•
•
Head Circumference
•
•
•
BSID-III
•
•
WPPSI-IV
•
CBCL
•
•
VABS-II
•
•
•
•
ADHD-RS-IV
•
SCQ
•
Physical Examination including tonsil 
examination 
•
•
•
•
Cerebral Palsy Assessment
•
Hearing Assessment Historyb
•
Pulmonary Morbidity Assessment
•
•
•
•
Survival assessment
•
•
•
•
•
•
•
HRQoLc
•
• i
• i
•i
•
•
• i
HCRU
•
• i
• i
•i
•
•
• i
HSCS-PS
•i
•
•
• i
Abdominal Ultrasound
•
Echocardiogram
•
Assessment of Participation in Other Clinical 
Studies
•
•
•
•
•
•
•
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Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 wks
6 
± 1 mth
12
± 3 mths
20 
-1 mthg
24
± 3 mth
3f
± 3 mths
4f
± 3 mths
4.75
-1 mthg
5
+ 6 mths
Medications
•
•
•
•
•
•
•
Adverse eventsd
•j
•
•
•
•
•
•
•
Abbreviations:  ADHD-RS-IV = Attention-Deficit/Hyperactivity Disorder Rating Scale-fourth edition; BSID-III = Bayley Scales of Infant and Toddler 
Development-Third Edition, CBCL = Child Behavior Checklist; CA = corrected age; HCRU = health care resource use; HRQoL = health-related quality of life; 
HSCS-PS = Health Status Classification System; mth(s) = months; 
; PedsQL = Pediatric Quality of Life Inventory; 
SCQ = Social Communication Questionnaire; VABS-II = Vineland Adaptive Behavior Scales, Second Edition; wks = weeks; WPPSI-IV = Wechsler Preschool 
and Primary Scale of Intelligence, Fourth Edition
a
The tools used to assess visual acuity will change as the subject ages during their participation in the study. The tools that will be used in this study and are 
summarized by applicable study visit in Table 12-1.
b
Historical hearing test data may be recorded at any time during the study prior to the 6-month visit.
c
HRQoL will be assessed via the validated PedsQL™  scales appropriate for the child’s age of development as specified in the Study Operations Manual
d
Adverse event collection will include an assessment of the specified targeted medical events 
e
The Initial Visit may be performed prior to 40 weeks CA for any subject who discontinued from Study ROPP-2008-01 and, for all subjects, any time after 
40 weeks CA, up to the study visit to occur at 3 months CA.
f
Visits at 3 months, 3 years, and 4 years CA will be conducted by telephone.
g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments.
h
Refraction with cycloplegia will be performed as part of the corrective lens determination procedure.
i
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through clinical site staff if there 
are time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through clinical site staff and 
may be performed at any time within the visit window.
j
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201):  any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
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Table 12-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
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Appendix 2
Summary of Changes
Description of Change
Section(s)
Eliminate repetitive study procedures – the Refraction with Cycloplegia 
assessment is completed as part of the corrective lens determination that 
occurs at the 20 month and the 4.75 year visits. This procedure is 
removed from the 24 month and the 5year visits. Added visual acuity to 
20 month visit and 4.75 year visit. Added assessment of participation in 
other clinical studies to 20 month visit.
Removed “Refraction with cycloplegia” from assessment performed at 
the 20 month and the 4.75 years visits.
Section 4.1–  
Figure 4-1
Section 8.2
Section 8.2.2.1
Section 8.2.2.2
Appendix 1
The 20 month visit was added with the following assessments:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Assessment of participation in other clinical studies
The 4.75 year visit was added with the following assessments:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)
Section 8.2.2
Clarify by using the term “Pulmonary Morbidity Assessment” throughout 
the protocol for consistency.
Replaced “Questionnaire” with “Assessment” 
Section 7.6.5
Section 10.5.2
All phone contacts are performed by site staff, no call center was set up 
for the study.
Replace “call center” to “by clinical site staff”
Section 7.6.7.1
Section 7.6.8
Section 7.6.8.1
Appendix 1
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SHP607-201 Protocol & Amendment 1
CONFIDENTIAL 
Version 1.0,  Final
19 February 2016 
Page 65 of 68
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Description of Change
Section(s)
The overall list of Target Medical Events to be captured in the study was 
reassessed and updated to ensure all any events with a potential impact to 
the primary and secondary endpoint are tracked.
For this study only the following AEs will be collected:  

those considered related to investigational product (rhIGF-
1/rhIGFBP-3 as administered in Study ROPP  2008 01, Section 
D)

those considered related to procedures performed in this study 
(Study SHP 607 201)

specified targeted medical events (Section 7.9.1.3) regardless of 
causality
Only the following SAEs will be collected:

Fatal SAEs regardless of causality

SAEs related to ROP

SAEs related to congenital malformations not identified at birth 
which may impact neurocognitive development
Section 7.9.1.1
Section 7.9.1.2
Capture SAE from the end-of–study visit in ROPP-2008-01 Section D 
and the start of the SHP-607-201 study for safety purpose.
Added “When possible, subject’s parents or legally authorized 
representative(s) should be consented at the end of study visit for the 
ROPP-2008-01.However, Serious Adverse Events that the subject 
experiences between ROPP-2008-001 end-of-study visit and the start of 
the SHP-607-201, will be reported by the Investigator.” in Section 7.9.5.1
Added “SAEs that the subject experiences between ROPP-2008-001 end-
of-study visit and the start of the SHP-607-201 will be reported by the 
Investigator.” in Section 8.1
Section 7.9.5.1
Section 8.1
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SHP607-201 Protocol & Amendment 1
CONFIDENTIAL 
Version 1.0,  Final
19 February 2016 
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CONFIDENTIAL 
Page 2 
Clinical Trial Protocol: SHP-607-201 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) 
 
21 Feb 2017 
 
 
SYNOPSIS 
Sponsor: 
Premacure AB, A Member of the Shire Group of Companies 
Name of Finished Product: 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)  
Study Title: 
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated with 
rhIGF-1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or Who Received 
Standard Neonatal Care  
Study Number: 
SHP-607-201 
Study Phase:  II 
Investigational Product, Dose, and Mode of Administration: 
Not applicable. 
Primary Objectives  
The primary objectives of this study are: 
 
To evaluate the long-term efficacy outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) 
as assessed by ROP associated visual outcomes 
 
To evaluate the long-term safety outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) 
Secondary Objectives 
The secondary objectives of this study are to evaluate the effect following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) on: 
 
Growth parameters 
 
Cognitive development 
 
Physical development 
 
Child behavior 
 
Pulmonary morbidity 
 
Survival 
 
Health-related quality of life (HRQoL) 
 
Health utility 
 
Health care resource use (HCRU) 
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Clinical Trial Protocol: SHP-607-201
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
21 Feb 2017
Efficacy Assessments:
Efficacy will be assessed by visual outcomes, growth parameters, cognitive development, physical 
development, child behavior, pulmonary morbidity, and survival.
Safety Assessments:
Safety will be assessed by physical examination (including tonsil examination), AEs (as
specified), echocardiogram, and abdominal ultrasound.
Statistical Methods
Details regarding the statistical methods and definitions will be provided in the Statistical Analysis 
Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses will be 
performed by the sponsor or CRO after the database is locked. Statistical analyses will be 
performed using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or 
standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from 
Study ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
Date of Original Protocol:  27 August 2014
Date of Amendment 1: 19 February 2016
Date of Amendment 2: 21 February 2017
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CONFIDENTIAL
Page 6
Clinical Trial Protocol: SHP-607-201
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
21 Feb 2017
TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
TABLE OF CONTENTS.................................................................................................................6
LIST OF IN-TEXT TABLES ........................................................................................................10
LIST OF IN-TEXT FIGURES.......................................................................................................10
LIST OF APPENDICES................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................11
1
INTRODUCTION..................................................................................................................13
2
STUDY OBJECTIVES ..........................................................................................................15
2.1
Primary Objectives...................................................................................................15
2.2
Secondary Objectives...............................................................................................15
2.3
Exploratory Objective ..............................................................................................15
3
STUDY ENDPOINTS............................................................................................................16
3.1
Efficacy Endpoints ...................................................................................................16
3.1.1
Primary Efficacy Endpoints...................................................................................16
3.1.2
Secondary Efficacy Endpoints...............................................................................16
3.2
Health Economic Outcome Research Endpoints......................................................16
3.3
Safety Endpoints ......................................................................................................17
3.4
Exploratory Endpoints..............................................................................................17
4
INVESTIGATIONAL PLAN.................................................................................................18
4.1
Overall Study Design and Plan ................................................................................18
4.2
Rationale for Study Design ......................................................................................19
4.3
Study Duration .........................................................................................................20
5
STUDY POPULATION SELECTION ..................................................................................21
5.1
Study Population ......................................................................................................21
5.2
Inclusion Criteria......................................................................................................21
5.3
Exclusion Criteria.....................................................................................................21
6
STUDY TREATMENT..........................................................................................................22
6.1
Description of Treatment .........................................................................................22
6.2
Treatments Administered .........................................................................................22
6.3
Selection and Timing of Dose for Each Subject ......................................................22
6.4
Method of Assigning Subjects to Treatment Groups...............................................22
6.5
Masking....................................................................................................................22
6.6
Medications ..............................................................................................................22
6.7
Restrictions...............................................................................................................22
6.7.1
Prior Therapy .........................................................................................................22
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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6.7.2
Other Restrictions ..................................................................................................22
6.7.3
Treatment Compliance...........................................................................................22
6.7.4
Packaging and Labeling.........................................................................................22
6.8
Storage and Accountability ......................................................................................22
7
STUDY PROCEDURES........................................................................................................23
7.1
Informed Consent.....................................................................................................23
7.2
Study Entrance Criteria and Eligibility....................................................................23
7.3
Study Enrollment......................................................................................................23
7.4
Demographics...........................................................................................................23
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference .......23
7.5.1
Length and Height..................................................................................................23
7.5.2
Body Weight ..........................................................................................................24
7.5.3
Head Circumference ..............................................................................................24
7.6
Efficacy Assessments...............................................................................................24
7.6.1
Visual Assessments................................................................................................24
7.6.1.1
Visual Acuity..........................................................................................24
7.6.1.2
Corrective Lens Determination ..............................................................25
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)..................25
7.6.1.4
Refraction with Cycloplegia...................................................................26
7.6.1.5
Stereoacuity............................................................................................26
7.6.1.6
7.6.2
Hearing Assessment History..................................................................................27
7.6.3
Behavioral Assessments.........................................................................................27
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition........27
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)..........27
7.6.3.3
Child Behavior Checklist (CBCL) .........................................................28
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition ............................28
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale.........................28
7.6.3.6
Social Communication Questionnaire – Lifetime Form ........................29
7.6.4
Cerebral Palsy Assessment ....................................................................................29
7.6.5
Pulmonary Morbidity Assessment.........................................................................29
7.6.6
Cerebral Magnetic Resonance Imaging.................................................................29
7.6.7
Survival Assessment..............................................................................................29
7.6.8
Health Economic Outcome Research Assessments...............................................29
7.6.8.1
Health Related Quality of Life...............................................................29
7.6.9
Health Care Resource Use .....................................................................................30
7.6.9.1
Health Status Classification System-Preschool......................................30
7.7
Safety Assessments ..................................................................................................31
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
21 Feb 2017
7.7.1
Abdominal ultrasound............................................................................................31
7.7.2
Echocardiogram .....................................................................................................31
7.7.3
Physical Examination.............................................................................................31
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate ................................................32
7.8
Medication Assessment............................................................................................32
7.9
Adverse Events Assessments ...................................................................................32
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions ................................................................32
7.9.1.1
Adverse Event ........................................................................................32
7.9.1.2
Serious Adverse Event ...........................................................................33
7.9.1.3
Suspected Unexpected Serious Adverse Reaction.................................34
7.9.1.4
Targeted Medical Events........................................................................34
7.9.2
Classification of Adverse Events and Serious Adverse Events.............................34
7.9.3
Clarification between Serious and Severe .............................................................35
7.9.4
Relatedness of Adverse Events and Serious Adverse Events................................35
7.9.5
Procedures for Recording and Reporting Adverse Events ....................................35
7.9.5.1
Adverse Event Monitoring and Period of Observation..........................35
7.9.5.2
Reporting Serious Adverse Events.........................................................36
7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting..................................................................................37
7.10
Removal of Subjects from the Trial .........................................................................37
7.11
Other Study Procedures............................................................................................38
7.11.1 Participation in Other Clinical Studies ..................................................................38
7.12
Appropriateness of Measurements...........................................................................38
8
STUDY ACTIVITIES............................................................................................................39
8.1
Initial Study Visit (40 weeks CA [term equivalent]) ...............................................39
8.2
Study Visits ..............................................................................................................39
8.2.1
Outcome Assessment Visits Conducted by Telephone .........................................40
8.2.2
Clinical Site Visits .................................................................................................40
8.2.2.1
Outcome Assessment Site Visits............................................................40
8.2.2.2
Visits Dedicated to Corrective Lens Determination...............................44
8.3
Assessments upon Discontinuation..........................................................................44
9
QUALITY CONTROL AND ASSURANCE ........................................................................45
10 STATISTICAL ANALYSES.................................................................................................46
10.1
General Methodology...............................................................................................46
10.2
Determination of Sample Size..................................................................................46
10.3
Method of Assigning Study Subjects to Treatment Groups.....................................46
10.4
Population Description.............................................................................................46
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10.4.1 Analysis Populations..............................................................................................46
10.4.2 Subject Disposition................................................................................................47
10.4.3 Protocol Violations and Deviations .......................................................................47
10.4.4 Demographics and Baseline Characteristics..........................................................47
10.5
Efficacy Analysis .....................................................................................................47
10.5.1 Primary Efficacy Analysis.....................................................................................47
10.5.2 Secondary Efficacy Analysis .................................................................................48
10.5.3 Subset Analyses .....................................................................................................49
10.5.4 Exploratory Analyses.............................................................................................49
10.6
Health Economics and Outcomes Research Analyses .............................................49
10.7
Analysis of Safety ....................................................................................................49
10.8
Statistical/Analytical Issues......................................................................................50
10.8.1 Adjustment for Covariates.....................................................................................50
10.8.2 Handling of Dropouts or Missing Data..................................................................50
10.8.3 Interim Analyses and Data Monitoring..................................................................50
10.8.4 Multiple Comparisons/Multiplicity .......................................................................50
10.8.5 Sensitivity Analyses...............................................................................................50
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................51
11.1
Investigators and Study Administrative Structure ...................................................51
11.2
Institutional Review Board or Independent Ethics Committee Approval................51
11.3
Ethical Conduct of the Study ...................................................................................51
11.4
Subject Information and Consent.............................................................................51
11.5
Subject Confidentiality.............................................................................................52
11.6
Study Monitoring .....................................................................................................52
11.7
Case Report Forms and Study Records....................................................................53
11.7.1 Case Report Forms.................................................................................................53
11.7.2 Critical Documents ................................................................................................53
11.8
Data Monitoring Committee ....................................................................................54
11.9
Protocol Violations/Deviations ................................................................................54
11.10
Premature Closure of the Study ...............................................................................54
11.11
Access to Source Documentation.............................................................................55
11.12
Data Generation and Analysis..................................................................................55
11.13
Retention of Data .....................................................................................................55
11.14
Financial Disclosure.................................................................................................55
11.15
Publication and Disclosure Policy............................................................................56
12 LIST OF REFERENCES........................................................................................................57
13 APPENDICES ........................................................................................................................61
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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LIST OF IN-TEXT TABLES
Table 7-1
Summary of Visual Acuity Assessments ...........................................................25
Table 7-2
Assessments for Physical Examinations ............................................................31
Table 7-3
Adverse Event Severity......................................................................................34
Table 13-1
Summary of Visual Acuity Assessments ...........................................................65
LIST OF IN-TEXT FIGURES
Figure 4-1
Overview of Study Design, Study SHP-607-201...............................................19
LIST OF APPENDICES
Appendix 1 Study Schedule of Events...................................................................................62
Appendix 2 Pulmonary Morbidity Assessment (Clinical Site Visits at 6 and 12 
Months CA)........................................................................................................66
Appendix 3 Pulmonary Morbidity Assessment 2 (Clinical Site Visits at 24 Months 
and 5 Years CA).................................................................................................67
Appendix 4 Pulmonary Morbidity Assessment (Phone Interviews at 30 Months, 3 
Years, 3.5 Years, 4 Years, and 4.5 Years CA)...................................................73
Appendix 5 Summary of Changes .........................................................................................75
Appendix 6 Protocol Signature Page .....................................................................................77
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AAO
American Academy of Ophthalmology
ADHD
attention-deficit hyperactivity disorder
ADHD-RS
Attention-Deficit/Hyperactivity Disorder Rating Scale
AE
adverse event
ASD
Autism Spectrum Disorder
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CBCL
Child Behavior Checklist (1 ½ to 5)
CFR
Code of Federal Regulations
CA
corrected age
CI
confidence interval
CRF
case report form (electronic)
CRO
contract research organization
DMC
data monitoring committee
eCRF
electronic case report form
EOS
end of study
ETDRS
Early Treatment of Diabetic Retinopathy Study
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GH
growth hormone
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IND
Investigational New Drug application
IRB
institutional review board
LV
left ventricle
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
magnetic resonance imaging
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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Abbreviation
Definition
OD
right eye
OS
left eye
OU
both eyes
PedsQL
Pediatric Quality of Life Inventory 
REB
research ethics board
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SCQ
Social Communication Questionnaire
SD
standard deviation
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
UK
United Kingdom
US
United States
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
VLBW
very low birth weight
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI
Wechsler Preschool and Primary Scale of Intelligence
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
21 Feb 2017
1
INTRODUCTION
Retinopathy of prematurity (ROP) is a rare disorder of the developing retinal blood vessels and 
retinal neurons of the preterm infant and is one of the leading causes of preventable blindness in 
children.1
Visual acuity is decreased in infants with a history of ROP.2 In addition to acuity, other aspects 
of eye health are also significantly impacted by ROP. Strabismus and myopia are clearly 
increased in patients with a history of ROP.3-6  Additionally, more than half of patients at 6 to 
10 years of age with a history of Stage 1 and Stage 2 ROP were reported to have ongoing visual 
issues.7
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. During fetal life, IGF-1 is available through placental 
absorption and ingestion from amniotic fluid.8 Deprivation of such factors is likely to cause 
inhibition or improper stimulation of important pathways, which in the eye may cause abnormal 
retinal vascular development, the hallmark of ROP.
The finding in both a mouse model of ROP and preterm infants that development of ROP is 
associated with low levels of IGF-1 after premature birth, indicates a possible role for 
replacement of IGF-1 to levels found in utero as a strategy to potentially decrease abnormal 
retinal vascularization and abnormal retinal neural development, and ultimately, ROP. 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) is the human recombinant form of the naturally 
occurring protein complex of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was developed to enhance the systemic exposure of administered rhIGF-1 
and to improve the safety profile of rhIGF-1 therapy. rhIGF-1/rhIGFBP-3 was approved by the 
Food and Drug Administration (FDA) in 2005 for the treatment of growth failure in children 
with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have 
developed neutralizing antibodies to GH. 
The pharmacokinetics and safety of rhIGF-1/rhIGFBP-3 have been evaluated in a Phase I study 
(ROPP-2005-01) and pharmacokinetics, safety, and efficacy are being evaluated in the ongoing 
phase II study (ROPP-2008-01). Sections A-C of the ROPP-2008-01 study are complete. 
Section D of the ROPP-2008-01 study is currently being conducted to assess pharmacokinetics, 
safety and efficacy of rhIGF-1/rhIGFBP-3 for the prevention of ROP in premature infants (up to 
a corrected age [CA] of 40 weeks [± 4 days]). Subjects in Study ROPP-2008-01are randomly 
assigned to receive rhIGF-1/rhIGFBP-3 or standard neonatal care. The target dose of 
rhIGF-1/rhIGFBP-3 for Study Section D is 250 μg/kg/24 hours to be administered via 
continuous infusion starting on Study Day 0 (day of birth) and continuing through postmenstrual 
age (gestational age + time elapsed from birth) 29 weeks + 6 days.
Although the rhIGF-1/rhIGFBP-3 therapy in Section D of the Phase II study 
(Study ROPP-2008-01) represents a short-term exposure (< 2 months for each subject), 
rhIGF-1/rhIGFBP-3 may have long-lasting effects on visual outcomes as well as other potential 
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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outcomes related to complications of prematurity such as neurodevelopment, pulmonary 
function, and growth. In addition, it is critical to understand any long term safety effects from
short term exposure to rhIGF-1/rhIGFBP-3. 
The long-term outcomes assessed in this study will require utilization of different assessment 
tools than are utilized in the Phase II study, ROPP-2008-01 Section D, given the changes in 
physical and cognitive development that will occur in the subjects as they age during their 
participation in this study. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of rhIGF-1/rhIGFBP-3.
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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints

Visual acuity as assessed by an age-appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
3.1.2
Secondary Efficacy Endpoints

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

Physical development as assessed by standardized, age appropriate tools including 
physical examination, neurological examination for assessment of cerebral palsy, and 
hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) for the 
assessment of symptoms of attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
3.2
Health Economic Outcome Research Endpoints

Health Related Quality of Life (HRQoL) 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, respectively)
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3
(treated) or standard neonatal care (control). Enrolled subjects in this study will be followed 
through age 5 years CA. This study will enroll both subjects who were in the treated (received 
rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of Study 
ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term efficacy and 
safety outcomes versus standard neonatal care. No investigational product will be administered 
in this study. 
In this study, the Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon 
discontinuation from Study ROPP-2008-01 or may occur any time up to the visit at 3 months 
CA. Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age of 
23 weeks + 0 days to 27 weeks + 6 days.
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. 
Both telephone and clinical site visits are included to help maintain contact with subjects 
throughout the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required. 
See Appendix 1 for the Study Schedule of Events table.
The overall study design is outlined in Figure 4-1.
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Insulin-like growth factor-1 (IGF-1) mediates its primary actions by binding to its specific 
receptor, the insulin-like growth factor 1 receptor (IGF-1R), which is present on many cell types 
in many tissues. Binding to its receptor initiates intracellular signaling including via the AKT 
signaling pathway. This pathway is involved in stimulation of cell division, growth and 
differentiation and inhibits programmed cell death. Specifically regarding premature infants, 
IGF-1 is an important mediator of fetal growth and has been shown to play a role in early 
postnatal growth following pre-term delivery.9,10
Insulin-like growth factor-1 (IGF-1) has also been shown to play a role in pulmonary 
development11 and neural development.12,13 Given the potential role for IGF-1 in the 
development of multiple systems, this study has been designed to evaluate the long-term effects 
of rhIGF-1/rhIGFBP-3, both from a safety and efficacy perspective, on the development of the 
premature infant.
4.3
Study Duration
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years CA.
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5
STUDY POPULATION SELECTION
5.1
Study Population
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks + 0 days to 27 weeks + 6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. Up to 
120 subjects are planned to be randomized in Study ROPP-2008-01 Section D.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject was randomized in Study ROPP-2008-01, Section D
2. Subject’s parent or legally authorized representative(s) must provide written informed 
consent prior to performing any study-related activities. Study-related activities are any 
procedures that would not have been performed during normal management of the subject.
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. Any other condition or therapy that, in the Investigator’s opinion, may pose a risk to the 
subject or interfere with the subject’s ability to be compliant with this protocol or interfere 
with the interpretation of results
2. The subject or subject’s parent or legally authorized representative(s) is unable to comply 
with the protocol as determined by the Investigator
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6
STUDY TREATMENT
6.1
Description of Treatment
No investigational product will be administered in this study.
6.2
Treatments Administered
Not applicable.
6.3
Selection and Timing of Dose for Each Subject
Not applicable.
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable.
6.5
Masking
Not applicable.
6.6
Medications
Any medications administered to the subjects will be collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued). Any 
investigational product received by subjects will be recorded separately as part of an assessment 
of subjects’ participation in other clinical studies (Section 7.11.1).
6.7
Restrictions 
6.7.1
Prior Therapy
There are no restrictions related to prior therapy.
6.7.2
Other Restrictions
There are no restrictions related to fluid or food intake, or subject activity.
6.7.3
Treatment Compliance
Not applicable.
6.7.4
Packaging and Labeling
Not applicable.
6.8
Storage and Accountability
Not applicable
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7
STUDY PROCEDURES
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events in Appendix 1). 
All data collected are to be recorded on the subject’s appropriate eCRF. 
Details for study procedures are described in the Operations Manual for this study.
7.1
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).
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 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria and Eligibility
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 informed consent is not obtained at or before the 3-month visit in Study ROPP-2008-01 for 
inclusion in this study (SHP607-201), the subject may still be enrolled until they turn 2 years CA
+3 months. Subjects are no longer eligible to participate in this study after they turn 2 years CA
+3 months. 
7.3
Study Enrollment
Subjects will be considered enrolled in the study once written informed consent has been 
obtained from the subject’s parent(s) or legally authorized representative(s).
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be recorded.
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference
7.5.1
Length and Height
Body length (supine measurement) will be collected when subjects are 24-months CA or 
younger. For the length measurement, the subject will be placed on his or her back so that the 
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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 when subjects are older than 24-months CA. 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). 
7.5.2
Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures 
(type of scale will depend upon subject’s age). Care should be taken to remove any extraneous 
clothing prior to measures and shoes should be removed.
The measure should be recorded to the nearest 0.1 kg.
7.5.3
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.
7.6
Efficacy Assessments
7.6.1
Visual Assessments
After corrective lens determination has occurred (Section 7.6.1.2), all visual assessments should 
be conducted with best-corrected vision, ie, with corrective lenses in place (if required); this 
applies to 24-month and 5-year visits.
7.6.1.1
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. It will be assessed by 
the methods summarized in Table 7-1; the method employed will be selected based on the 
subject’s age (CA) at the time of the study visit. Visual acuity measurements will be measured 
and recorded for the left (OS), right (OD) eye, and both eyes (OU).
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At ages 6 months and 12 months CA, visual acuity will be assessed with Teller acuity cards. At 
ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner 
determines that it will not be possible to perform an accurate assessment with the relevant LEA 
tool, visual acuity should be assessed with the Teller acuity cards. 
The visual acuity assessments should be performed by an optometrist or ophthalmologist trained 
in pediatrics. 
Table 7-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
7.6.1.2
Corrective Lens Determination
An assessment to determine if the subject requires vision correction with corrective lenses will 
be performed. This is being performed to ensure the accuracy of subjects’ subsequent visual 
acuity assessments (at the 24-month and 5-year visits). The corrective lens determination will be 
performed according to the guidelines published by the American Academy of Ophthalmology 
(AAO).14
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)
Ocular alignment will be assessed in primary gaze by comparing the position of the corneal light 
reflection in OS and OD (corneal light reflection assessment). Presence or absence of strabismus 
will be recorded in primary gaze and in as many of the 9 positions of gaze as feasible with the 
cover test assessment of refixation movement. Extraocular muscle over-action or deficiency will 
be recorded. The assessment will be performed according to the AAO guidelines.14
Presence or absence of nystagmus as observed during the ocular alignment assessments will also
be recorded.
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7.6.2
Hearing Assessment History
Results of previously completed hearing assessments will be recorded at the 5-year CA visit;
hearing tests are not being performed as part of this study. 
7.6.3
Behavioral Assessments
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition
The BSID-III will be used to assess cognitive, motor, and language skills, and is applicable to 
children aged 1 to 42 months. 
The BSID-III is an assessment tool designed to measure a young child's skills in the 3 core areas 
of development:  cognitive, language, and motor. There are 5 subscales, the cognitive subscale 
stands alone while 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 examiner's manual.
The BSID-III 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.
7.6.3.2
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.19  It is applicable to preschoolers and young children aged 
2 years + 6 months to 7 years + 7 months, and is a direct assessment of a child’s cognitive skills.
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 standardization20 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. Scores to be recorded 
are detailed in the Study Operations Manual.
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7.6.3.3
Child Behavior Checklist (CBCL)
The CBCL (1 ½ to 5) is a parent-reported outcome measure used to assess behavioral, emotional, 
and social functioning of toddlers and preschool children aged 18 to 60 months.21 It is composed 
of 99 items that are rated on a Likert scale and includes the following 7 syndrome scales 
arranged under 2 domains (ie, Internalizing and Externalizing Problems):22

Internalizing Problems

Emotionally Reactive

Anxious/Depressed

Somatic Complaints

Withdrawn

Sleep Problems

Attention Problems

Aggressive Behavior
The questionnaire is widely used and has been employed to assess long-term behavioral 
outcomes in children born prematurely, aged similarly to the subjects expected in this study 
population.22-24 It is associated with well-established normative data;25 norms may be selected to 
aid in interpretation of the scale scores.
The CBCL (1 ½ to 5) is a questionnaire that will be administered to 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.
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition
The VABS-II Expanded Interview Form will be used to measure the personal and social skills of 
subjects serially over time; these scales are organized within a 3-domain structure:  
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what he or she is able to do. 
The VABS-II Expanded Interview Form will be administered to 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.
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale
The ADHD-RS was developed to measure the behaviors of children with ADHD. The 
ADHD-RS consists of 18 items designed to reflect current symptomatology of ADHD based on 
DSM-IV 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. 
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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,26 will be completed by the subject’s parent(s) or legally authorized 
representative(s). Scores to be recorded are detailed in the Study Operations Manual.
7.6.3.6
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children27 that can be used for screening for autism or autism spectrum disorders in the general 
population.28
The SCQ will be completed by the subject’s parent(s) or legally authorized representative(s). 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.
7.6.4
Cerebral Palsy Assessment
Comprehensive neurological examination for the diagnosis of cerebral palsy (CP) will be 
conducted. The Amiel-Tison neurological examination framework29 will be utilized for this 
assessment and conducted by trained medical professionals.
7.6.5
Pulmonary Morbidity Assessment
Pulmonary morbidity will be assessed with questions related to family history and smoking 
status as well as diagnosis of select pulmonary symptoms, conditions and related 
hospitalizations. The assessment will be administered to the subject’s parent(s) or legally 
authorized representative(s). Assessments will be performed as outlined in the Schedule of 
Events (see Appendix 1).Questionnaires that will be used for these assessments at clinical site
visits are provided in Appendix 2 for the 6-month and 12-month CA visits and Appendix 3 for 
the 24-month and 5-year CA visits. The questionnaire that will be used for these assessments 
during phone interviews at the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year CA visits is
provided in Appendix 4.
7.6.6
Cerebral Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) of the brain will be performed. The MRI should be 
performed without sedation. If the scan is unsuccessful, a second attempt should be made. 
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.     
7.6.7
Survival Assessment
Survival status will be assessed and recorded.
7.6.8
Health Economic Outcome Research Assessments
7.6.8.1
Health Related Quality of Life
Health-related quality of life (HRQoL) is an important outcome towards improving the health 
care of pediatric patients as it is that part of a person’s overall quality of life that is determined 
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primarily by their health status and which can be influenced by clinical interventions. It is an 
important concept, which is also used in determining the value of health care services in this 
population.30,31 It is a multidimensional construct whose content is guided by the World Health 
Organization;32 minimally it includes physical, psychological (including emotional and 
cognitive), and social health dimensions.
In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL™) Scales appropriate for the child’s age of development.33-35  The development of the 
PedsQL was based on the delineations of the World Health Organization (WHO) and is a 
modular approach to assessing HRQoL in the pediatric population. Initially, the PedsQL Generic 
Scales were developed and continue to be used in children aged 2 to 18 years. More recently 
Infant Scales have been developed that apply to ages 1 to 24 months.34
The following scales will be used in this study:

Infant Scale for ages 1-12 months (36 Items)

Infant Scale for ages 13–24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent and may be conducted via telephone by 
clinical site staff. The scale(s) to be administered at each visit will be specified in the 
Study Operations Manual.
7.6.9
Health Care Resource Use
To understand the value of the investigational product administered in Study ROPP-2008-01 
(Section D), the resource use associated with inpatient visits, outpatient visits, and medical and 
pharmacy utilization in this study will be recorded. 
This assessment may be conducted via telephone by clinical site staff.
7.6.9.1
Health Status Classification System-Preschool
Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS), which is a validated instrument adapted for use via parent proxy 
within the pediatric population age 2.5 to 5 (adapted from the validated Health Utilities Index 
Mark 2 and 3 [HUI 2/3]).36  Validity of the HSCS-PS concepts has not been established for ages 
younger than 2.5 years.
The HSCS-PS was developed to provide a consistent measure of health status in preschool-aged 
children who had been born prematurely.36 The system is applicable to children with special 
needs as may be included in this study; validation cohorts for the system included children with 
very low birth weight (VLBW), which is congruent with this study population.
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The instrument is composed of 12 dimensions (Vision, Hearing, Speech, Mobility, Dexterity, 
Self-care, Emotion, Learn/remember, Think/problem solve, Pain, General Health, and Behavior) 
intended to provide a comprehensive assessment of a child’s health status as it pertains to 
health-related quality of life. The individual domains of the instrument will be scored as a mean 
score, representing the overall state for each concept individually. The global score will be 
recorded as well as the scores for each of the dimensions.
The HSCS-PS is a questionnaire that will be administered to the subject’s parent(s) or legally 
authorized representative(s) and may be conducted via telephone by clinical site staff.
7.7
Safety Assessments
7.7.1
Abdominal ultrasound
An abdominal ultrasound will be performed to assess the size of the spleen and kidneys. The 
spleen will be measured in the coronal longitudinal plane and the longest longitudinal length will 
be measured for each kidney (left and right).37 Ultrasound results will be assessed by a central 
reader.
Organ size will be interpreted in the context of reference values established for children.37,38
7.7.2
Echocardiogram
Echocardiographic examination (conventional M-mode recording of the left ventricle [LV] 
parasternal long axis view) will be performed for the evaluation of cardiac size, assessed by 
measuring the following:

interventricular septal thickness (during end diastole)

LV posterior wall thickness

LV intracavity volume (both in end diastole and end systole)
Echocardiogram results will be assessed by a central reader.
7.7.3
Physical Examination
Physical examinations will include a review of the subject’s general appearance, neurological 
examination, as well as a tonsillar examination (Table 7-2). Any abnormal change in findings 
will be recorded as an AE. 
Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
Throat
Musculoskeletal
Chest and lungs
Neurological
Tonsils
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate
Blood pressure, heart rate, and respiratory will be measured at the 5-year CA visit.
7.8
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 7.11.1).
7.9
Adverse Events Assessments
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions
7.9.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset 
of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
In this long-term outcome study in follow-up to Study ROPP-2008-01 (Section D), no 
investigational product is being administered. However, the relationship to the investigational 
product (rhIGF-1/rhIGFBP-3) as administered in Study ROPP-2008-01 (Section D) will be 
assessed. 
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For the purposes of this study only the following adverse events will be collected:  

those considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP -2008-01, Section D)

those considered related to procedures performed in this study (Study SHP-607-201)

specified targeted medical events (Section 7.9.1.3) regardless of causality
Throughout the study, the Investigator must record AEs on the AE electronic case report form 
(eCRF), regardless of the severity. The Investigator should treat subjects with AEs appropriately 
and observe them at suitable intervals until the events stabilize or resolve. Adverse events may 
be discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given are regarded as AEs and 
will be documented on the appropriate pages of the eCRF. Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as 
AEs and must be documented as such in the eCRF.
7.9.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
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 one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
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For the purposes of this study only SAE listed in the following will be collected:

fatal SAEs regardless of causality

SAEs related to ROP

SAEs related to congenital malformations not identified at birth which may impact 
neurocognitive development 
7.9.1.3
Suspected Unexpected Serious Adverse Reaction
Suspected unexpected serious adverse reactions (SUSAR) are suspected adverse reactions related 
to an investigational product (investigational products and comparators [if applicable]), which 
occur in the concerned study, and that are both serious and unexpected according to the current 
Investigator’s Brochure.
7.9.1.4
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, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D):

intracranial hypertension

any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and 
diabetes)

tonsillar hypertrophy (based on tonsil exam [part of the physical exam])

increased kidney size 

increased cardiac size

increased spleen size
7.9.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
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7.9.3
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.9.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product (rhIGF-1/rhIGFBP-3 as administered in 
Study ROPP-2008-01, Section D) is to be determined by the Investigator based on the following 
definitions (See Table 7-4).
Table 7-4
Adverse Event Relatedness
Relationship to Product
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, follows a known or suspected response 
pattern to the investigational product, is confirmed by improvement 
upon stopping the investigational product (de-challenge), and 
reappears upon repeated exposure (re-challenge). Note that this is not 
to be construed as requiring re-exposure of the subject to 
investigational product; however, the determination of definitely 
related can only be used when recurrence of event is observed.
7.9.5
Procedures for Recording and Reporting Adverse Events
7.9.5.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored throughout the study. 
For the purposes of this study, the period of observation begins from the time at which the 
subject’s parent(s) or legally authorized representative(s) gives informed consent until the 
subject’s final evaluation of the study. When possible, subject’s parents or legally authorized 
representative(s) should be consented at the end of study visit for the ROPP-2008-01. However,
if this is not possible, subject’s parents or legally authorized representative(s) will be asked to 
provide consent for any Serious Adverse Events that the subject experiences between 
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If a subject or the subject’s parent(s) or the subject’s legally authorized representative(s) acting 
on behalf of the subject, discontinues participation in the study, or the subject is discontinued by 
the Investigator, reasonable efforts will be made to follow the subject through the end of study 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the subject withdraws from the study, the subject will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.11
Other Study Procedures
7.11.1
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in another 
clinical study that involves 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 being evaluated in the study, and the subject’s treatment assignment 
in the study (if possible). 
7.12
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. These are the pulmonary 
morbidity assessment and the cerebral palsy assessment. In these cases, the tools are either based 
on validated tools or the current state of knowledge in the literature. For example, the cerebral 
palsy assessment is based on the Amiel-Tison neurological examination framework29 and the 
pulmonary assessment is based on published research in a similar pediatric population.39,40
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8
STUDY ACTIVITIES
The timing of the visits in this study is based on subjects’ corrected age (CA). 
8.1
Initial Study Visit (40 weeks CA [term equivalent])
The Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon discontinuation from 
Study ROPP-2008-01, Section D or any time up to the visit at 3 months CA. 
For subjects enrolled between the ages of 9 months CA and 2 years +3 months CA, missed 
procedures such as neurocognitive assessments, abdominal ultrasounds, and echocardiograms are 
not required.
At the Initial Visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data.
The following AE data, collected as part of Study ROPP-2008-01 (Section D) will be recorded:

Ongoing targeted medical events regardless of causality

Ongoing study drug-related AEs, including SAEs
SAEs, as outlined in Section 7.9.1.1 and Section 7.9.1.2, that the subject experiences between the 
ROPP-2008-01 end-of-study visit and the time of informed consent for the SHIP-607-201 study 
will be reported by the Investigator, pending permission for subject’s parent or legally authorized 
representative(s), as documented on the informed consent form.
8.2
Study Visits
Study visits for follow-up outcome assessments will take place at the following time points in 
CA:

3 months (±2 weeks) – conducted by telephone

6 months (±1 month) – clinical site visit

12 months (±3 months) – clinical site visit

20 months (-1 months) – clinical site visit

24 months (±3 months) – clinical site visit

30 months (±3 months) – conducted by telephone

3 years (±3 months) – conducted by telephone

3.5 years (±3 months) – conducted by telephone

4 years (±3 month) – conducted by telephone

4.5 years (±3 month) – conducted by telephone

4.75 years (-1 months) – clinical site visit

5 years (+6 months) – clinical site visit
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In addition, there will be 2 visits that must occur at least 1 month prior to the 24-month and 
5-year CA study visits to assess the need for corrective lenses. The timing of these 2 visits 
(20 months [-1 month] and 4.75 years [-1 month]) was set to ensure that any prescribed 
corrective lenses would be worn for at least 1 month prior to the visual assessments at the 
24-month and 5-year study visits CA.
The activities at the study visits are described in Sections 8.2.1 and 8.2.2.
8.2.1
Outcome Assessment Visits Conducted by Telephone
Visits at 3 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted by 
telephone. The following outcome assessments will be conducted at each of these 6 visits, unless 
otherwise indicated:

HRQoL (3-month, 3-year, and 4-year visits)

HCRU (3-month, 3-year, and 4-year visits) 

HSCS-PS (3-year and 4-year visits)

Pulmonary morbidity assessment (30-month, 3-year, 3.5-year, 4-year, and 4.5-year 
visits)

Medications (3-month, 3-year, and 4-year visits)

Survival assessment (3-month, 3-year, and 4-year visits)

Assessment of participation in other clinical studies (3-month, 3-year, and 4-year 
visits) 

Adverse events, including targeted medical events (3-month, 3-year, and 4-year visits) 
8.2.2
Clinical Site Visits
8.2.2.1
Outcome Assessment Site Visits
The following clinical site visits (in CA) to capture follow-up outcome data will occur at the 
clinical site:

6 months (±1 month)

12 months (±3 months) 

20 months (-1 month)

24 months (±3 months)

4.75 years (-1 months)

5 years (+6 months)
The following assessments will be performed at the 6-month visit:

Visual acuity

Refraction with cycloplegia
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
Length

Weight

Head circumference

VABS-II

Physical examination (including tonsil examination)

Hearing Assessment History (Historical hearing test data may be recorded at any time 
prior to the 6-month visit) 

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Abdominal ultrasound

Echocardiogram

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 12-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

VABS-II

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)
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
HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 20-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Assessment of participation in other clinical studies
The following assessments will be performed at the 24-month visit:

Visual acuity

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

CBCL

VABS-II

Physical examination (including tonsil examination)

Cerebral Palsy assessment

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
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The following assessments will be performed at 4.75-year visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)
The following assessments will be performed at the 5-year visit:

Visual acuity

Ocular alignment and motility

Stereoacuity

Height

Weight

WPPSI

CBCL

VABS-II

ADHD-RS

SCQ

Physical examination (including tonsil examination)

Blood pressure, heart rate, and respiratory rate

Pulmonary morbidity assessment

Hearing assessment history

Survival assessment


Cerebral MRI

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
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8.2.2.2
Visits Dedicated to Corrective Lens Determination
The following clinical site visits are dedicated solely to corrective lens determination in 
preparation for the outcome assessment visits at 24-months and 5-years CA:

20 months (-1 month) 

4.75 years (-1 month) 
At these visits, the following will be performed:

Visual acuity

Corrective lens determination (includes refraction with cycloplegia)
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior 
to the 24-month and 5-year visits, respectively. Any prescribed corrective lenses must be worn 
for at least 1 month prior to the 24 month and 5 year assessments.
8.3
Assessments upon Discontinuation
If a subject discontinues prior to the 5-year CA visit, every attempt will be made to complete the 
assessments scheduled for the subject’s next visit. 
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 Code of Federal Regulations (CFR) Part 
11 Guidance. The clinical trial database will include an audit trail to document any evidence of 
data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses 
will be performed by the Biometrics department at Shire. Statistical analyses will be performed 
using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3
or standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be extracted and summarized with the data from this study (SHP-607-201).
For consented patients, additional biomarker analysis may be performed on prior collected blood 
samples from Study ROPP-2008-01.
10.2
Determination of Sample Size
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study.
10.3
Method of Assigning Study Subjects to Treatment Groups
Not applicable.
10.4
Population Description
10.4.1
Analysis Populations
Enrolled Population- the Enrolled Population will consist of all subjects for whom written 
informed consent has been provided for this study. 
Safety Population- the Safety Population will consist of the subjects in the Enrolled Population
who have safety follow-up data in this long-term outcome study.
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10.4.2
Subject Disposition
Subjects who complete the study and subjects who prematurely discontinue from the study will 
be summarized by treatment group using descriptive statistics. In addition, for subjects who 
prematurely discontinue from the study, the reasons for discontinuation will be summarized by 
treatment group.
10.4.3
Protocol Violations and Deviations
Protocol violations and deviations will be listed. Details of the criteria for deviations and 
violations will be provided in the SAP.
10.4.4
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for the Enrolled Population. 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. Continuous variables such as age (including corrected age), weight, and 
length/height will be summarized using number of observations, mean, standard deviation, 
median, minimum and maximum values. Categorical variables, like gender and race, will be 
summarized using number of observations and percentages.
Medical history, including maternal and perinatal history, (as obtained from the antecedent 
study, ROPP-2008-01) will be summarized by treatment group using the number of observations 
and percentages of subjects reporting each category.
10.5
Efficacy Analysis
All efficacy analyses will be performed using the Enrolled Population.
10.5.1
Primary Efficacy Analysis
The primary efficacy endpoints consist of the following:

Visual Acuity:  Visual acuity will be categorized as the following: 
o
normal (measurable acuity ≥20/40), 
o
below normal (20/200≤measurable acuity <20/40), 
o
poor (measurable acuity ≤20/200)
o
blind/low vision (only the ability to detect the 2.2 cm wide stripes on the 
low-vision Teller acuity card and at any location in the visual field). 
The number and proportion of patients within each category listed above will be 
summarized by treatment group and visit. In addition, acuity results in the normal and 
below normal categories will be classified as favorable outcomes, and acuity results in 
the poor and blind/low-vision categories will be classified as unfavorable outcomes. 
Tabular summaries by treatment group and visit will include the frequency and the 
percentage for each visual acuity category. 
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In addition, shift tables of favorable outcomes from baseline (first assessment during 
this study) to each of the subsequent assessments, including the last assessment, will 
be presented by treatment group.

Ocular Alignment and Oculomotor Exam (Motility):  Findings from the ocular 
motility assessment will be either presence or absence of strabismus (esotropia, 
exotropia, hypertropia, or hypotropia). Tabular summaries by treatment group and 
visit will include the frequency and the percentage in each category. In addition, shift 
tables from baseline (first assessment during this study) to the last assessment will be 
provided by treatment group.

Nystagmus:  Presence or absence of nystagmus will be summarized by treatment 
group and visit

Refraction with Cycloplegia:  Findings from the refraction with cycloplegia will be 
summarized by treatment group and visit

Stereoacuity:  Presence or absence of stereopsis will be summarized by treatment 
group and visit
10.5.2
Secondary Efficacy Analysis

Growth Parameters (body weight, body length [and height], and head circumference):  
A standard Z-score, utilizing WHO child growth standards, will be calculated for each 
assessment by adjusting age- and sex- matched means and standard deviations (norm). 
The descriptive statistics of the Z-score for each of these parameters will be 
summarized at each assessment and the corresponding change from baseline. When 
appropriate, a 95% CI for the corresponding mean change within each group and the 
difference in the mean change between the 2 treatment groups and the corresponding 
95% CI will be presented as appropriate. If the parametric assumption for the 
distribution of the above endpoints cannot be justified, a non-parametric approach will 
be utilized to estimate the treatment difference (ie, median difference or 
Hodges-Lehmann estimator and the corresponding confidence intervals)

BSID-III and WPPSI:  The raw score for each domain within each questionnaire will 
be summarized by treatment group and visit using descriptive statistics.

ADHD-RS:  ADHD-RS total score and subscales (Hyperactivity/Impulsivity and 
Inattentiveness) will be summarized by treatment group and visit using descriptive 
statistics.

SCQ:  The SCQ subscales (communication and social) will be summarized by 
treatment group and visit using descriptive statistics

VABS-II:  The raw score for each domain of the scale will be summarized by 
treatment group and visit using descriptive statistics.

CBCL:  The raw score and change from baseline for each domain of the scale will be 
summarized by treatment group and visit using descriptive statistics.
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
Pulmonary morbidity assessment:  The binary response of each question will be by 
treatment group and visit using descriptive statistics.

Survival:  For subjects who have an event (ie, death), the event time will be calculated 
as the length of time from the subject’s date of birth to death during the study due to 
any cause. Subjects who do not have an event (ie, death) during the study will be 
censored at the end of the study. The survival endpoint will be analyzed by treatment 
group using Kaplan-Meier methods.
10.5.3
Subset Analyses
Subgroup analyses may be explored based on factors that may have influence on the efficacy or 
safety endpoints. Subgroup analyses will be specified in the SAP.
10.5.4
Exploratory Analyses
10.6
Health Economics and Outcomes Research Analyses
For PedsQL, descriptive statistics will be provided for summary scores by treatment group 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 and at each time point.
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.
10.7
Analysis of Safety
Safety summaries will be based on all assessments post-baseline. The safety data will be 
assessed by AE monitoring, change in cardiac size, and kidney and spleen size over time. 
Adverse events will be summarized by system organ class and preferred term for each treatment 
group and overall, the number and percentage of subjects having any AE, having an AE in each 
body system and having each individual AE. In addition, those events which resulted in death, or 
were otherwise classified as serious will be presented in a separate listing. In addition, the 
summary of AEs will be presented by severity and relationship to trial medication. 
The change in cardiac size, and size of kidney and spleen will be assessed at the 6-month CA 
visit via echocardiogram and abdominal ultrasound, respectively.  These data will be analyzed as 
a binary response (ie, normal/abnormal) and summarized using frequency count.  The number 
and proportion of patients with each category (ie, normal/abnormal) for each of these safety 
endpoints will be summarized by treatment group.  
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In addition, the 2-sided 95% CI for the proportion of patients with a normal status for each of the 
endpoints will be estimated by treatment group.
Physical examinations findings will be summarized descriptively. 
10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
If any baseline data are imbalanced and are considered to be clinically relevant, between-group 
comparisons for efficacy outcomes will be adjusted for covariates and detailed in the SAP. 
10.8.2
Handling of Dropouts or Missing Data
Handling of missing data rules will be described in the SAP.
10.8.3
Interim Analyses and Data Monitoring
An interim analysis will be performed after all data from all enrolled subjects in this study have 
either completed 2-year follow-up (24-month visit) assessments or have prematurely withdrawn 
from the study (before completing 2 years of follow-up) has been entered into the database, 
queried and discrepancies resolved. A full 2-year study report based on these data, including 
efficacy and safety endpoint analyses, will be completed.
Additionally, descriptive analyses of the data at other time points before study completion may 
be performed for safety monitoring, regulatory reporting or general planning purposes.
10.8.4
Multiple Comparisons/Multiplicity
Not applicable.
10.8.5
Sensitivity Analyses
Sensitivity analyses for the efficacy outcomes will be detailed in the SAP, as necessary.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 and Investigator Agreement. Curriculum vitae must be provided for the Investigators 
and sub-investigators listed on Form FDA 1572 or Investigator Agreement. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, and their study related duties and functions. 
The Investigator must maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form. This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study. Within 3 months of study completion or termination, 
a final report must be provided to the IRB/IECREB. A copy of these reports will be sent to the 
study clinical monitor. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are reported to the US (FDA or other Regulatory agencies (Safety Reports) must be 
submitted promptly to the IRB/IEC/REB.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent) form must be in a language understandable to the subject or the subject’s 
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parent(s) or legally authorized representative(s) and must specify who informed the subject, the 
subject’s parent(s), or the subject’s legally authorized representative(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the subject, the subject’s parent(s) or the subject’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the Sponsor. Only the subject number - will be recorded in 
the eCRF, and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The subjects will be told that 
representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed.
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The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Electronic case report forms (eCRFs) are provided for each subject. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the Investigator to ensure that the following documents are available to Sponsor 
or their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed 
within 12 months of study initiation)

Copy of Investigator and sub-investigator(s) current medical license (indicating 
license number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC/REB clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written 
information to be provided regarding subject recruitment procedures

Copy of IRB/IEC/REB approved Subject Information/Informed Consent Form/any 
other written information/advertisement (with IRB approval stamp and date of 
approval)

Current list of IRB/IEC/REB Committee members/constitution (dated within 
12 months prior to study initiation)

Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
Given that any long-term safety signal observed in this study could impact the safety profile of 
rhIGF-1/rhIGFBP-3 as administered in premature neonates being enrolled in the antecedent 
study (ROPP-2008-01, Section D), the Data Monitoring Committee (DMC) for Study 
ROPP-2008-01 will review safety data from this long-term outcome study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities, where applicable, 
have given approval/favorable opinion. Modifications to the protocol will not be made without 
agreement of the Sponsor. Changes to the protocol will require written IRB/IEC/REB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable 
regulatory authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The 
Sponsor will submit all protocol modifications to the regulatory authorities, where applicable, in 
accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC/REB.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to the FDA or other applicable international regulatory authority 
before initiation, if applicable.
11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:
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
The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC/REB, or the Sponsor may request access to all source 
documents, eCRFs, and other study documentation for onsite audit or inspection. Direct access to 
these documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. The Sponsor or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-Drug Dictionary (WHO-DD). Central reads 
will be employed as described in the study manual to aid in consistent measurement of 
abdominal ultrasound and echocardiogram parameters. 
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
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11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with the Sponsor, 
provided the Sponsor a copy of the draft document intended for publication, and obtained the 
Sponsor’s written consent for such publication. All information obtained during the conduct of 
this study will be regarded as confidential. 
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12
LIST OF REFERENCES
1. Maida JM, Mathers K, Alley CL. Pediatric ophthalmology in the developing world. Current 
opinion in ophthalmology 2008;19:403-8.
2. O'Connor AR, Stephenson TJ, Johnson A, et al. Visual function in low birthweight children. 
The British journal of ophthalmology 2004;88:1149-53.
3. Keith CG, Kitchen WH. Ocular morbidity in infants of very low birth weight. The British 
journal of ophthalmology 1983;67:302-5.
4. Laws D, Shaw DE, Robinson J, Jones HS, Ng YK, Fielder AR. Retinopathy of prematurity: a 
prospective study. Review at six months. Eye (London, England) 1992;6:477-83.
5. O'Connor AR, Stephenson T, Johnson A, et al. Long-term ophthalmic outcome of low birth 
weight children with and without retinopathy of prematurity. Pediatrics 2002;109:12-8.
6. Schaffer DB, Quinn GE, Johnson L. Sequelae of arrested mild retinopathy of prematurity. 
Archives of ophthalmology 1984;102:373-6.
7. Cats BP, Tan KE. Prematures with and without regressed retinopathy of prematurity: 
comparison of long-term (6-10 years) ophthalmological morbidity. Journal of pediatric 
ophthalmology and strabismus 1989;26:271-5.
8. Chard T. Insulin-like growth factors and their binding proteins in normal and abnormal 
human fetal growth. Growth Regul 1994;4:91-100.
9. Hansen-Pupp I, Lofqvist C, Polberger S, et al. Influence of insulin-like growth factor I and 
nutrition during phases of postnatal growth in very preterm infants. Pediatric research 
2011;69:448-53.
10. Ohkawa N, Shoji H, Kitamura T, et al. IGF-I, leptin and active ghrelin levels in very low 
birth weight infants during the first 8 weeks of life. Acta paediatrica (Oslo, Norway : 1992) 
2010;99:37-41.
11. Lofqvist C, Hellgren G, Niklasson A, Engstrom E, Ley D, Hansen-Pupp I. Low postnatal 
serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD). Acta paediatrica 
(Oslo, Norway : 1992) 2012;101:1211-6.
12. Ishii DN, Glazner GW, Whalen LR. Regulation of peripheral nerve regeneration by insulin-
like growth factors. Annals of the New York Academy of Sciences 1993;692:172-82.
13. Lewis ME, Neff NT, Contreras PC, et al. Insulin-like growth factor-I: potential for treatment 
of motor neuronal disorders. Experimental neurology 1993;124:73-88.
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26. DuPaul G, Power T, Anastopoulos A, Reed R. The ADHD rating scale IV: checklists, norms 
and clinical interpretation. New York: Guilford Press; 1998.
27. Rutter M, Bailey A, Lord C. Manual for the Social Communication Questionnaire2003.
28. Chandler S, Charman T, Baird G, et al. Validation of the social communication questionnaire 
in a population cohort of children with autism spectrum disorders. Journal of the American 
Academy of Child and Adolescent Psychiatry 2007;46:1324-32.
29. Gosselin J, Amiel-Tison C. Neurological Assessment from Birth to 6 Years. 2nd ed. 
Montreal: CHU Sainte-Justine; 2011.
30. Matza LS, Swensen AR, Flood EM, Secnik K, Leidy NK. Assessment of health-related 
quality of life in children: a review of conceptual, methodological, and regulatory issues. Value 
in health : the journal of the International Society for Pharmacoeconomics and Outcomes 
Research 2004;7:79-92.
31. Varni JW, Burwinkle TM, Lane MM. Health-related quality of life measurement in pediatric 
clinical practice: an appraisal and precept for future research and application. Health and quality 
of life outcomes 2005;3:34.
32. Constitution of the World Health Organization: basic document. Geneva, Switzerland: World 
Health Organization; 1948.
33. Varni JW, Limbers CA. The pediatric quality of life inventory: measuring pediatric health-
related quality of life from the perspective of children and their parents. Pediatric clinics of North 
America 2009;56:843-63.
34. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL Infant Scales: feasibility, internal 
consistency reliability, and validity in healthy and ill infants. Quality of life research : an 
international journal of quality of life aspects of treatment, care and rehabilitation 2011;20:45-55.
35. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical care 
2001;39:800-12.
36. Saigal S, Rosenbaum P, Stoskopf B, et al. Development, reliability and validity of a new 
measure of overall health for pre-school children. Quality of life research : an international 
journal of quality of life aspects of treatment, care and rehabilitation 2005;14:243-57.
37. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal 
children. AJR Am J Roentgenol 1984;142:467-9.
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38. Rosenberg HK, Markowitz RI, Kolberg H, Park C, Hubbard A, Bellah RD. Normal splenic 
size in infants and children: sonographic measurements. AJR Am J Roentgenol 1991;157:119-
21.
39. Stevens TP, Finer NN, Carlo WA, et al. Respiratory Outcomes of the Surfactant Positive 
Pressure and Oximetry Randomized Trial (SUPPORT). The Journal of pediatrics 2014;165:240-
9.e4.
40. Zivanovic S, Peacock J, Alcazar-Paris M, et al. Late outcomes of a randomized trial of high-
frequency oscillation in neonates. The New England journal of medicine 2014;370:1121-30.
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13
APPENDICES
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Appendix 1
Study Schedule of Events
Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30
± 3 mth
3f
± 
3 mths
3.5
± 
3 mth
4f
± 3 mths
4.5
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Informed Consent
•
Eligibility Criteria
•
Demographics
•
Visual acuitya
•
•
•
•
•
•
Corrective lens determinationh
•
•g
•g
Ocular alignment and motility
•
•
•
Refraction with cycloplegiah
•
Stereoacuity
•
Length
•
•
•
Height
•
Weight
•
•
•
•
Head Circumference
•
•
•
BSID-III
•
•
WPPSI
•
CBCL
•
•
VABS-II
•
•
•
•
ADHD-RS
•
SCQ
•
Physical Examination including 
tonsil examination 
•
•
•
•
Blood Pressure, Heart Rate, and 
Respiratory Rate
•
Cerebral Palsy Assessment
•
Hearing Assessment Historyb
•
•
Pulmonary Morbidity Assessment 
1
•
•
Pulmonary Morbidity Assessment 
2  (clinical site visit)
•
•
Pulmonary Morbidity Assessment 
(phone interview)
•
•
•
•
•
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Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30
± 3 mth
3f
± 
3 mths
3.5
± 
3 mth
4f
± 3 mths
4.5
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Survival assessment
•
•
•
•
•
•
•
Cerebral MRI
•
HRQoLc
•
• i
• i
•i
•
•
• i
HCRU
•
• i
• i
•i
•
•
• i
HSCS-PS
•i
•
•
• i
Abdominal Ultrasound
•
Echocardiogram
•
Assessment of Participation in 
Other Clinical Studies
•
•
•
•
•
•
•
Medications
•
•
•
•
•
•
•
Adverse eventsd
•j
•
•
•
•
•
•
•
Abbreviations:  ADHD-RS = Attention-Deficit/Hyperactivity Disorder Rating Scale; BSID-III = Bayley Scales of Infant and Toddler Development-Third 
Edition, CBCL = Child Behavior Checklist; CA = corrected age; HCRU = health care resource use; HRQoL = health-related quality of life; HSCS-PS = Health 
Status Classification System; mth(s) = months; 
; PedsQL = Pediatric Quality of Life Inventory; SCQ = Social 
Communication Questionnaire; VABS-II = Vineland Adaptive Behavior Scales, Second Edition; wks = weeks; WPPSI = Wechsler Preschool and Primary 
Scale of Intelligence
a
The tools used to assess visual acuity will change as the subject ages during their participation in the study. The tools that will be used in this study and are 
summarized by applicable study visit in Table 13-1.
b
Historical hearing test data may be recorded at any time during the study prior to the 6-month visit.
c
HRQoL will be assessed via the validated PedsQL™  scales appropriate for the child’s age of development as specified in the Study Operations Manual 
d
Adverse event collection will include an assessment of the specified targeted medical events 
e
The Initial Visit may be performed prior to 40 weeks CA for any subject who discontinued from Study ROPP-2008-01 and, for all subjects, any time after 
40 weeks CA, up to the study visit to occur at 3 months CA.
f
Visits at 3 months, 3 years, and 4 years CA will be conducted by telephone.
g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments.
h
Refraction with cycloplegia will be performed as part of the corrective lens determination procedure.
i
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through clinical site staff if 
there are time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through clinical site staff 
and may be performed at any time within the visit window.
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Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30
± 3 mth
3f
± 
3 mths
3.5
± 
3 mth
4f
± 3 mths
4.5
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
j
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201):  any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
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Table 13-1
Summary of Visual Acuity Assessments 
Visual Acuity Assessment 
Tool
Description
Unit of Measure
Applicable 
Age/Study Visit 
(CA)
Teller acuity cards
Resolution acuity – discrimination 
of a grating optotype from a 
background with the same mean 
luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols (ETDRS-style) 
chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA Symbols Test 
and LEA Symbols Chart, respectively. If during this attempt, the examiner determines that it will not be 
possible to perform an accurate assessment with the relevant LEA tool, visual acuity should be assessed with 
the Teller acuity cards.
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Appendix 2
Pulmonary Morbidity Assessment (Clinical Site Visits at 6 and 12 Months
CA)
Subject Name
Subject Number
The SHP-607-201 Protocol refers to a “Pulmonary Morbidity Questionnaire” however; there is no formal 
questionnaire for the pulmonary morbidity assessment. These questions are built into the pulmonary 
morbidity eCRF page, which will be completed after obtaining this information at the 6mo, 12movisits.  The 
data will be captured in EDC, not through MedAvante and will not scored in any way.  
To assist with capturing these data, Pulmonary Morbidity Assessment Site Source Document has been 
developed for your use.
1.
Was the Pulmonary Morbidity Assessment done?    
If NO, please explain why not:
2.
Date of 
Examination:
Month
Day
Year
FAMILY HISTORY
3.
Does anyone living in the same home with subject smoke?
4.
Have any immediate family members (parents or siblings) of the subject 
been diagnosed with asthma or wheezing?
5.
Have the parents/family of the subject had to change their plans because 
the subject’s breathing problems or pulmonary health in the last six 
months?
PATIENT DATA
6.
Has the subject had asthma, wheezing, or bronchopulmonary dysplasia 
(BPD) exacerbation or flare-up in the last six months?
If YES, how many episodes in the last six months? 
7.
Has the subject had bronchiolitis, bronchitis, or pneumonia diagnosed in 
the last six months?
If YES, how many episodes in the last six months? 
8.
Has the subject had to use oxygen at home during the last six months?
If YES, how many days did the subject use oxygen in the last month?
9.
Has the subject had to visit an emergency room or urgent care for 
respiratory or pulmonary problems in the last six months?
If YES, how many times in the last six months? 
10. Has the subject had to stay in a hospital overnight for respiratory or 
pulmonary problems in the last six months?
If yes, how many overnights has the subject spent in the hospital? 
 
 
 
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Appendix 3
Pulmonary Morbidity Assessment 2 (Clinical Site Visits at 24 Months and 5 
Years CA)
Subject Name
Subject Number
The SHP-607-201 Protocol refers to a “Pulmonary Morbidity Assessment – In Person Interview”. These 
questions are built into the pulmonary morbidity assessment in person interview eCRF page. It will be 
completed at M24 and Year 5. The questions will be administrated to the child caregiver during study visit by 
site personnel. The data will be captured in EDC on eCRF pages, no scoring is required.
1.
Was the Pulmonary Morbidity Assessment done?    
If NO, please explain why not:
2.
Date of Examination:
Month
Day
Year
3.
This questionnaire was administered to:
4.
Was this questionnaire administered to the same responder as last time?
5.
Has the child been with this caregiver during the six months
HOME ENVIRONMENT
6.
Does anyone living in the same home with subject smoke?
7.
If YES, which of the following three statements best describes the situation regarding smoking in the 
child’s home?
Smoking is allowed in any common room of the home
Smoking is limited to part of the house where the child rarely goes
There is no smoking inside
Are there any exceptions to this situation?
               
If YES, under what circumstances are the exceptions allowed?
8.
Which of the following five statement best describes the situation regarding smoking in the car the child 
usually rides in? (check only one below)
Do not have a car
Smoking is usually or always allowed
Smoking is sometimes allowed
Smoking occurs in the car only when the child is not inside
There is no smoking inside the car
 
 
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9.
How often has the baby’s mother or primary caretaker smoked since the child was born
Never
Occasionally
Daily
Don’t know
10. Altogether, how many people who live in the child’s home smoke, even if they 
smoke outside?
11. Approximately how many hours per week does the child spend at a babysitters 
home or daycare
hours
12. Is smoking permitted at the child’s daycare facility 
How frequent is the smoke exposure at the babysitter or daycare?
Never
Occasionally
Daily
Don’t know
Approximately how many children beside your child are in the daycare?
13. How many children under 12 live in the house? (including subject)
14. Is there a pet inside the home
If YES, how many dogs?
How many cats?
How many other pets?
Specify other pets
PATIENT MEDICAL HISTORY DATA
15. Has the child had any medical office visit during the past six month
If YES, how many visit in the last six months? 
If YES, how many of these visits were because of wheezing or breathing 
problems?
16. For what other reason did the child have a medical visit?
17. Has the child visited the urgent care during the past six months?
If YES, is this urgent care part of your doctor’s office?
If YES, how many visit in the last six months?
If YES, how many of these visits were because of wheezing or breathing 
problems?
18. Has the child visited the emergency room during the past six months?
If YES, how many visit in the last six months?
If YES, how many of these visits were because of wheezing or breathing 
problems?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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19. Has the child stayed in the hospital during the past six months?
If YES, how many visit in the last six months?
If YES, how many of these visits were because of wheezing or breathing 
problems?
If YES, what was the diagnosis?
20. How many colds has the child had in the last six months
21. Has the child's breathing sounded wheezy or whistling in the last six months?
If YES, has this occurred with colds?
22. During what month did your child’s chest first sound wheezy or whistling?
January
February
March
April
May
June
July
August
September
October
November
December
Not Sure
Don’t Know
Year:
23. On average how often has your child’s chest sounded wheezy or whistling during the day time? (check 
only one below)
Never
Twice a week or less
More than two times a 
week but not every day
Every day but not all the time
Everyday all the time
Don’t know
During night time? (check only one below)
Never
once every two weeks or 
less
Once a week
Two or more times a week
More than three nights a 
week/ Frequently
Don’t know
During the worst two week period, how often has your child’s chest sounded wheezy or whistling during 
the daytime? (check only one below)
Never
Twice a week or less
More than two times a 
week but not every day
Every day but not all the time
Everyday all the time
Don’t know
24. Has your child been diagnosed with wheezing by a doctor?
25. Has your child had a cough for more than three days when he/she did not have a 
cold?
What time of the day has this cough usually occurred?
In the morning shortly after rising
Later in the day
During the night
No relation to time of day
26. Has your child coughed on most days for as much as 2 to 3 months?
 
 
 
 
 
 
 
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During what month did your child first develop the cough? (Check only one below)
January
February
March
April
May
June
July
August
September
October
November
December
Not Sure
Don’t Know
Year:
27. Has your child’s chest ever sounded wheezy or whistling with episodes of 
coughing?
28. On average how often has your child had coughing during the daytime in the past six months? (check 
only one below)
Don’t know
Twice a week or less
More than two times a week but not every day
Never
Everyday all the time
Every day but not all the time
During the worst two week period, how often has your child’s had coughing during the daytime in the 
past six month? (check only one below)
Don’t know
Twice a week or less
More than two times a week but not every day
Never
Everyday all the time
Every day but not all the time
29. Has your child ever had breathing problems that has caused you to change your 
plans and stay home with your child?
On average, how many days per month did you have to change your daytime or evening plans 
becauase of your child’s breathing problems? (check only one below)
none, we never had to change plans
7 or more days
3-6 days
More than none but less than 3 days
Don’t know
During the worst two week period, how many days did you have to change your daytime or evening 
plans because of your child’s breathing problems? (check only one below)
none, we never had to change plans
7 or more days
3-6 days
More than none but less than 3 days
Don’t know
30. Has the child had any of the following diagnosed by a doctor in the past six month? (check all that 
apply)
Asthmas
Reactive airway 
disease
BPD flare-up
Bronchiolitis
Bronchitis
Pneumonia
Croup
31. Does the child have other medical problems?
If YES, list other medical problems
32. Please mark any medications your child is taking
Brochiodilators
Inhaled Steriods
Oral Steriods
Antibiotics
Diuretics
Synagis
Other, specify
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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33. Has the child ever had shots to prevent Respiratory Synsytial Virus (palivizxumab, 
or RSV shot)?
34. Has the child had a flu shot?
35. Has the child had to use oxygen therapy at home during the last six months?
If YES, how many days did the child use oxygen in the last month?
Is the oxygen administered by nasal canula?
If YES, what is the FiOx
mmHg
Liter per minutes (LPM)?: (check only one below)
< 0.25
0.25
0.5
0.75
1
1.25
2
2.25
2.5
2.75
3
>3
36. Is your baby in an oxygen hood or tent?
37. Is your baby on a ventilator or CPAP?
If YES, what are the ventilator settings?
38. Has the child taken any medication during the past six months?
Albuterol
Proventil
Serevent
Ventolin
Volmax
Xopenex
Cromolyn (Intal)
Flovent
Advair
Aerobid
Azmacort
Beclovent
Nedocromil (Tilade)
Vanceril
Pulmicort
Decadron
Prednisone
Prednisolone
Accolate
Diuril
Lasix
Aldactixide
Aldactone
Nebulizer
Theophylline
Singulair
Does your child take that medicine every day, sometimes or only when sick? (check all that apply 
below)
Every Day
Medication: 
Sometimes
Medication:
Only when sick
Medication:
PATIENT FAMILY DATA
39. Have the parents/family of the child had to change their plans because the child’s 
breathing problems or pulmonary health in the last six months?
40. Did mother smoke during pregnancy?
41. Did father smoke during pregnancy?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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42. Family history of atopy: (Check all that apply below)
Mother
Asthma
Eczema
Seasonal Allergies
Father
Asthma
Eczema
Seasonal Allergies
Siblings
Asthma
Eczema
Seasonal Allergies
43. Does your child frequently have a stuffy nose or runny nose?
If YES, how many infections has your child had for which antibiotics were 
prescribed since the last interview six months ago.
What area of the body was infected? (check all that apply below)
Nose
Lungs
Throat
Eye
Skin
Mouth
Genitals
urinary tract
Other, (Specify)
44. Does your child take a daily vitamin?
45. Does your child take daily iron (separate or in the vitamin)?
 
 
 
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Appendix 4
Pulmonary Morbidity Assessment (Phone Interviews at 30 Months, 3 Years, 
3.5 Years, 4 Years, and 4.5 Years CA)
Subject Name
Subject Number
The SHP-607-201 Protocol refers to a “Pulmonary Morbidity Assessment- phone interview”. These questions 
are built into the pulmonary morbidity eCRF page. It will be completed every 6 months after the M24 visit. The 
questions are administered to the child’s caregiver over the phone by site personnel. The data will be captured 
in EDC, no scoring is required.  
1.
Was the Pulmonary Morbidity Assessment done?    
If NO, please explain:
2.
Date of Examination:
Month
Day
Year
3.
This questionnaire was administered to:
4.
Was this questionnaire administered to the same responder as last time?
5.
Has the child been with this caregiver during the six months
6.
Since the last contact, has the smoking status of anyone in the child’s home or 
the child’s day care provider changed?
If YES, please explain:
PATIENT DATA
7.
Has the child had any medical office visit during the past six month
If YES, how many visit in the last six months? 
If YES, were any of these visits for respiratory symptoms?
(Cold, wheezing or other breathing problems)
If YES, what was the diagnosis?
If YES, did the doctor prescribe any medication
If YES, what was the medication
8.
Has the child visited an urgent care facility in the past six month?
If YES, were any of these visits related to respiratory symptoms?
(colds, wheezing or other breathing problems?) 
If YES, what was the diagnosis?
If YES, did the doctor prescribe any medication
 
 
 
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If YES, what was the medication
9.
Has the child visited the emergency room facility in the past six months?
If YES, is this urgent care part of the doctor’s office?
If YES, were any of these visits related to respiratory symptoms?
(colds, wheezing or other breathing problems?) 
If YES, what was the diagnosis?
If YES, did the doctor prescribe any medication
If YES, what was the medication
10. Has the child had to stay in a hospital overnight in the last six months?
If YES, how many overnights in the last six months 
If YES, were any of these visits related to respiratory symptoms?
(colds, wheezing or other breathing problems)
If YES, what was the diagnosis?
11. Has the child had a flu shot?
12. Has the child had to use oxygen therapy at home during the last six months?
If YES, how many days did the child use oxygen in the last month?
Is the oxygen administered by nasal canula?
If YES, what is the FiO2
Liter per minutes (LPM)?: (check only one below)
< 0.25
0.25
0.5
0.75
1
1.25
2
2.25
2.5
2.75
3
>3
13. Is your child in an oxygen hood or tent?
14. Is your child on a ventilator or CPAP?
If YES, what are the ventilator settings?
15. Has your child taken any medication during the past six months?
Albuterol
Proventil
Serevent
Ventolin
Volmax
Xopenex
Cromolyn (Intal)
Flovent
Advair
Aerobid
Azmacort
Beclovent
Nedocromil (Tilade)
Vanceril
Pulmicort
Decadron
Prednisone
Prednisolone
Accolate
Diuril
Lasix
Aldactixide
Aldactone
Nebulizer
Theophylline
Singulair
 
 
 
 
 
 
 
 
 
 
 
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Appendix 5
Summary of Changes
Description of Change
Section(s)
Added pulmonary morbidity assessments which will be conducted during 
phone interviews at the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year 
CA visits.
Provided the pulmonary morbidity assessments at clinical site visits
(Appendix 2 for the 6-month and 12-month CA visits; Appendix 3 for the 
24-month and 5-year CA visits) and phone interviews (Appendix 4 for 
the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year CA visits).
Section 4.1,
Figure 4-1
Section 7.6.5
Section 8.2
Section 8.2.1
Appendix 1
Appendix 2
Appendix 3
Appendix 4
Added cerebral magnetic resonance imaging (MRI) to the 5-year CA 
visit.
Section 7.6.6
Section 8.2.2.1
Appendix 1
Added hearing assessment history at the 5-year CA visits.
Section 7.6.2
Section 8.2.2.1
Appendix 1
Added blood pressure, heart rate, and respiratory rate measurements at 
the 5-year CA visit.
Section 7.7.4
Section 8.2.2.1
Appendix 1
Clarified that if informed consent is not obtained at or before the 3-month 
visit in Study ROPP-2008-01 for inclusion in this study (SHP607-201), 
the subject may still be enrolled until they turn 2 years +3 months CA.
Section 7.2
Clarified that for subjects enrolled between the ages of 9 months CA and 
2 years +3 months CA, missed procedures such as neurocognitive 
assessments, abdominal ultrasounds, and echocardiograms are not 
required.
Section 8.1
Clarified that for consented patients, additional biomarker analysis may 
be performed on prior collected blood samples from Study 
ROPP-2008-01.
Section 10.1
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Appendix 6 
Protocol Signature Page 
Study Title: 
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 
Previously Treated with rhIGF-1/rhIGFBP-3 for the Prevention of 
Retinopathy of Prematurity (ROP) or Who Received Standard Neonatal 
Care 
Study Number: 
SHP-607-201 
Final Date: 
21 February 2017 
Version  
Amendment 2 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
Signatory: 
 
 
 
 
 
 
 
 
Investigator 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
Printed Name 
 
 
I have read and approve the protocol described above. 
Signatory: 
 
 
 
 
 
 
 
 
Shire Medical 
Monitor  
 
 
Signature 
Date 
 
 
 
 
, MD, MPH 
 
 
Printed Name 
 
 
Shire  
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21 Feb 2017 
 
 
 
 
 
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
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SYNOPSIS
Sponsor:
Premacure AB, A Member of the Shire Group of Companies
Name of Finished Product:
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
Study Title:
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated with
rhIGF-1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or Who Received 
Standard Neonatal Care
Study Number:
SHP-607-201
Study Phase:  II
Investigational Product, Dose, and Mode of Administration:
Not applicable.
Primary Objectives
The primary objectives of this study are:

To evaluate the long-term efficacy outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) 
as assessed by ROP associated visual outcomes

To evaluate the long-term safety outcomes following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D)
Secondary Objectives
The secondary objectives of this study are to evaluate the effect following short-term exposure to 
rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (Section D) on:

Growth parameters

Cognitive development

Physical development

Child behavior

Pulmonary morbidity

Survival

Health-related quality of life (HRQoL)

Health utility

Health care resource use (HCRU)
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Efficacy Assessments:
Efficacy will be assessed by visual outcomes, growth parameters, cognitive development, physical 
development, child behavior, pulmonary morbidity, and survival.
Safety Assessments:
Safety will be assessed by physical examination (including tonsil examination), AEs (as
specified), echocardiogram, and abdominal ultrasound.
Statistical Methods
Details regarding the statistical methods and definitions will be provided in the Statistical Analysis 
Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses will be 
performed by the sponsor or CRO after the database is locked. Statistical analyses will be 
performed using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or 
standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
Date of Original Protocol:  27 August 2014
Date of Amendment 1: 19 February 2016
Date of Amendment 2: 21 February 2017
Date of Amendment 3: 11 May 2017
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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
LIST OF IN-TEXT TABLES ........................................................................................................10
LIST OF IN-TEXT FIGURES.......................................................................................................10
LIST OF APPENDICES................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................11
1
INTRODUCTION..................................................................................................................13
2
STUDY OBJECTIVES ..........................................................................................................15
2.1
Primary Objectives...................................................................................................15
2.2
Secondary Objectives...............................................................................................15
2.3
Exploratory Objective ..............................................................................................15
3
STUDY ENDPOINTS............................................................................................................16
3.1
Efficacy Endpoints ...................................................................................................16
3.1.1
Primary Efficacy Endpoints...................................................................................16
3.1.2
Secondary Efficacy Endpoints...............................................................................16
3.2
Health Economic Outcome Research Endpoints......................................................17
3.3
Safety Endpoints ......................................................................................................17
3.4
Exploratory Endpoints..............................................................................................17
4
INVESTIGATIONAL PLAN.................................................................................................18
4.1
Overall Study Design and Plan ................................................................................18
4.2
Rationale for Study Design ......................................................................................19
4.3
Study Duration .........................................................................................................20
5
STUDY POPULATION SELECTION ..................................................................................21
5.1
Study Population ......................................................................................................21
5.2
Inclusion Criteria......................................................................................................21
5.3
Exclusion Criteria.....................................................................................................21
6
STUDY TREATMENT..........................................................................................................22
6.1
Description of Treatment .........................................................................................22
6.2
Treatments Administered .........................................................................................22
6.3
Selection and Timing of Dose for Each Subject ......................................................22
6.4
Method of Assigning Subjects to Treatment Groups...............................................22
6.5
Masking....................................................................................................................22
6.6
Medications ..............................................................................................................22
6.7
Restrictions...............................................................................................................22
6.7.1
Prior Therapy .........................................................................................................22
6.7.2
Other Restrictions ..................................................................................................22
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6.7.3
Treatment Compliance...........................................................................................22
6.7.4
Packaging and Labeling.........................................................................................22
6.8
Storage and Accountability ......................................................................................22
7
STUDY PROCEDURES........................................................................................................23
7.1
Informed Consent.....................................................................................................23
7.2
Study Entrance Criteria and Eligibility....................................................................23
7.3
Study Enrollment......................................................................................................23
7.4
Demographics...........................................................................................................23
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference .......23
7.5.1
Length and Height..................................................................................................23
7.5.2
Body Weight ..........................................................................................................24
7.5.3
Head Circumference ..............................................................................................24
7.6
Efficacy Assessments...............................................................................................24
7.6.1
Visual Assessments................................................................................................24
7.6.1.1
Visual Acuity..........................................................................................24
7.6.1.2
Corrective Lens Determination ..............................................................25
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)..................25
7.6.1.4
Refraction with Cycloplegia...................................................................26
7.6.1.5
Stereoacuity............................................................................................26
7.6.1.6
7.6.2
Hearing Assessment History..................................................................................27
7.6.3
Behavioral Assessments.........................................................................................27
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition........27
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)..........27
7.6.3.3
Child Behavior Checklist (CBCL) .........................................................28
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition ............................28
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale.........................28
7.6.3.6
Social Communication Questionnaire – Lifetime Form ........................29
7.6.4
Cerebral Palsy Assessment ....................................................................................29
7.6.5
Pulmonary Morbidity Assessment.........................................................................29
7.6.6
Optional Cerebral Magnetic Resonance Imaging..................................................29
7.6.7
Survival Assessment..............................................................................................30
7.6.8
Health Economic Outcome Research Assessments...............................................30
7.6.8.1
Health Related Quality of Life...............................................................30
7.6.9
Health Care Resource Use .....................................................................................30
7.6.9.1
Health Status Classification System-Preschool......................................30
7.7
Safety Assessments ..................................................................................................31
7.7.1
Abdominal ultrasound............................................................................................31
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7.7.2
Echocardiogram .....................................................................................................31
7.7.3
Physical Examination.............................................................................................31
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate ................................................32
7.8
Medication Assessment............................................................................................32
7.9
Adverse Events Assessments ...................................................................................32
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions ................................................................32
7.9.1.1
Adverse Event ........................................................................................32
7.9.1.2
Serious Adverse Event ...........................................................................33
7.9.1.3
Suspected Unexpected Serious Adverse Reaction.................................34
7.9.1.4
Targeted Medical Events........................................................................34
7.9.2
Classification of Adverse Events and Serious Adverse Events.............................34
7.9.3
Clarification between Serious and Severe .............................................................35
7.9.4
Relatedness of Adverse Events and Serious Adverse Events................................35
7.9.5
Procedures for Recording and Reporting Adverse Events ....................................35
7.9.5.1
Adverse Event Monitoring and Period of Observation..........................35
7.9.5.2
Reporting Serious Adverse Events.........................................................36
7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting..................................................................................37
7.10
Removal of Subjects from the Trial .........................................................................37
7.11
Other Study Procedures............................................................................................38
7.11.1 Participation in Other Clinical Studies ..................................................................38
7.12
Appropriateness of Measurements...........................................................................38
8
STUDY ACTIVITIES............................................................................................................39
8.1
Initial Study Visit (40 weeks CA [term equivalent]) ...............................................39
8.2
Study Visits ..............................................................................................................39
8.2.1
Outcome Assessment Visits Conducted by Telephone .........................................40
8.2.2
Clinical Site Visits .................................................................................................40
8.2.2.1
Outcome Assessment Site Visits............................................................40
8.2.2.2
Visits Dedicated to Corrective Lens Determination...............................44
8.3
Assessments upon Discontinuation..........................................................................44
9
QUALITY CONTROL AND ASSURANCE ........................................................................45
10 STATISTICAL ANALYSES.................................................................................................46
10.1
General Methodology...............................................................................................46
10.2
Determination of Sample Size..................................................................................46
10.3
Method of Assigning Study Subjects to Treatment Groups.....................................46
10.4
Population Description.............................................................................................46
10.4.1 Analysis Populations..............................................................................................46
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10.4.2 Subject Disposition................................................................................................47
10.4.3 Protocol Violations and Deviations .......................................................................47
10.4.4 Demographics and Baseline Characteristics..........................................................47
10.5
Efficacy Analysis .....................................................................................................47
10.5.1 Primary Efficacy Analysis.....................................................................................47
10.5.2 Secondary Efficacy Analysis .................................................................................48
10.5.3 Subset Analyses .....................................................................................................49
10.5.4 Exploratory Analyses.............................................................................................49
10.6
Health Economics and Outcomes Research Analyses .............................................49
10.7
Analysis of Safety ....................................................................................................49
10.8
Statistical/Analytical Issues......................................................................................50
10.8.1 Adjustment for Covariates.....................................................................................50
10.8.2 Handling of Dropouts or Missing Data..................................................................50
10.8.3 Interim Analyses and Data Monitoring..................................................................50
10.8.4 Multiple Comparisons/Multiplicity .......................................................................50
10.8.5 Sensitivity Analyses...............................................................................................50
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................51
11.1
Investigators and Study Administrative Structure ...................................................51
11.2
Institutional Review Board or Independent Ethics Committee Approval................51
11.3
Ethical Conduct of the Study ...................................................................................51
11.4
Subject Information and Consent.............................................................................51
11.5
Subject Confidentiality.............................................................................................52
11.6
Study Monitoring .....................................................................................................53
11.7
Case Report Forms and Study Records....................................................................53
11.7.1 Case Report Forms.................................................................................................53
11.7.2 Critical Documents ................................................................................................53
11.8
Data Monitoring Committee ....................................................................................54
11.9
Protocol Violations/Deviations ................................................................................54
11.10
Premature Closure of the Study ...............................................................................55
11.11
Access to Source Documentation.............................................................................55
11.12
Data Generation and Analysis..................................................................................55
11.13
Retention of Data .....................................................................................................55
11.14
Financial Disclosure.................................................................................................56
11.15
Publication and Disclosure Policy............................................................................56
12 LIST OF REFERENCES........................................................................................................57
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LIST OF IN-TEXT TABLES
Table 7-1
Summary of Visual Acuity Assessments ......................................................25
Table 7-2
Assessments for Physical Examinations .......................................................32
Table 7-3
Adverse Event Severity.................................................................................35
Table 7-4
Adverse Event Relatedness ...........................................................................35
LIST OF IN-TEXT FIGURES
Figure 4-1
Overview of Study Design, Study SHP-607-201..........................................19
LIST OF APPENDICES
Appendix 1
Study Schedule of Events..............................................................................60
Appendix 2
Summary of Changes ....................................................................................64
Appendix 3
Protocol Signature Page ................................................................................65
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AAO
American Academy of Ophthalmology
ADHD
attention-deficit hyperactivity disorder
ADHD-RS
Attention-Deficit/Hyperactivity Disorder Rating Scale
AE
adverse event
ASD
Autism Spectrum Disorder
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CBCL
Child Behavior Checklist (1 ½ to 5)
CFR
Code of Federal Regulations
CA
corrected age
CI
confidence interval
CRF
case report form (electronic)
CRO
contract research organization
DMC
data monitoring committee
eCRF
electronic case report form
EOS
end of study
ETDRS
Early Treatment of Diabetic Retinopathy Study
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GH
growth hormone
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IND
Investigational New Drug application
IRB
institutional review board
LV
left ventricle
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
magnetic resonance imaging
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Abbreviation
Definition
OD
right eye
OS
left eye
OU
both eyes
PedsQL
Pediatric Quality of Life Inventory 
REB
research ethics board
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SCQ
Social Communication Questionnaire
SD
standard deviation
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
UK
United Kingdom
US
United States
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
VLBW
very low birth weight
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI
Wechsler Preschool and Primary Scale of Intelligence
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1
INTRODUCTION
Retinopathy of prematurity (ROP) is a rare disorder of the developing retinal blood vessels and 
retinal neurons of the preterm infant and is one of the leading causes of preventable blindness in 
children.1
Visual acuity is decreased in infants with a history of ROP.2 In addition to acuity, other aspects 
of eye health are also significantly impacted by ROP. Strabismus and myopia are clearly 
increased in patients with a history of ROP.3-6  Additionally, more than half of patients at 6 to 
10 years of age with a history of Stage 1 and Stage 2 ROP were reported to have ongoing visual 
issues.7
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. During fetal life, IGF-1 is available through placental 
absorption and ingestion from amniotic fluid.8 Deprivation of such factors is likely to cause 
inhibition or improper stimulation of important pathways, which in the eye may cause abnormal 
retinal vascular development, the hallmark of ROP.
The finding in both a mouse model of ROP and preterm infants that development of ROP is 
associated with low levels of IGF-1 after premature birth, indicates a possible role for 
replacement of IGF-1 to levels found in utero as a strategy to potentially decrease abnormal 
retinal vascularization and abnormal retinal neural development, and ultimately, ROP. 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) is the human recombinant form of the naturally 
occurring protein complex of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was developed to enhance the systemic exposure of administered rhIGF-1 
and to improve the safety profile of rhIGF-1 therapy. rhIGF-1/rhIGFBP-3 was approved by the 
Food and Drug Administration (FDA) in 2005 for the treatment of growth failure in children 
with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have 
developed neutralizing antibodies to GH. 
The pharmacokinetics and safety of rhIGF-1/rhIGFBP-3 have been evaluated in a Phase I study 
(ROPP-2005-01) and pharmacokinetics, safety, and efficacy are being evaluated in the ongoing 
phase II study (ROPP-2008-01). Sections A-C of the ROPP-2008-01 study are complete. 
Section D of the ROPP-2008-01 study is currently being conducted to assess pharmacokinetics, 
safety and efficacy of rhIGF-1/rhIGFBP-3 for the prevention of ROP in premature infants (up to 
a corrected age [CA] of 40 weeks [± 4 days]). Subjects in Study ROPP-2008-01 are randomly 
assigned to receive rhIGF-1/rhIGFBP-3 or standard neonatal care. The target dose of 
rhIGF-1/rhIGFBP-3 for Study Section D is 250 μg/kg/24 hours to be administered via 
continuous infusion starting on Study Day 0 (day of birth) and continuing through postmenstrual 
age (gestational age + time elapsed from birth) 29 weeks + 6 days.
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Although the rhIGF-1/rhIGFBP-3 therapy in Section D of the Phase II study 
(Study ROPP-2008-01) represents a short-term exposure (< 2 months for each subject), 
rhIGF-1/rhIGFBP-3 may have long-lasting effects on visual outcomes as well as other potential 
outcomes related to complications of prematurity such as neurodevelopment, pulmonary 
function, and growth. In addition, it is critical to understand any long term safety effects from 
short term exposure to rhIGF-1/rhIGFBP-3. 
The long-term outcomes assessed in this study will require utilization of different assessment 
tools than are utilized in the Phase II study, ROPP-2008-01 Section D, given the changes in 
physical and cognitive development that will occur in the subjects as they age during their 
participation in this study. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of rhIGF-1/rhIGFBP-3.
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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints

Visual acuity as assessed by an age-appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
3.1.2
Secondary Efficacy Endpoints

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

Physical development as assessed by standardized, age appropriate tools including 
physical examination, neurological examination for assessment of cerebral palsy, and 
hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) for the 
assessment of symptoms of attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3
(treated) or standard neonatal care (control). Enrolled subjects in this study will be 
followed through age 5 years CA. This study will enroll both subjects who were in the 
treated (received rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of 
Study ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term 
efficacy and safety outcomes versus standard neonatal care. No investigational product will be
administered in this study. 
In this study, the Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon 
discontinuation from Study ROPP-2008-01 or may occur any time up to the visit at 3 months 
CA. Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age of 
23 weeks + 0 days to 27 weeks + 6 days.
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. Both 
telephone and clinical site visits are included to help maintain contact with subjects throughout 
the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required. 
See Appendix 1 for the Study Schedule of Events table.
The overall study design is outlined in Figure 4-1.
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Insulin-like growth factor-1 (IGF-1) mediates its primary actions by binding to its specific 
receptor, the insulin-like growth factor 1 receptor (IGF-1R), which is present on many cell types 
in many tissues. Binding to its receptor initiates intracellular signaling including via the AKT 
signaling pathway. This pathway is involved in stimulation of cell division, growth and 
differentiation and inhibits programmed cell death. Specifically regarding premature infants, 
IGF-1 is an important mediator of fetal growth and has been shown to play a role in early 
postnatal growth following pre-term delivery.9,10
Insulin-like growth factor-1 (IGF-1) has also been shown to play a role in pulmonary 
development11 and neural development.12,13 Given the potential role for IGF-1 in the 
development of multiple systems, this study has been designed to evaluate the long-term effects 
of rhIGF-1/rhIGFBP-3, both from a safety and efficacy perspective, on the development of the 
premature infant.
4.3
Study Duration
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years CA.
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5
STUDY POPULATION SELECTION
5.1
Study Population
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks + 0 days to 27 weeks + 6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. Up to 
120 subjects are planned to be randomized in Study ROPP-2008-01 Section D.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject was randomized in Study ROPP-2008-01, Section D
2. Subject’s parent or legally authorized representative(s) must provide written informed 
consent prior to performing any study-related activities. Study-related activities are any 
procedures that would not have been performed during normal management of the subject.
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. Any other condition or therapy that, in the Investigator’s opinion, may pose a risk to the 
subject or interfere with the subject’s ability to be compliant with this protocol or interfere 
with the interpretation of results
2. The subject or subject’s parent or legally authorized representative(s) is unable to comply 
with the protocol as determined by the Investigator
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6
STUDY TREATMENT
6.1
Description of Treatment
No investigational product will be administered in this study.
6.2
Treatments Administered
Not applicable.
6.3
Selection and Timing of Dose for Each Subject
Not applicable.
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable.
6.5
Masking
Not applicable.
6.6
Medications
Any medications administered to the subjects will be collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued). Any 
investigational product received by subjects will be recorded separately as part of an assessment 
of subjects’ participation in other clinical studies (Section 7.11.1).
6.7
Restrictions 
6.7.1
Prior Therapy
There are no restrictions related to prior therapy.
6.7.2
Other Restrictions
There are no restrictions related to fluid or food intake, or subject activity.
6.7.3
Treatment Compliance
Not applicable.
6.7.4
Packaging and Labeling
Not applicable.
6.8
Storage and Accountability
Not applicable
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7
STUDY PROCEDURES
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events in Appendix 1). 
All data collected are to be recorded on the subject’s appropriate eCRF. 
Details for study procedures are described in the Operations Manual for this study.
7.1
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).
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 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria and Eligibility
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 informed consent is not obtained at or before the 3-month visit in Study ROPP-2008-01 for 
inclusion in this study (SHP607-201), the subject may still be enrolled until they turn 2 years CA
+3 months. Subjects are no longer eligible to participate in this study after they turn 2 years CA
+3 months. 
7.3
Study Enrollment
Subjects will be considered enrolled in the study once written informed consent has been 
obtained from the subject’s parent(s) or legally authorized representative(s).
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be recorded.
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference
7.5.1
Length and Height
Body length (supine measurement) will be collected when subjects are 24-months CA or 
younger. For the length measurement, the subject will be placed on his or her back so that the 
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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 when subjects are older than 24-months CA. 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). 
7.5.2
Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures 
(type of scale will depend upon subject’s age). Care should be taken to remove any extraneous 
clothing prior to measures and shoes should be removed.
The measure should be recorded to the nearest 0.1 kg.
7.5.3
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.
7.6
Efficacy Assessments
7.6.1
Visual Assessments
After corrective lens determination has occurred (Section 7.6.1.2), all visual assessments should 
be conducted with best-corrected vision, ie, with corrective lenses in place (if required); this 
applies to 24-month and 5-year visits.
7.6.1.1
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. It will be assessed by 
the methods summarized in Table 7-1; the method employed will be selected based on the 
subject’s age (CA) at the time of the study visit. Visual acuity measurements will be measured 
and recorded for the left (OS), right (OD) eye, and both eyes (OU).
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At ages 6 months and 12 months CA, visual acuity will be assessed with Teller acuity cards. At 
ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner 
determines that it will not be possible to perform an accurate assessment with the relevant LEA 
tool, visual acuity should be assessed with the Teller acuity cards. 
The visual acuity assessments should be performed by an optometrist or ophthalmologist trained 
in pediatrics. 
Table 7-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
7.6.1.2
Corrective Lens Determination
An assessment to determine if the subject requires vision correction with corrective lenses will 
be performed. This is being performed to ensure the accuracy of subjects’ subsequent visual 
acuity assessments (at the 24-month and 5-year visits). The corrective lens determination will be 
performed according to the guidelines published by the American Academy of Ophthalmology 
(AAO).14
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)
Ocular alignment will be assessed in primary gaze by comparing the position of the corneal light 
reflection in OS and OD (corneal light reflection assessment). Presence or absence of strabismus 
will be recorded in primary gaze and in as many of the 9 positions of gaze as feasible with the 
cover test assessment of refixation movement. Extraocular muscle over-action or deficiency will 
be recorded. The assessment will be performed according to the AAO guidelines.14
Presence or absence of nystagmus as observed during the ocular alignment assessments will also 
be recorded.
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7.6.2
Hearing Assessment History
Results of previously completed hearing assessments will be recorded at the 6-month CA and 
5-year CA visits; hearing tests are not being performed as part of this study. 
7.6.3
Behavioral Assessments
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition
The BSID-III will be used to assess cognitive, motor, and language skills, and is applicable to 
children aged 1 to 42 months. 
The BSID-III is an assessment tool designed to measure a young child's skills in the 3 core areas 
of development:  cognitive, language, and motor. There are 5 subscales, the cognitive subscale 
stands alone while 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 examiner's manual.
The BSID-III 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.
7.6.3.2
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.19  It is applicable to preschoolers and young children aged 
2 years + 6 months to 7 years + 7 months, and is a direct assessment of a child’s cognitive skills.
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 standardization20 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. Scores to be recorded 
are detailed in the Study Operations Manual.
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7.6.3.3
Child Behavior Checklist (CBCL)
The CBCL (1 ½ to 5) is a parent-reported outcome measure used to assess behavioral, emotional, 
and social functioning of toddlers and preschool children aged 18 to 60 months.21 It is composed 
of 99 items that are rated on a Likert scale and includes the following 7 syndrome scales 
arranged under 2 domains (ie, Internalizing and Externalizing Problems):22

Internalizing Problems

Emotionally Reactive

Anxious/Depressed

Somatic Complaints

Withdrawn

Sleep Problems

Attention Problems

Aggressive Behavior
The questionnaire is widely used and has been employed to assess long-term behavioral 
outcomes in children born prematurely, aged similarly to the subjects expected in this study 
population.22-24 It is associated with well-established normative data;25 norms may be selected to 
aid in interpretation of the scale scores.
The CBCL (1 ½ to 5) is a questionnaire that will be administered to 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.
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition
The VABS-II Expanded Interview Form will be used to measure the personal and social skills of 
subjects serially over time; these scales are organized within a 3-domain structure:  
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what he or she is able to do. 
The VABS-II Expanded Interview Form will be administered to 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.
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale
The ADHD-RS was developed to measure the behaviors of children with ADHD. The 
ADHD-RS consists of 18 items designed to reflect current symptomatology of ADHD based on 
DSM-IV 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. 
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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,26 will be completed by the subject’s parent(s) or legally authorized 
representative(s). Scores to be recorded are detailed in the Study Operations Manual.
7.6.3.6
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children27 that can be used for screening for autism or autism spectrum disorders in the general 
population.28
The SCQ will be completed by the subject’s parent(s) or legally authorized representative(s). 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.
7.6.4
Cerebral Palsy Assessment
Comprehensive neurological examination for the diagnosis of cerebral palsy (CP) will be 
conducted. The Amiel-Tison neurological examination framework29 will be utilized for this 
assessment and conducted by trained medical professionals.
7.6.5
Pulmonary Morbidity Assessment
Pulmonary morbidity will be assessed with questions related to family history and smoking 
status as well as diagnosis of select pulmonary symptoms, conditions and related 
hospitalizations. The assessment will be administered to the subject’s parent(s) or legally 
authorized representative(s). Assessments will be performed as outlined in the Schedule of 
Events (see Appendix 1). Questionnaires that will be used for these assessments at clinical site
visits are provided in the Study Operations Manual for the 6-month,12-month 24-month, and 
5-year CA visits. The questionnaire that will be used for these assessments during phone 
interviews at the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year CA visits is provided in the 
Study Operations Manual.
7.6.6
Optional Cerebral Magnetic Resonance Imaging
Participation in the MRI assessment is optional and has no impact on participating in the main 
study.  If consented to, magnetic resonance imaging (MRI) of the brain will be performed. 
The MRI may be performed with or without sedation. If the scan is performed without sedation 
and the first attempt is unsuccessful, a second attempt should be made. 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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7.6.7
Survival Assessment
Survival status will be assessed and recorded.
7.6.8
Health Economic Outcome Research Assessments
7.6.8.1
Health Related Quality of Life
Health-related quality of life (HRQoL) is an important outcome towards improving the health 
care of pediatric patients as it is that part of a person’s overall quality of life that is determined 
primarily by their health status and which can be influenced by clinical interventions. It is an 
important concept, which is also used in determining the value of health care services in this 
population.30,31 It is a multidimensional construct whose content is guided by the World Health 
Organization;32 minimally it includes physical, psychological (including emotional and 
cognitive), and social health dimensions.
In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL™) Scales appropriate for the child’s age of development.33-35  The development of the 
PedsQL was based on the delineations of the World Health Organization (WHO) and is a 
modular approach to assessing HRQoL in the pediatric population. Initially, the PedsQL Generic 
Scales were developed and continue to be used in children aged 2 to 18 years. More recently 
Infant Scales have been developed that apply to ages 1 to 24 months.34
The following scales will be used in this study:

Infant Scale for ages 1-12 months (36 Items)

Infant Scale for ages 13–24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent and may be conducted via telephone by 
clinical site staff. The scale(s) to be administered at each visit will be specified in the Study 
Operations Manual.
7.6.9
Health Care Resource Use
To understand the value of the investigational product administered in Study ROPP-2008-01 
(Section D), the resource use associated with inpatient visits, outpatient visits, and medical and 
pharmacy utilization in this study will be recorded. 
This assessment may be conducted via telephone by clinical site staff.
7.6.9.1
Health Status Classification System-Preschool
Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS), which is a validated instrument adapted for use via parent proxy 
within the pediatric population age 2.5 to 5 (adapted from the validated Health Utilities Index 
Mark 2 and 3 [HUI 2/3]).36  Validity of the HSCS-PS concepts has not been established for ages 
younger than 2.5 years.
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The HSCS-PS was developed to provide a consistent measure of health status in preschool-aged 
children who had been born prematurely.36 The system is applicable to children with special 
needs as may be included in this study; validation cohorts for the system included children with 
very low birth weight (VLBW), which is congruent with this study population.
The instrument is composed of 12 dimensions (Vision, Hearing, Speech, Mobility, Dexterity, 
Self-care, Emotion, Learn/remember, Think/problem solve, Pain, General Health, and Behavior) 
intended to provide a comprehensive assessment of a child’s health status as it pertains to 
health-related quality of life. The individual domains of the instrument will be scored as a mean 
score, representing the overall state for each concept individually. The global score will be 
recorded as well as the scores for each of the dimensions.
The HSCS-PS is a questionnaire that will be administered to the subject’s parent(s) or legally 
authorized representative(s) and may be conducted via telephone by clinical site staff.
7.7
Safety Assessments
7.7.1
Abdominal ultrasound
An abdominal ultrasound will be performed to assess the size of the spleen and kidneys. The 
spleen will be measured in the coronal longitudinal plane and the longest longitudinal length will 
be measured for each kidney (left and right).37 Ultrasound results will be assessed by a central 
reader.
Organ size will be interpreted in the context of reference values established for children.37,38
7.7.2
Echocardiogram
Echocardiographic examination (conventional M-mode recording of the left ventricle [LV] 
parasternal long axis view) will be performed for the evaluation of cardiac size, assessed by 
measuring the following:

interventricular septal thickness (during end diastole)

LV posterior wall thickness

LV intracavity volume (both in end diastole and end systole)
Echocardiogram results will be assessed by a central reader.
7.7.3
Physical Examination
Physical examinations will include a review of the subject’s general appearance, neurological 
examination, as well as a tonsillar examination (Table 7-2). Any abnormal change in findings 
will be recorded as an AE. 
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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Tonsils
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate
Blood pressure, heart rate, and respiratory will be measured at the 5-year CA visit.
7.8
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 7.11.1).
7.9
Adverse Events Assessments
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions
7.9.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset 
of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
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In this long-term outcome study in follow-up to Study ROPP-2008-01 (Section D), no 
investigational product is being administered. However, the relationship to the investigational 
product (rhIGF-1/rhIGFBP-3) as administered in Study ROPP-2008-01 (Section D) will be 
assessed. 
For the purposes of this study only the following adverse events will be collected:  

those considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP -2008-01, Section D)

those considered related to procedures performed in this study (Study SHP-607-201)

specified targeted medical events (Section 7.9.1.3) regardless of causality
Throughout the study, the Investigator must record AEs on the AE electronic case report form 
(eCRF), regardless of the severity. The Investigator should treat subjects with AEs appropriately 
and observe them at suitable intervals until the events stabilize or resolve. Adverse events may 
be discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given are regarded as AEs and 
will be documented on the appropriate pages of the eCRF. Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as 
AEs and must be documented as such in the eCRF.
7.9.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
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 one of the 
outcomes listed in this definition. 
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A life-threatening AE is defined as an AE that placed the subject, in the view of the initial 
reporter, at immediate risk of death from the AE as it occurred (ie, it does not include an AE that, 
had it occurred in a more severe form, might have caused death).
For the purposes of this study only SAE listed in the following will be collected:

fatal SAEs regardless of causality

SAEs related to ROP

SAEs related to congenital malformations not identified at birth which may impact 
neurocognitive development 
7.9.1.3
Suspected Unexpected Serious Adverse Reaction
Suspected unexpected serious adverse reactions (SUSAR) are suspected adverse reactions related 
to an investigational product (investigational products and comparators [if applicable]), which 
occur in the concerned study, and that are both serious and unexpected according to the current 
Investigator’s Brochure.
7.9.1.4
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, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D):

intracranial hypertension

any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and 
diabetes)

tonsillar hypertrophy (based on tonsil exam [part of the physical exam])

increased kidney size 

increased cardiac size

increased spleen size
7.9.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
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Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.9.3
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.9.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product (rhIGF-1/rhIGFBP-3 as administered in 
Study ROPP-2008-01, Section D) is to be determined by the Investigator based on the following 
definitions (See Table 7-4).
Table 7-4
Adverse Event Relatedness
Relationship to Product
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, follows a known or suspected response 
pattern to the investigational product, is confirmed by improvement 
upon stopping the investigational product (de-challenge), and 
reappears upon repeated exposure (re-challenge). Note that this is not 
to be construed as requiring re-exposure of the subject to 
investigational product; however, the determination of definitely 
related can only be used when recurrence of event is observed.
7.9.5
Procedures for Recording and Reporting Adverse Events
7.9.5.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored throughout the study. 
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If a subject or the subject’s parent(s) or the subject’s legally authorized representative(s) acting 
on behalf of the subject, discontinues participation in the study, or the subject is discontinued by 
the Investigator, reasonable efforts will be made to follow the subject through the end of study 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the subject withdraws from the study, the subject will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.11
Other Study Procedures
7.11.1
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in another 
clinical study that involves 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 being evaluated in the study, and the subject’s treatment assignment 
in the study (if possible). 
7.12
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. These are the pulmonary 
morbidity assessment and the cerebral palsy assessment. In these cases, the tools are either based 
on validated tools or the current state of knowledge in the literature. For example, the cerebral 
palsy assessment is based on the Amiel-Tison neurological examination framework29 and the 
pulmonary assessment is based on published research in a similar pediatric population39,40.
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8
STUDY ACTIVITIES
The timing of the visits in this study is based on subjects’ corrected age (CA). 
8.1
Initial Study Visit (40 weeks CA [term equivalent])
The Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon discontinuation from 
Study ROPP-2008-01, Section D or any time up to the visit at 3 months CA. 
For subjects enrolled between the ages of 9 months CA and 2 years +3 months CA, missed 
procedures such as neurocognitive assessments, abdominal ultrasounds, and echocardiograms are 
not required.
At the Initial Visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data.
The following AE data, collected as part of Study ROPP-2008-01 (Section D) will be recorded:

Ongoing targeted medical events regardless of causality

Ongoing study drug-related AEs, including SAEs
SAEs, as outlined in Section 7.9.1.1 and Section 7.9.1.2, that the subject experiences between the 
ROPP-2008-01 end-of-study visit and the time of informed consent for the SHIP-607-201 study 
will be reported by the Investigator, pending permission for subject’s parent or legally authorized 
representative(s), as documented on the informed consent form.
8.2
Study Visits
Study visits for follow-up outcome assessments will take place at the following time points in 
CA:

3 months (±2 weeks) – conducted by telephone

6 months (±1 month) – clinical site visit

12 months (±3 months) – clinical site visit

20 months (-1 months) – clinical site visit

24 months (±3 months) – clinical site visit

30 months (±3 months) – conducted by telephone

3 years (±3 months) – conducted by telephone

3.5 years (±3 months) – conducted by telephone

4 years (±3 month) – conducted by telephone

4.5 years (±3 month) – conducted by telephone

4.75 years (-1 months) – clinical site visit

5 years (+6 months) – clinical site visit
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In addition, there will be 2 visits that must occur at least 1 month prior to the 24-month and 
5-year CA study visits to assess the need for corrective lenses. The timing of these 2 visits 
(20 months [-1 month] and 4.75 years [-1 month]) was set to ensure that any prescribed 
corrective lenses would be worn for at least 1 month prior to the visual assessments at the 
24-month and 5-year study visits CA.
The activities at the study visits are described in Sections 8.2.1 and 8.2.2.
8.2.1
Outcome Assessment Visits Conducted by Telephone
Visits at 3 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted by 
telephone. The following outcome assessments will be conducted at each of these 6 visits, unless 
otherwise indicated:

HRQoL (3-month, 3-year, and 4-year visits)

HCRU (3-month, 3-year, and 4-year visits) 

HSCS-PS (3-year and 4-year visits)

Pulmonary morbidity assessment (30-month, 3-year, 3.5-year, 4-year, and 4.5-year 
visits)

Medications (3-month, 30 months, 3-year, 3.5 year, 4-year and 4.5 year visits)

Survival assessment (3-month, 30 month, 3-year, 3.5 year, 4-year and 4.5 year visits)

Assessment of participation in other clinical studies (3-month, 30 months, 3-year, 3.5 
year, 4-year and 4.5 year visits) 

Adverse events, including targeted medical events (3-month, 30 month, 3-year, 3.5 
year, 4-year and 4.5 year visits) 
8.2.2
Clinical Site Visits
8.2.2.1
Outcome Assessment Site Visits
The following clinical site visits (in CA) to capture follow-up outcome data will occur at the 
clinical site:

6 months (±1 month)

12 months (±3 months) 

20 months (-1 month)

24 months (±3 months)

4.75 years (-1 months)

5 years (+6 months)
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The following assessments will be performed at the 6-month visit:

Visual acuity

Refraction with cycloplegia

Length

Weight

Head circumference

VABS-II

Physical examination (including tonsil examination)

Hearing Assessment History (Historical hearing test data may be recorded at any time 
prior to the 6-month visit) 

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Abdominal ultrasound

Echocardiogram

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 12-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

VABS-II

Physical examination (including tonsil examination)

Pulmonary morbidity assessment
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
Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 20-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Assessment of participation in other clinical studies
The following assessments will be performed at the 24-month visit:

Visual acuity

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

CBCL

VABS-II

Physical examination (including tonsil examination)

Cerebral Palsy assessment

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)
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
Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at 4.75-year visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)
The following assessments will be performed at the 5-year visit:

Visual acuity

Ocular alignment and motility

Stereoacuity

Height

Weight

WPPSI

CBCL

VABS-II

ADHD-RS

SCQ

Physical examination (including tonsil examination)

Blood pressure, heart rate, and respiratory rate

Pulmonary morbidity assessment

Hearing assessment history

Survival assessment


Cerebral MRI

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies
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
Medications

Adverse events (including targeted medical events)
8.2.2.2
Visits Dedicated to Corrective Lens Determination
The following clinical site visits are dedicated solely to corrective lens determination in 
preparation for the outcome assessment visits at 24-months and 5-years CA:

20 months (-1 month) 

4.75 years (-1 month) 
At these visits, the following will be performed:

Visual acuity

Corrective lens determination (includes refraction with cycloplegia)
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior 
to the 24-month and 5-year visits, respectively. Any prescribed corrective lenses must be worn 
for at least 1 month prior to the 24 month and 5 year assessments.
8.3
Assessments upon Discontinuation
If a subject discontinues prior to the 5-year CA visit, every attempt will be made to complete the 
assessments scheduled for the subject’s next visit. 
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 Code of Federal Regulations (CFR) Part 
11 Guidance. The clinical trial database will include an audit trail to document any evidence of 
data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses 
will be performed by the Biometrics department at Shire. Statistical analyses will be performed 
using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3
or standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be extracted and summarized with the data from this study (SHP-607-201).
For consented patients, additional biomarker analysis may be performed on prior collected blood 
samples from Study ROPP-2008-01.
10.2
Determination of Sample Size
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study.
10.3
Method of Assigning Study Subjects to Treatment Groups
Not applicable.
10.4
Population Description
10.4.1
Analysis Populations
Enrolled Population- the Enrolled Population will consist of all subjects for whom written 
informed consent has been provided for this study. 
Safety Population- the Safety Population will consist of the subjects in the Enrolled Population
who have safety follow-up data in this long-term outcome study.
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10.4.2
Subject Disposition
Subjects who complete the study and subjects who prematurely discontinue from the study will 
be summarized by treatment group using descriptive statistics. In addition, for subjects who 
prematurely discontinue from the study, the reasons for discontinuation will be summarized by 
treatment group.
10.4.3
Protocol Violations and Deviations
Protocol violations and deviations will be listed. Details of the criteria for deviations and 
violations will be provided in the SAP.
10.4.4
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for the Enrolled Population. 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. Continuous variables such as age (including corrected age), weight, and 
length/height will be summarized using number of observations, mean, standard deviation, 
median, minimum and maximum values. Categorical variables, like gender and race, will be 
summarized using number of observations and percentages.
Medical history, including maternal and perinatal history, (as obtained from the antecedent 
study, ROPP-2008-01) will be summarized by treatment group using the number of observations 
and percentages of subjects reporting each category.
10.5
Efficacy Analysis
All efficacy analyses will be performed using the Enrolled Population.
10.5.1
Primary Efficacy Analysis
The primary efficacy endpoints consist of the following:

Visual Acuity:  Visual acuity will be categorized as the following: 
o
normal (measurable acuity ≥20/40), 
o
below normal (20/200≤measurable acuity <20/40), 
o
poor (measurable acuity ≤20/200)
o
blind/low vision (only the ability to detect the 2.2 cm wide stripes on the 
low-vision Teller acuity card and at any location in the visual field). 
The number and proportion of patients within each category listed above will be 
summarized by treatment group and visit. In addition, acuity results in the normal and 
below normal categories will be classified as favorable outcomes, and acuity results in 
the poor and blind/low-vision categories will be classified as unfavorable outcomes. 
Tabular summaries by treatment group and visit will include the frequency and the 
percentage for each visual acuity category. 
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In addition, shift tables of favorable outcomes from baseline (first assessment during 
this study) to each of the subsequent assessments, including the last assessment, will 
be presented by treatment group.

Ocular Alignment and Oculomotor Exam (Motility):  Findings from the ocular 
motility assessment will be either presence or absence of strabismus (esotropia, 
exotropia, hypertropia, or hypotropia). Tabular summaries by treatment group and 
visit will include the frequency and the percentage in each category. In addition, shift 
tables from baseline (first assessment during this study) to the last assessment will be 
provided by treatment group.

Nystagmus:  Presence or absence of nystagmus will be summarized by treatment 
group and visit

Refraction with Cycloplegia:  Findings from the refraction with cycloplegia will be 
summarized by treatment group and visit

Stereoacuity:  Presence or absence of stereopsis will be summarized by treatment 
group and visit
10.5.2
Secondary Efficacy Analysis

Growth Parameters (body weight, body length [and height], and head circumference):  
A standard Z-score, utilizing WHO child growth standards, will be calculated for each 
assessment by adjusting age- and sex- matched means and standard deviations (norm). 
The descriptive statistics of the Z-score for each of these parameters will be 
summarized at each assessment and the corresponding change from baseline. When 
appropriate, a 95% CI for the corresponding mean change within each group and the 
difference in the mean change between the 2 treatment groups and the corresponding 
95% CI will be presented as appropriate. If the parametric assumption for the 
distribution of the above endpoints cannot be justified, a non-parametric approach will 
be utilized to estimate the treatment difference (ie, median difference or 
Hodges-Lehmann estimator and the corresponding confidence intervals)

BSID-III and WPPSI:  The raw score, age equivalent scores, and standard scores for 
each domain within each questionnaire will be summarized by treatment group and 
visit using descriptive statistics.

ADHD-RS:  ADHD-RS total score and subscales (Hyperactivity/Impulsivity and 
Inattentiveness) will be summarized by treatment group and visit using descriptive 
statistics.

SCQ:  The SCQ subscales (communication and social) will be summarized by 
treatment group and visit using descriptive statistics

VABS-II:  The raw score, age equivalent scores, and standard scores for each domain 
of the scale will be summarized by treatment group and visit using descriptive 
statistics.

CBCL:  The raw score and change from baseline for each domain of the scale will be 
summarized by treatment group and visit using descriptive statistics.
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
Pulmonary morbidity assessment:  The binary response of each question will be by 
treatment group and visit using descriptive statistics.

Survival:  For subjects who have an event (ie, death), the event time will be calculated 
as the length of time from the subject’s date of birth to death during the study due to 
any cause. Subjects who do not have an event (ie, death) during the study will be 
censored at the end of the study. The survival endpoint will be analyzed by treatment 
group using Kaplan-Meier methods.
10.5.3
Subset Analyses
Subgroup analyses may be explored based on factors that may have influence on the efficacy or 
safety endpoints. Subgroup analyses will be specified in the SAP.
10.5.4
Exploratory Analyses
10.6
Health Economics and Outcomes Research Analyses
For PedsQL, descriptive statistics will be provided for summary scores by treatment group 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 and at each time point.
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.
10.7
Analysis of Safety
Safety summaries will be based on all assessments post-baseline. The safety data will be 
assessed by AE monitoring, change in cardiac size, and kidney and spleen size over time. 
Adverse events will be summarized by system organ class and preferred term for each treatment 
group and overall, the number and percentage of subjects having any AE, having an AE in each 
body system and having each individual AE. In addition, those events which resulted in death, or 
were otherwise classified as serious will be presented in a separate listing. In addition, the 
summary of AEs will be presented by severity and relationship to trial medication. 
The change in cardiac size, and size of kidney and spleen will be assessed at the 6-month CA 
visit via echocardiogram and abdominal ultrasound, respectively.  These data will be analyzed as 
a binary response (ie, normal/abnormal) and summarized using frequency count.  The number 
and proportion of patients with each category (ie, normal/abnormal) for each of these safety 
endpoints will be summarized by treatment group.  
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In addition, the 2-sided 95% CI for the proportion of patients with a normal status for each of the 
endpoints will be estimated by treatment group.
Physical examinations findings will be summarized descriptively. 
10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
If any baseline data are imbalanced and are considered to be clinically relevant, between-group 
comparisons for efficacy outcomes will be adjusted for covariates and detailed in the SAP. 
10.8.2
Handling of Dropouts or Missing Data
Handling of missing data rules will be described in the SAP.
10.8.3
Interim Analyses and Data Monitoring
An interim analysis will be performed after all data from all enrolled subjects in this study have 
either completed 2-year follow-up (24-month visit) assessments or have prematurely withdrawn 
from the study (before completing 2 years of follow-up) has been entered into the database, 
queried and discrepancies resolved. A full 2-year study report based on these data, including 
efficacy and safety endpoint analyses, will be completed.
Additionally, descriptive analyses of the data at other time points before study completion may 
be performed for safety monitoring, regulatory reporting or general planning purposes.
10.8.4
Multiple Comparisons/Multiplicity
Not applicable.
10.8.5
Sensitivity Analyses
Sensitivity analyses for the efficacy outcomes will be detailed in the SAP, as necessary.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 and Investigator Agreement. Curriculum vitae must be provided for the Investigators 
and sub-investigators listed on Form FDA 1572 or Investigator Agreement. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, and their study related duties and functions. 
The Investigator must maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form. This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study. Within 3 months of study completion or termination, 
a final report must be provided to the IRB/IECREB. A copy of these reports will be sent to the 
study clinical monitor. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are reported to the US (FDA or other Regulatory agencies (Safety Reports) must be 
submitted promptly to the IRB/IEC/REB.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s) or legally 
authorized representative(s) must consent to participate after the nature, scope, and 
possible consequences of the clinical study have been explained in a form understandable to 
him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. 
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The informed consent (or assent) form must be in a language understandable to the subject or the 
subject’s parent(s) or legally authorized representative(s) and must specify who informed the 
subject, the subject’s parent(s), or the subject’s legally authorized representative(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the subject, the subject’s parent(s) or the subject’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the Sponsor. Only the subject number - will be recorded in 
the eCRF, and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The subjects will be told that 
representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified.
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11.6
Study Monitoring
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Electronic case report forms (eCRFs) are provided for each subject. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the Investigator to ensure that the following documents are available to Sponsor 
or their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed 
within 12 months of study initiation)

Copy of Investigator and sub-investigator(s) current medical license (indicating 
license number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC/REB clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written 
information to be provided regarding subject recruitment procedures

Copy of IRB/IEC/REB approved Subject Information/Informed Consent Form/any 
other written information/advertisement (with IRB approval stamp and date of 
approval)
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
Current list of IRB/IEC/REB Committee members/constitution (dated within 
12 months prior to study initiation)

Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
Given that any long-term safety signal observed in this study could impact the safety profile of 
rhIGF-1/rhIGFBP-3 as administered in premature neonates being enrolled in the antecedent 
study (ROPP-2008-01, Section D), the Data Monitoring Committee (DMC) for Study 
ROPP-2008-01 will review safety data from this long-term outcome study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities, where applicable, 
have given approval/favorable opinion. Modifications to the protocol will not be made without 
agreement of the Sponsor. Changes to the protocol will require written IRB/IEC/REB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable 
regulatory authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The 
Sponsor will submit all protocol modifications to the regulatory authorities, where applicable, in 
accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC/REB.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to the FDA or other applicable international regulatory authority 
before initiation, if applicable.
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11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC/REB, or the Sponsor may request access to all source 
documents, eCRFs, and other study documentation for onsite audit or inspection. Direct access to 
these documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. The Sponsor or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-Drug Dictionary (WHO-DD). Central reads 
will be employed as described in the study manual to aid in consistent measurement of 
abdominal ultrasound and echocardiogram parameters. 
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
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11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other study personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with the Sponsor, 
provided the Sponsor a copy of the draft document intended for publication, and obtained the 
Sponsor’s written consent for such publication. All information obtained during the conduct of 
this study will be regarded as confidential. 
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32. Constitution of the World Health Organization:  basic document. Geneva, Switzerland:  
World Health Organization; 1948.
33. Varni JW, Limbers CA. The pediatric quality of life inventory:  measuring pediatric health-
related quality of life from the perspective of children and their parents. Pediatr Clin North 
Am 2009;56:843-63.
34. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL Infant Scales:  feasibility, internal 
consistency reliability, and validity in healthy and ill infants. Quality of life research :  an 
international journal of quality of life aspects of treatment, care and rehabilitation 
2011;20:45-55.
35. Varni JW, Seid M, Kurtin PS. PedsQL 4.0:  reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical 
care 2001;39:800-12.
36. Saigal S, Rosenbaum P, Stoskopf B, et al. Development, reliability and validity of a new 
measure of overall health for pre-school children. Quality of life research :  an international 
journal of quality of life aspects of treatment, care and rehabilitation 2005;14:243-57.
37. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal 
children. Am J Roentgenol 1984;142:467-9.
38. Rosenberg HK, Markowitz RI, Kolberg H, Park C, Hubbard A, Bellah RD. Normal splenic 
size in infants and children:  sonographic measurements. Am J Roentgenol 1991;157:119-21.
39. Stevens TP, Finer NN, Carlo WA, et al. Respiratory Outcomes of the Surfactant Positive 
Pressure and Oximetry Randomized Trial (SUPPORT). J Pediatr 2014;165:240-9.e4.
40. Zivanovic S, Peacock J, Alcazar-Paris M, et al. Late outcomes of a randomized trial of high-
frequency oscillation in neonates. N Engl J Med 2014;370:1121-30.
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Appendix 1
Study Schedule of Events
Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Informed Consent
•
Eligibility Criteria
•
Demographics
•
Visual acuitya
•
•
•
•
•
•
Corrective lens determinationh
•
•g
•g
Ocular alignment and motility
•
•
•
Refraction with cycloplegiah
•
Stereoacuity
•
Length
•
•
•
Height
•
Weight
•
•
•
•
Head Circumference
•
•
•
BSID-III
•
•
WPPSI
•
CBCL
•
•
VABS-II
•
•
•
•
ADHD-RS
•
SCQ
•
Physical Examination including 
tonsil examination 
•
•
•
•
Blood Pressure, Heart Rate, and 
Respiratory Rate
•
Cerebral Palsy Assessment
•
Hearing Assessment Historyb
•
•
Pulmonary Morbidity Assessment 
1
•
•
Pulmonary Morbidity Assessment 
2  (clinical site visit)
•
•
Pulmonary Morbidity Assessment 
(phone interview)
•
•
•
•
•
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Clinical Trial Protocol: SHP-607-201
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Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Survival assessment
•
•
•
•
•
•
•
•
•
•
Cerebral MRI
•
HRQoLc
•
• i
• i
•i
•
•
• i
HCRU
•
• i
• i
•i
•
•
• i
HSCS-PS
•i
•
•
• i
Abdominal Ultrasound
•
Echocardiogram
•
Assessment of Participation in 
Other Clinical 
Studies
•
•
•
•
•
•
•
•
•
•
Medications
•
•
•
•
•
•
•
•
•
•
Adverse eventsd
•j
•
•
•
•
•
•
•
•
•
•
Abbreviations:  ADHD-RS = Attention-Deficit/Hyperactivity Disorder Rating Scale; BSID-III = Bayley Scales of Infant and Toddler Development-Third 
Edition, CBCL = Child Behavior Checklist; CA = corrected age; HCRU = health care resource use; HRQoL = health-related quality of life; HSCS-PS = Health 
Status Classification System; mth(s) = months; 
; PedsQL = Pediatric Quality of Life Inventory; SCQ = Social 
Communication Questionnaire; VABS-II = Vineland Adaptive Behavior Scales, Second Edition; wks = weeks; WPPSI = Wechsler Preschool and Primary 
Scale of Intelligence
a
The tools used to assess visual acuity will change as the subject ages during their participation in the study. The tools that will be used in this study and are 
summarized by applicable study visit in Table A1.
b
Historical hearing test data may be recorded at any time during the study prior to the 6-month visit.
c
HRQoL will be assessed via the validated PedsQL™ scales appropriate for the child’s age of development as specified in the Study Operations Manual.
d
Adverse event collection will include an assessment of the specified targeted medical events.
e
The Initial Visit may be performed prior to 40 weeks CA for any subject who discontinued from Study ROPP-2008-01 and, for all subjects, any time after 
40 weeks CA, up to the study visit to occur at 3 months CA.
f
Visits at 3 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted by telephone.
g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments.
h
Refraction with cycloplegia will be performed as part of the corrective lens determination procedure.
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Clinical Trial Protocol: SHP-607-201
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
11 May 2017
Procedures
Initial Study 
Visite
Months (CA)
Years (CA)
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
i
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through clinical site staff if 
there are time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through clinical site staff 
and may be performed at any time within the visit window.
j
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201):  any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
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Clinical Trial Protocol: SHP-607-201
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
11 May 2017
Table A1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
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Clinical Trial Protocol: SHP-607-201
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
11 May 2017
Appendix 2
Summary of Changes
Description of Change
Section(s) Affected
Added hearing assessment history to the 6-month CA visit.
Section 7.6.2
Added language explaining that cerebral magnetic resonance 
imagining (MRI) procedures are optional.  Language was also 
added explaining that the nature, scope, risks, benefits, and potential 
sedation associated with cerebral MRI will be explained to the 
subject and subject’s parent(s) or legally authorized 
representative(s).
Section 7.6.6
Added cerebral MRI to the 5-year CA visit.
Section 7.6.6
Section 8.2.2.1
Appendix 1
Added medications, survival assessment, assessment of 
participation in other clinical studies and adverse events, including 
targeted medical events to the 30 months, 3.5 years, 4.5 years CA 
visits conducted by telephone.
Section 8.2.1
Appendix 1
Clarified that age equivalent scores and standard scores will be 
summarized for Bayley Scales of Infant and Toddler Development, 
Third Edition (BSID-III), Wechsler Preschool and Primary Scale of 
Intelligence (WPPSI), and Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II).
Section 10.5.2
Removed the pulmonary morbidity assessments from the 
appendices as they will be provided in the Study Operations 
Manual.
Section 7.6.5
(formerly) Appendix 2,
(formerly) Appendix 3, 
(formerly) Appendix 4
Administrative errors were corrected throughout the protocol.
All sections
For non-commercial use only


Appendix 3 
Protocol Signature Page 
Study Title: 
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 
Previously Treated with rhIGF-1/rhIGFBP-3 for the Prevention of 
Retinopathy of Prematurity (ROP) or Who Received Standard Neonatal 
Care 
Study Number: 
SHP-607-201 
Final Date: 
11 May 2017 
Version  
Amendment 3 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
Signatory: 
Investigator 
Signature 
Date 
Printed Name 
I have read and approve the protocol described above. 
Signatory: 
Shire Medical 
Monitor  
Signature 
Date 
 MD, MPH 
Printed Name 
 .BZ 
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CONFIDENTIAL 
Page 65 
Clinical Trial Protocol: SHP-607-201 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) 
11 May 2017 
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For non-commercial use only


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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018

Study Endpoints
The primary efficacy endpoints of this study are:

Visual acuity as assessed by an age appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
The secondary efficacy endpoints of this study are:

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

Physical development as assessed by the following standardized, age appropriate tools:
o
Physical exam
o
Neurological examination for assessment of cerebral palsy
o
Hearing assessment
o
Blood pressure, heart rate, and respiratory rate

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) for the 
assessment of symptoms of attention deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism 
Spectrum Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
The exploratory efficacy endpoints of this study are:


The health economic outcome research endpoints of this study are:

Health-related quality of life (HRQoL) will be assessed by the Pediatric Quality of Life 
Inventory (PedsQL™) Scales appropriate for the child's age of development with the 
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Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018
Total Scale Score and 5 domains within Physical Health (Physical Functioning and 
Physical Symptoms) and Psychosocial Health Scores (Emotional, Social, and 
Cognitive Functioning, respectively)

Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS) and the Health Utilities Index Mark 2 (HUI2) and Mark 
3 (HUI3)

Resource use associated with inpatient visits, outpatient visits, medical utilization and  
pharmacy utilization will be assessed 
The safety endpoints of this study are:

Physical examination including tonsil examination

Adverse events (AEs), as follows:  
o
those considered related to rhIGF-1/rhIGFBP-3 (as administered in Study 
ROPP-2008-01, Section D)
o
those considered related to procedures performed in this study (Study 
SHP-607-201)
o
specified targeted medical events regardless of causality
o
fatal SAEs regardless of causality

Cardiac size as assessed by echocardiogram 

Kidney and spleen size and any other gross abnormalities as assessed by abdominal 
ultrasound
Study Population:  
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks + 0 days to 27 weeks + 6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. Up to 
120 subjects are planned to be randomized into Study ROPP-2008-01 Section D.
Study Design:
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01. Enrolled subjects in this study will be 
followed through age 5 years corrected age (CA). This study will enroll both subjects who were in 
the treated (received rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of 
Study ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term efficacy 
and safety outcomes versus standard neonatal care. No investigational product will be 
administered in this study. 
Study Duration:
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years corrected age (CA).
Study Inclusion and Exclusion Criteria:
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study. 
Subjects will not be excluded from participating in other clinical studies.
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Efficacy Assessments:
Efficacy will be assessed by visual outcomes, growth parameters, cognitive development, physical 
development, child behavior, pulmonary morbidity, and survival.
Safety Assessments:
Safety will be assessed by physical examination (including tonsil examination), AEs (as
specified), echocardiogram, and abdominal ultrasound.
Statistical Methods
Details regarding the statistical methods and definitions will be provided in the Statistical Analysis 
Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses will be 
performed by the sponsor or CRO after the database is locked. Statistical analyses will be 
performed using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or 
standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be summarized with the data from this study (SHP-607-201).
Date of Original Protocol:  27 August 2014
Date of Amendment 1: 19 February 2016
Date of Amendment 2: 21 February 2017
Date of Amendment 3: 11 May 2017
Date of Amendment 4: 09 April 2018
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09 Apr 2018
TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
LIST OF IN-TEXT TABLES ........................................................................................................10
LIST OF IN-TEXT FIGURES.......................................................................................................10
LIST OF APPENDICES................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................11
1
INTRODUCTION..................................................................................................................13
2
STUDY OBJECTIVES ..........................................................................................................15
2.1
Primary Objectives...................................................................................................15
2.2
Secondary Objectives...............................................................................................15
2.3
Exploratory Objectives.............................................................................................15
3
STUDY ENDPOINTS............................................................................................................16
3.1
Efficacy Endpoints ...................................................................................................16
3.1.1
Primary Efficacy Endpoints...................................................................................16
3.1.2
Secondary Efficacy Endpoints...............................................................................16
3.1.3
Exploratory Efficacy Endpoints.............................................................................16
3.2
Health Economic Outcome Research Endpoints......................................................17
3.3
Safety Endpoints ......................................................................................................17
4
INVESTIGATIONAL PLAN.................................................................................................18
4.1
Overall Study Design and Plan ................................................................................18
4.2
Rationale for Study Design ......................................................................................19
4.3
Study Duration .........................................................................................................20
5
STUDY POPULATION SELECTION ..................................................................................21
5.1
Study Population ......................................................................................................21
5.2
Inclusion Criteria......................................................................................................21
5.3
Exclusion Criteria.....................................................................................................21
6
STUDY TREATMENT..........................................................................................................22
6.1
Description of Treatment .........................................................................................22
6.2
Treatments Administered .........................................................................................22
6.3
Selection and Timing of Dose for Each Subject ......................................................22
6.4
Method of Assigning Subjects to Treatment Groups...............................................22
6.5
Masking....................................................................................................................22
6.6
Medications ..............................................................................................................22
6.7
Restrictions...............................................................................................................22
6.7.1
Prior Therapy .........................................................................................................22
6.7.2
Other Restrictions ..................................................................................................22
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6.7.3
Treatment Compliance...........................................................................................22
6.7.4
Packaging and Labeling.........................................................................................22
6.8
Storage and Accountability ......................................................................................22
7
STUDY PROCEDURES........................................................................................................23
7.1
Informed Consent.....................................................................................................23
7.2
Study Entrance Criteria and Eligibility....................................................................23
7.3
Study Enrollment......................................................................................................23
7.4
Demographics...........................................................................................................23
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference .......23
7.5.1
Length and Height..................................................................................................23
7.5.2
Body Weight ..........................................................................................................24
7.5.3
Head Circumference ..............................................................................................24
7.6
Efficacy Assessments...............................................................................................24
7.6.1
Visual Assessments................................................................................................24
7.6.1.1
Visual Acuity..........................................................................................24
7.6.1.2
Corrective Lens Determination ..............................................................25
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)..................25
7.6.1.4
Refraction with Cycloplegia...................................................................26
7.6.1.5
Stereoacuity............................................................................................26
7.6.2
Hearing Assessment History..................................................................................26
7.6.3
Behavioral Assessments.........................................................................................26
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition........26
7.6.3.2
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)..........27
7.6.3.3
Child Behavior Checklist (CBCL) .........................................................27
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition ............................28
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale.........................28
7.6.3.6
Social Communication Questionnaire – Lifetime Form ........................28
7.6.4
Cerebral Palsy Assessment ....................................................................................29
7.6.5
Pulmonary Morbidity Assessment.........................................................................29
7.6.6
..........................................................................
7.6.7
..................................................
7.6.8
Survival Assessment..............................................................................................29
7.6.9
Health Economic Outcome Research Assessments...............................................30
7.6.9.1
Health Related Quality of Life...............................................................30
7.6.10 Health Care Resource Use .....................................................................................30
7.6.10.1
Health Utility..........................................................................................30
7.7
Safety Assessments ..................................................................................................31
7.7.1
Abdominal ultrasound............................................................................................31
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7.7.2
Echocardiogram .....................................................................................................31
7.7.3
Physical Examination.............................................................................................32
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate ................................................33
7.8
Medication Assessment............................................................................................33
7.9
Adverse Events Assessments ...................................................................................33
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions ................................................................33
7.9.1.1
Adverse Event ........................................................................................33
7.9.1.2
Serious Adverse Event ...........................................................................34
7.9.1.3
Suspected Unexpected Serious Adverse Reaction.................................35
7.9.1.4
Targeted Medical Events........................................................................35
7.9.2
Classification of Adverse Events and Serious Adverse Events.............................35
7.9.3
Clarification between Serious and Severe .............................................................36
7.9.4
Relatedness of Adverse Events and Serious Adverse Events................................36
7.9.5
Procedures for Recording and Reporting Adverse Events ....................................36
7.9.5.1
Adverse Event Monitoring and Period of Observation..........................36
7.9.5.2
Reporting Serious Adverse Events.........................................................37
7.9.5.3
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting..................................................................................38
7.10
Removal of Subjects from the Trial .........................................................................38
7.11
Other Study Procedures............................................................................................39
7.11.1 Participation in Other Clinical Studies ..................................................................39
7.12
Appropriateness of Measurements...........................................................................39
8
STUDY ACTIVITIES............................................................................................................40
8.1
Initial Study Visit (40 weeks CA [term equivalent]) ...............................................40
8.2
Study Visits ..............................................................................................................40
8.2.1
Outcome Assessment Visits Conducted by Telephone .........................................41
8.2.2
Clinical Site Visits .................................................................................................41
8.2.2.1
Outcome Assessment Site Visits............................................................41
8.2.2.2
Visits Dedicated to Corrective Lens Determination...............................45
8.3
Assessments upon Discontinuation..........................................................................45
9
QUALITY CONTROL AND ASSURANCE ........................................................................46
10 STATISTICAL ANALYSES.................................................................................................47
10.1
General Methodology...............................................................................................47
10.2
Determination of Sample Size..................................................................................47
10.3
Method of Assigning Study Subjects to Treatment Groups.....................................47
10.4
Population Description.............................................................................................47
10.4.1 Analysis Populations..............................................................................................47
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10.4.2 Subject Disposition................................................................................................48
10.4.3 Protocol Violations and Deviations .......................................................................48
10.4.4 Demographics and Baseline Characteristics..........................................................48
10.5
Efficacy Analysis .....................................................................................................48
10.5.1 Primary Efficacy Analysis.....................................................................................48
10.5.2 Secondary Efficacy Analysis .................................................................................49
10.5.3 Subset Analyses .....................................................................................................50
10.5.4 Exploratory Analyses.............................................................................................50
10.6
Health Economics and Outcomes Research Analyses .............................................50
10.7
Analysis of Safety ....................................................................................................51
10.8
Statistical/Analytical Issues......................................................................................51
10.8.1 Adjustment for Covariates.....................................................................................51
10.8.2 Handling of Dropouts or Missing Data..................................................................51
10.8.3 Interim Analyses and Data Monitoring..................................................................51
10.8.4 Multiple Comparisons/Multiplicity .......................................................................51
10.8.5 Sensitivity Analyses...............................................................................................51
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................52
11.1
Investigators and Study Administrative Structure ...................................................52
11.2
Institutional Review Board or Independent Ethics Committee Approval................52
11.3
Ethical Conduct of the Study ...................................................................................52
11.4
Subject Information and Consent.............................................................................52
11.5
Subject Confidentiality.............................................................................................53
11.6
Study Monitoring .....................................................................................................54
11.7
Case Report Forms and Study Records....................................................................54
11.7.1 Case Report Forms.................................................................................................54
11.7.2 Critical Documents ................................................................................................54
11.8
Data Monitoring Committee ....................................................................................55
11.9
Protocol Violations/Deviations ................................................................................55
11.10
Premature Closure of the Study ...............................................................................55
11.11
Access to Source Documentation.............................................................................56
11.12
Data Generation and Analysis..................................................................................56
11.13
Retention of Data .....................................................................................................56
11.14
Financial Disclosure.................................................................................................56
11.15
Publication and Disclosure Policy............................................................................57
12 LIST OF REFERENCES........................................................................................................58
13 APPENDICES ........................................................................................................................61
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LIST OF IN-TEXT TABLES
Table 7-1
Summary of Visual Acuity Assessments ......................................................25
Table 7-2
Assessments for Physical Examinations .......................................................33
Table 7-3
Adverse Event Severity.................................................................................36
Table 7-4
Adverse Event Relatedness ...........................................................................36
LIST OF IN-TEXT FIGURES
Figure 4-1
Overview of Study Design, Study SHP-607-201..........................................19
LIST OF APPENDICES
Appendix 1
Study Schedule of Events..............................................................................62
Appendix 2
Summary of Changes ....................................................................................66
Appendix 3
Protocol Signature Page ................................................................................68
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AAO
American Academy of Ophthalmology
ADHD
attention-deficit hyperactivity disorder
ADHD-RS
Attention-Deficit/Hyperactivity Disorder Rating Scale
AE
adverse event
ASD
Autism Spectrum Disorder
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CBCL
Child Behavior Checklist (1 ½ to 5)
CFR
Code of Federal Regulations
CA
corrected age
CI
confidence interval
CRF
case report form (electronic)
CRO
contract research organization
DMC
data monitoring committee
eCRF
electronic case report form
EOS
end of study
ETDRS
Early Treatment of Diabetic Retinopathy Study
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
FEV1
forced expiratory volume over 1 second
FVC
forced vital capacity
GCP
Good Clinical Practice
GH
growth hormone
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
HUI
Health Utilities Index
HUI2/3
Health Utilities Index Mark 2 and Mark 3
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IND
Investigational New Drug application
IRB
institutional review board
LV
left ventricle
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Abbreviation
Definition
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
magnetic resonance imaging
OD
right eye
OS
left eye
OU
both eyes
PedsQL
Pediatric Quality of Life Inventory 
REB
research ethics board
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SCQ
Social Communication Questionnaire
SD
standard deviation
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
UK
United Kingdom
US
United States
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
VLBW
very low birth weight
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI
Wechsler Preschool and Primary Scale of Intelligence
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1
INTRODUCTION
Retinopathy of prematurity (ROP) is a rare disorder of the developing retinal blood vessels and 
retinal neurons of the preterm infant and is one of the leading causes of preventable blindness in 
children.1
Visual acuity is decreased in infants with a history of ROP.2 In addition to acuity, other aspects 
of eye health are also significantly impacted by ROP. Strabismus and myopia are clearly 
increased in patients with a history of ROP.3-6  Additionally, more than half of patients at 
6-10 years of age with a history of Stage 1 and Stage 2 ROP were reported to have ongoing 
visual issues.7
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. During fetal life, IGF-1 is available through placental 
absorption and ingestion from amniotic fluid.8 Deprivation of such factors is likely to cause 
inhibition or improper stimulation of important pathways, which in the eye may cause abnormal 
retinal vascular development, the hallmark of ROP.
The finding in both a mouse model of ROP and preterm infants that development of ROP is 
associated with low levels of IGF-1 after premature birth, indicates a possible role for 
replacement of IGF-1 to levels found in utero as a strategy to potentially decrease abnormal 
retinal vascularization and abnormal retinal neural development, and ultimately, ROP. 
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3) is the human recombinant form of the naturally 
occurring protein complex of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was developed to enhance the systemic exposure of administered rhIGF-1 
and to improve the safety profile of rhIGF-1 therapy. rhIGF-1/rhIGFBP-3 was approved by the 
Food and Drug Administration (FDA) in 2005 for the treatment of growth failure in children 
with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletions who have 
developed neutralizing antibodies to GH. 
The pharmacokinetics and safety of rhIGF-1/rhIGFBP-3 have been evaluated in a Phase I study 
(ROPP-2005-01) and pharmacokinetics, safety, and efficacy were evaluated in the Phase II study 
(ROPP-2008-01). Section D of the ROPP-2008-01 study was conducted to assess 
pharmacokinetics, safety, and efficacy of rhIGF-1/rhIGFBP-3 for the prevention of ROP in 
premature infants (up to a corrected age [CA] of 40 weeks [± 4 days]). Subjects in Study 
ROPP-2008-01 were randomly assigned to receive rhIGF-1/rhIGFBP-3 or standard neonatal 
care. The target dose of rhIGF-1/rhIGFBP-3 for Study Section D was 250 μg/kg/24 hours to be 
administered via continuous infusion starting on Study Day 0 (day of birth) and continuing 
through postmenstrual age (gestational age + time elapsed from birth) 29 weeks + 6 days.
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Although the rhIGF-1/rhIGFBP-3 therapy in Section D of the Phase II study 
(Study ROPP-2008-01) represented a short-term exposure (<2 months for each subject), 
rhIGF-1/rhIGFBP-3 may have long-lasting effects on visual outcomes as well as other potential 
outcomes related to complications of prematurity such as neurodevelopment, pulmonary 
function, and growth. In addition, it is critical to understand any long term safety effects from 
short term exposure to rhIGF-1/rhIGFBP-3. 
The long-term outcomes assessed in this study will require utilization of different assessment 
tools than were utilized in the Phase II study, ROPP-2008-01 Section D, given the changes in 
physical and cognitive development that will occur in the subjects as they age during their 
participation in this study. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of rhIGF-1/rhIGFBP-3.
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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
3.1.1
Primary Efficacy Endpoints

Visual acuity as assessed by an age-appropriate method

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
3.1.2
Secondary Efficacy Endpoints

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate 
tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

Physical development as assessed by standardized, age appropriate tools including 
physical examination, neurological examination for assessment of cerebral palsy, and 
hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) for the 
assessment of symptoms of attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, 
pulmonary medications)

Survival as assessed by death during the study due to any cause
3.1.3
Exploratory Efficacy Endpoints


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3.2
Health Economic Outcome Research Endpoints

Health Related Quality of Life (HRQoL) 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, respectively)

Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS) and the Health Utilities Index Mark 2 (HUI2) and Mark 
3 (HUI3).

Resource use associated with inpatient visits, outpatient visits, medical utilization and  
pharmacy utilization will be assessed
3.3
Safety Endpoints

Physical examination including tonsil examination

Adverse events (AEs), as follows:  
o
those considered related to rhIGF-1/rhIGFBP-3 (as administered in Study 
ROPP-2008-01, Section D)
o
those considered related to procedures performed in this study (SHP-607-201)
o
specified targeted medical events regardless of causality
o
fatal serious adverse events (SAEs) regardless of causality

Cardiac size as assessed by echocardiogram 

Kidney and spleen size and any other gross abnormalities as assessed by abdominal 
ultrasound
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3
(treated) or standard neonatal care (control). Enrolled subjects in this study will be 
followed through age 5 years CA. This study will enroll both subjects who were in the 
treated (received rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of 
Study ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term 
efficacy and safety outcomes versus standard neonatal care. No investigational product will be
administered in this study. 
In this study, the Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon 
discontinuation from Study ROPP-2008-01, or may occur any time until 2 years CA +3 months. 
Subjects are no longer eligible to participate in this study after they turn 2 years CA +3 months.
Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age of 23 weeks 
+0 days to 27 weeks +6 days.
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. Both 
telephone and clinical site visits are included to help maintain contact with subjects throughout 
the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required. 
See Appendix 1 for the Study Schedule of Events table.
The overall study design is outlined in Figure 4-1.
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Insulin-like growth factor-1 (IGF-1) mediates its primary actions by binding to its specific 
receptor, the insulin-like growth factor 1 receptor (IGF-1R), which is present on many cell types 
in many tissues. Binding to its receptor initiates intracellular signaling including via the AKT 
signaling pathway. This pathway is involved in stimulation of cell division, growth and 
differentiation and inhibits programmed cell death. Specifically regarding premature infants, 
IGF-1 is an important mediator of fetal growth and has been shown to play a role in early 
postnatal growth following pre-term delivery.9,10
Insulin-like growth factor-1 (IGF-1) has also been shown to play a role in pulmonary 
development11 and neural development.12,13 Given the potential role for IGF-1 in the 
development of multiple systems, this study has been designed to evaluate the long-term effects 
of rhIGF-1/rhIGFBP-3, both from a safety and efficacy perspective, on the development of the 
premature infant.
4.3
Study Duration
Duration for an individual subject’s participation in the study will vary depending upon age at 
enrollment, but subjects will not be followed beyond age 5.5 years CA.
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5
STUDY POPULATION SELECTION
5.1
Study Population
Subjects randomized in Study ROPP-2008-01, Section D are eligible to enroll in this study; 
completion of Study ROPP-2008-01 Section D is not required. Subjects in Study ROPP-2008-01 
are premature infants (gestational age of 23 weeks +0 days to 27 weeks +6 days) who are 
randomized to receive either treatment with rhIGF-1/rhIGFBP-3 or standard neonatal care. A 
total of 121 subjects were randomized in Study ROPP-2008-01 Section D.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject was randomized in Study ROPP-2008-01, Section D
2. Subject’s parent or legally authorized representative(s) must provide written informed 
consent prior to performing any study-related activities. Study-related activities are any 
procedures that would not have been performed during normal management of the subject.
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. Any other condition or therapy that, in the Investigator’s opinion, may pose a risk to the 
subject or interfere with the subject’s ability to be compliant with this protocol or interfere 
with the interpretation of results
2. The subject or subject’s parent or legally authorized representative(s) is unable to comply 
with the protocol as determined by the Investigator
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6
STUDY TREATMENT
6.1
Description of Treatment
No investigational product will be administered in this study.
6.2
Treatments Administered
Not applicable.
6.3
Selection and Timing of Dose for Each Subject
Not applicable.
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable.
6.5
Masking
Not applicable.
6.6
Medications
Any medications administered to the subjects will be collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued). Any 
investigational product received by subjects will be recorded separately as part of an assessment 
of subjects’ participation in other clinical studies (Section 7.11.1).
6.7
Restrictions 
6.7.1
Prior Therapy
There are no restrictions related to prior therapy.
6.7.2
Other Restrictions
There are no restrictions related to fluid or food intake, or subject activity.
6.7.3
Treatment Compliance
Not applicable.
6.7.4
Packaging and Labeling
Not applicable.
6.8
Storage and Accountability
Not applicable
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7
STUDY PROCEDURES
Detailed descriptions of subject procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events in Appendix 1). 
All data collected are to be recorded on the subject’s appropriate eCRF. 
Details for study procedures are described in the Operations Manual for this study.
7.1
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).
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 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria and Eligibility
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 does not occur at or before 40 weeks CA, the subject may still be enrolled until 
2 years CA +3 months. Subjects are no longer eligible to participate in this study after they turn 2 
years CA +3 months. 
7.3
Study Enrollment
Subjects will be considered enrolled in the study once written informed consent has been 
obtained from the subject’s parent(s) or legally authorized representative(s).
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be recorded.
7.5
Growth Parameters:  Length (and Height), Weight, and Head Circumference
7.5.1
Length and Height
Body length (supine measurement) will be collected when subjects are 24-months CA or 
younger. 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. 
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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 when subjects are older than 24-months CA. 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). 
7.5.2
Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures 
(type of scale will depend upon subject’s age). Care should be taken to remove any extraneous 
clothing prior to measures and shoes should be removed.
The measure should be recorded to the nearest 0.1 kg.
7.5.3
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.
7.6
Efficacy Assessments
7.6.1
Visual Assessments
After corrective lens determination has occurred (Section 7.6.1.2), all visual assessments should 
be conducted with best-corrected vision, ie, with corrective lenses in place (if required); this 
applies to 24-month and 5-year visits.
7.6.1.1
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. It will be assessed by 
the methods summarized in Table 7-1; the method employed will be selected based on the 
subject’s age (CA) at the time of the study visit. Visual acuity measurements will be measured 
and recorded for the left (OS), right (OD) eye, and both eyes (OU).
At ages 6 months and 12 months CA, visual acuity will be assessed with Teller acuity cards. At 
ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
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Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner 
determines that it will not be possible to perform an accurate assessment with the relevant LEA 
tool, visual acuity should be assessed with the Teller acuity cards. 
The visual acuity assessments should be performed by an optometrist or ophthalmologist trained 
in pediatrics. 
Table 7-1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
7.6.1.2
Corrective Lens Determination
An assessment to determine if the subject requires vision correction with corrective lenses will 
be performed. This is being performed to ensure the accuracy of subjects’ subsequent visual 
acuity assessments (at the 24-month and 5-year visits). The corrective lens determination will be 
performed according to the guidelines published by the American Academy of Ophthalmology 
(AAO).14
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.3
Ocular Alignment and Oculomotor Examination (Motility)
Ocular alignment will be assessed in primary gaze by comparing the position of the corneal light 
reflection in OS and OD (corneal light reflection assessment). Presence or absence of strabismus 
will be recorded in primary gaze and in as many of the 9 positions of gaze as feasible with the 
cover test assessment of refixation movement. Extraocular muscle over-action or deficiency will 
be recorded. The assessment will be performed according to the AAO guidelines.14
Presence or absence of nystagmus as observed during the ocular alignment assessments will also 
be recorded.
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The assessment will be performed by a pediatric ophthalmologist or an ophthalmologist trained 
in the care of pediatric subjects with a history of premature birth. Degree of adherence to the 
AAO guidelines will be at the discretion of the examining physician in consideration of the need 
for patient cooperation. 
Ocular motility refers to eye movements, which are governed by the 6 extraocular muscles in 
each eye. It will be assessed by examiner observation of the subject’s ability to abduct, adduct, 
supra, and inferoduct each eye (to assess for strabismus). Any observed misalignment 
(strabismus classifications) will be recorded:

esotropia

exotropia

hypertropia

hypotropia
The frequency (constant or intermittent) with which any misalignment occurs and whether the 
turning eye is always the same eye or if it alternates between OS and OD, will be recorded. 
Extraocular muscle over-action or deficiency will be recorded.
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.4
Refraction with Cycloplegia
Refraction is a measure of the lens power required for a focused image on the retina. Refraction 
with cycloplegia will be measured and recorded in diopters for each eye individually (OS and 
OD).
Cycloplegia may be induced according to site standard practice.
This assessment should be performed by an optometrist or ophthalmologist trained in pediatrics. 
7.6.1.5
Stereoacuity
Stereoacuity is a measure of depth perception and will be assessed using the Lang Stereotest and 
performed by certified personnel. The presence or absence of stereopsis will be recorded.
7.6.2
Hearing Assessment History
Results of previously completed hearing assessments will be recorded at the 6-month CA and 
5-year CA visits; hearing tests are not being performed as part of this study. 
7.6.3
Behavioral Assessments
7.6.3.1
Bayley Scales of Infant and Toddler Development, Third Edition
The BSID-III will be used to assess cognitive, motor, and language skills, and is applicable to 
children aged 1-42 months. 
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The BSID-III is an assessment tool designed to measure a young child's skills in the 3 core areas 
of development:  cognitive, language, and motor. There are 5 subscales, the cognitive subscale 
stands alone while 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 examiner's manual.
The BSID-III 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.
7.6.3.2
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.15  It is applicable to preschoolers and young children aged 
2 years +6 months to 7 years +7 months, and is a direct assessment of a child’s cognitive skills.
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 standardization16 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. Scores to be recorded 
are detailed in the Study Operations Manual.
7.6.3.3
Child Behavior Checklist (CBCL)
The CBCL (1 ½ to 5) is a parent-reported outcome measure used to assess behavioral, emotional, 
and social functioning of toddlers and preschool children aged 18-60 months.17 It is composed 
of 99 items that are rated on a Likert scale and includes the following 7 syndrome scales 
arranged under 2 domains (ie, Internalizing and Externalizing Problems):18

Internalizing Problems

Emotionally Reactive
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
Anxious/Depressed

Somatic Complaints

Withdrawn

Sleep Problems

Attention Problems

Aggressive Behavior
The questionnaire is widely used and has been employed to assess long-term behavioral 
outcomes in children born prematurely, aged similarly to the subjects expected in this study 
population.18-20 It is associated with well-established normative data;21 norms may be selected to 
aid in interpretation of the scale scores.
The CBCL (1 ½ to 5) is a questionnaire that will be administered to 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.
7.6.3.4
Vineland Adaptive Behavior Scales, Second Edition
The VABS-II Expanded Interview Form will be used to measure the personal and social skills of 
subjects serially over time; these scales are organized within a 3-domain structure:  
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what he or she is able to do. 
The VABS-II Expanded Interview Form will be administered to 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.
7.6.3.5
Attention-Deficit/Hyperactivity Disorder Rating Scale
The ADHD-RS was developed to measure the behaviors of children with ADHD. The 
ADHD-RS consists of 18 items designed to reflect current symptomatology of ADHD based on 
DSM-IV 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,22 will be completed by the subject’s parent(s) or legally authorized 
representative(s). Scores to be recorded are detailed in the Study Operations Manual.
7.6.3.6
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children23 that can be used for screening for autism or autism spectrum disorders in the general 
population.24
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7.6.9
Health Economic Outcome Research Assessments
7.6.9.1
Health Related Quality of Life
Health-related quality of life (HRQoL) is an important outcome towards improving the health 
care of pediatric patients as it is that part of a person’s overall quality of life that is determined 
primarily by their health status and which can be influenced by clinical interventions. It is an 
important concept, which is also used in determining the value of health care services in this 
population.26,27 It is a multidimensional construct whose content is guided by the World Health 
Organization;28 minimally it includes physical, psychological (including emotional and 
cognitive), and social health dimensions.
In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL™) Scales appropriate for the child’s age of development.29-31 The development of the 
PedsQL was based on the delineations of the World Health Organization (WHO) and is a 
modular approach to assessing HRQoL in the pediatric population. Initially, the PedsQL Generic 
Scales were developed and continue to be used in children aged 2-18 years. More recently Infant 
Scales have been developed that apply to ages 1-24 months.30
The following scales will be used in this study:

Infant Scale for ages 1-12 months (36 Items)

Infant Scale for ages 13–24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent and may be conducted via telephone by 
clinical site staff. The scale(s) to be administered at each visit will be specified in the Study 
Operations Manual.
7.6.10
Health Care Resource Use
To understand the value of the investigational product administered in Study ROPP-2008-01 
(Section D), the resource use associated with inpatient visits, outpatient visits, and medical and 
pharmacy utilization in this study will be recorded. 
This assessment may be conducted via telephone by clinical site staff.
7.6.10.1
Health Utility
Health Status Classification System-Preschool
Health status (eg, health utility) will be measured by the Health Status Classification 
System-Preschool (HSCS-PS), which is a validated instrument adapted for use via parent proxy 
within the pediatric population age 2.5-5 (adapted from the validated Health Utilities Index Mark 
2 and 3 [HUI2/3]).32  Validity of the HSCS-PS concepts has not been established for ages 
younger than 2.5 years.
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The HSCS-PS was developed to provide a consistent measure of health status in preschool-aged 
children who had been born prematurely.32 The system is applicable to children with special 
needs as may be included in this study; validation cohorts for the system included children with 
very low birth weight (VLBW), which is congruent with this study population.
The instrument is composed of 12 dimensions (Vision, Hearing, Speech, Mobility, Dexterity, 
Self-care, Emotion, Learn/remember, Think/problem solve, Pain, General Health, and Behavior) 
intended to provide a comprehensive assessment of a child’s health status as it pertains to 
health-related quality of life. The individual domains of the instrument will be scored as a mean 
score, representing the overall state for each concept individually. The global score will be 
recorded as well as the scores for each of the dimensions.
The HSCS-PS is a questionnaire that will be administered to the subject’s parent(s) or legally 
authorized representative(s) and may be conducted via telephone by clinical site staff.
Health Utilities Index
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. The 
HUI2/3 each include a generic comprehensive health status classification system and a generic 
HRQoL utility scoring system.33 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 Events.
7.7
Safety Assessments
7.7.1
Abdominal ultrasound
An abdominal ultrasound will be performed to assess the size of the spleen and kidneys. The 
spleen will be measured in the coronal longitudinal plane and the longest longitudinal length will 
be measured for each kidney (left and right).35 Ultrasound results will be assessed by a central 
reader.
Organ size will be interpreted in the context of reference values established for children.34,35
7.7.2
Echocardiogram
Echocardiographic examination (conventional M-mode recording of the left ventricle [LV] 
parasternal long axis view) will be performed for the evaluation of cardiac size, assessed by 
measuring the following:

interventricular septal thickness (during end diastole)

LV posterior wall thickness

LV intracavity volume (both in end diastole and end systole)
Echocardiogram results will be assessed by a central reader.
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7.7.3
Physical Examination
Physical examinations will include a review of the subject’s general appearance, neurological 
examination, as well as a tonsillar examination (Table 7-2). Adverse events will be collected as 
described in Section 7.9.1.1.
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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Tonsils
7.7.4
Blood Pressure, Heart Rate, and Respiratory Rate
Blood pressure, heart rate, and respiratory will be measured at the 5-year CA visit.
7.8
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 7.11.1).
7.9
Adverse Events Assessments
7.9.1
Definitions of Adverse Events, Serious Adverse Events, and Suspected 
Unexpected Serious Adverse Reactions
7.9.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset 
of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
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In this long-term outcome study in follow-up to Study ROPP-2008-01 (Section D), no 
investigational product is being administered. However, the relationship to the investigational 
product (rhIGF-1/rhIGFBP-3) as administered in Study ROPP-2008-01 (Section D) will be 
assessed. 
For the purposes of this study only the following adverse events will be collected:  

Those considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP -2008-01, Section D)

Those considered related to procedures performed in this study (Study SHP-607-201)

AEs related to ROP

AEs related to congenital malformations not identified at birth which may impact 
neurocognitive development 

Additional illnesses present at the time when informed consent is given are to be 
regarded as AEs

Specified targeted medical events (Section 7.9.1.4) regardless of causality
Throughout the study, the Investigator must record these AEs or any AEs resulting in death in 
the eCRF, regardless of the severity or causality. The Investigator should treat subjects with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve. Adverse 
events may be discovered through observation or examination of the subject, questioning of the 
subject, complaint by the subject, or by abnormal clinical laboratory values.
7.9.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
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 one of the 
outcomes listed in this definition.
A life-threatening AE is defined as an AE that placed the subject, in the view of the initial 
reporter, at immediate risk of death from the AE as it occurred (ie, it does not include an AE that, 
had it occurred in a more severe form, might have caused death).
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For the purposes of this study only the SAEs listed below will be collected:

Fatal SAEs regardless of causality

SAEs considered related to investigational product (rhIGF-1/rhIGFBP-3 as 
administered in Study ROPP-2008-01, Section D)

SAEs considered related to procedures performed in this study (Study SHP-607-201)

SAEs related to ROP

SAEs related to congenital malformations not identified at birth which may impact 
neurocognitive development

SAEs related to additional illnesses present at the time when informed consent is given

Specified targeted medical events (Section 7.9.1.4) regardless of causality
7.9.1.3
Suspected Unexpected Serious Adverse Reaction
Suspected unexpected serious adverse reactions (SUSAR) are suspected adverse reactions related 
to an investigational product (investigational products and comparators [if applicable]), which 
occur in the concerned study, and that are both serious and unexpected according to the current 
Investigator’s Brochure.
7.9.1.4
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, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D):

intracranial hypertension

any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and 
diabetes)

tonsillar hypertrophy (based on tonsil exam [part of the physical exam])

increased kidney size 

increased cardiac size

increased spleen size
7.9.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
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Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.9.3
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.9.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product (rhIGF-1/rhIGFBP-3 as administered in 
Study ROPP-2008-01, Section D) is to be determined by the Investigator based on the following 
definitions (See Table 7-4).
Table 7-4
Adverse Event Relatedness
Relationship to Product
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, but which could 
also be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, follows a known or suspected response 
pattern to the investigational product, is confirmed by improvement 
upon stopping the investigational product (dechallenge), and reappears 
upon repeated exposure (rechallenge). Note that this is not to be 
construed as requiring re-exposure of the subject to investigational 
product; however, the determination of definitely related can only be 
used when recurrence of event is observed.
7.9.5
Procedures for Recording and Reporting Adverse Events
7.9.5.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored throughout the study. 
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If a subject or the subject’s parent(s) or the subject’s legally authorized representative(s) acting 
on behalf of the subject, discontinues participation in the study, or the subject is discontinued by 
the Investigator, reasonable efforts will be made to follow the subject through the end of study 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the subject withdraws from the study, the subject will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.11
Other Study Procedures
7.11.1
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in another 
clinical study that involves 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 being evaluated in the study, and the subject’s treatment assignment 
in the study (if possible). 
7.12
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. These are the pulmonary 
morbidity assessment and the cerebral palsy assessment. In these cases, the tools are either based 
on validated tools or the current state of knowledge in the literature. For example, the cerebral 
palsy assessment is based on the Amiel-Tison neurological examination framework25 and the 
pulmonary assessment is based on published research in a similar pediatric population.36,37
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8
STUDY ACTIVITIES
The timing of the visits in this study is based on subjects’ corrected age (CA). 
8.1
Initial Study Visit (40 weeks CA [term equivalent])
The Initial Visit will occur at 40 weeks CA (ie, term equivalent) or upon discontinuation from 
Study ROPP-2008-01, Section D or any time up to the visit at 3 months CA. 
For subjects enrolled between the ages of 9 months CA and 2 years +3 months CA, missed 
procedures such as neurocognitive assessments, abdominal ultrasounds, and echocardiograms are 
not required.
At the Initial Visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data.
The following AE data, collected as part of Study ROPP-2008-01 (Section D) will be recorded:

Ongoing targeted medical events regardless of causality

Ongoing study drug-related AEs, including SAEs
Serious adverse events, as outlined in Section 7.9.1.1 and Section 7.9.1.2, that the subject 
experiences between the ROPP-2008-01 end-of-study visit and the time of informed consent for 
Study SHP-607-201 will be reported by the Investigator, pending permission for subject’s parent 
or legally authorized representative(s), as documented on the informed consent form.
8.2
Study Visits
Study visits for follow-up outcome assessments will take place at the following time points in 
CA:

3 months (±2 weeks) – conducted by telephone

6 months (±1 month) – clinical site visit

12 months (±3 months) – clinical site visit

20 months (-1 months) – clinical site visit

24 months (±3 months) – clinical site visit

30 months (±3 months) – conducted by telephone

3 years (±3 months) – conducted by telephone

3.5 years (±3 months) – conducted by telephone

4 years (±3 month) – conducted by telephone

4.5 years (±3 month) – conducted by telephone
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
4.75 years (-1 months) – clinical site visit

5 years (+6 months) – clinical site visit
Multiple visits and/or phone contacts are allowed to complete all assessments, if needed. In 
addition, there will be 2 visits that must occur at least 1 month prior to the 24-month and 5-year 
CA study visits to assess the need for corrective lenses. The timing of these 2 visits (20 months [-
1 month] and 4.75 years [-1 month]) was set to ensure that any prescribed corrective lenses 
would be worn for at least 1 month prior to the visual assessments at the 24-month and 5-year 
study visits CA.
The activities at the study visits are described in Sections 8.2.1 and 8.2.2.
8.2.1
Outcome Assessment Visits Conducted by Telephone
Visits at 3 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted by 
telephone. The following outcome assessments will be conducted at each of these 6 visits, unless 
otherwise indicated:

HRQoL (3-month, 3-year, and 4-year visits)

HCRU (3-month, 3-year, and 4-year visits) 

HSCS-PS (3-year and 4-year visits)

Pulmonary morbidity assessment (30-month, 3-year, 3.5-year, 4-year, and 4.5-year 
visits)

Medications (3-month, 30 months, 3-year, 3.5 year, 4-year and 4.5 year visits)

Survival assessment (3-month, 30 month, 3-year, 3.5 year, 4-year and 4.5 year visits)

Assessment of participation in other clinical studies (3-month, 30 months, 3-year, 
3.5 year, 4-year and 4.5 year visits) 

Adverse events, including targeted medical events (3-month, 30 month, 3-year, 
3.5 year, 4-year and 4.5 year visits) 
8.2.2
Clinical Site Visits
8.2.2.1
Outcome Assessment Site Visits
The following clinical site visits (in CA) to capture follow-up outcome data will occur at the 
clinical site:

6 months (±1 month)

12 months (±3 months) 

20 months (-1 month)

24 months (±3 months)
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
4.75 years (-1 months)

5 years (+6 months)
The following assessments will be performed at the 6-month visit:

Visual acuity

Refraction with cycloplegia

Length

Weight

Head circumference

VABS-II

Physical examination (including tonsil examination)

Hearing Assessment History (Historical hearing test data may be recorded at any time 
prior to the 6-month visit) 

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Abdominal ultrasound

Echocardiogram

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 12-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III
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
VABS-II

Physical examination (including tonsil examination)

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at the 20-month visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)

Assessment of participation in other clinical studies
The following assessments will be performed at the 24-month visit:

Visual acuity

Ocular alignment and motility

Length

Weight

Head circumference

BSID-III

CBCL

VABS-II

Physical examination (including tonsil examination)

Cerebral Palsy assessment

Pulmonary morbidity assessment

Survival assessment

HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)
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
HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
The following assessments will be performed at 4.75-year visit:

Visual acuity

Corrective lens determination (including refraction with cycloplegia)
The following assessments will be performed at the 5-year visit:

Visual acuity

Ocular alignment and motility

Stereoacuity

Height

Weight

WPPSI

CBCL

VABS-II

ADHD-RS

SCQ

Physical examination (including tonsil examination)

Blood pressure, heart rate, and respiratory rate

Pulmonary morbidity assessment

Hearing assessment history

Survival assessment



HRQoL (may be performed by telephone if there are time constraints during this 
clinical site visit)

HCRU (may be performed by telephone if there are time constraints during this 
clinical site visit)

HSCS-PS (may be performed by telephone if there are time constraints during this 
clinical site visit)
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
HUI2/3 (may be performed by telephone if there are time constraints during this 
clinical site visit)

Assessment of participation in other clinical studies

Medications

Adverse events (including targeted medical events)
8.2.2.2
Visits Dedicated to Corrective Lens Determination
The following clinical site visits are dedicated solely to corrective lens determination in 
preparation for the outcome assessment visits at 24-months and 5-years CA:

20 months (-1 month) 

4.75 years (-1 month) 
At these visits, the following will be performed:

Visual acuity

Corrective lens determination (includes refraction with cycloplegia)
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior 
to the 24-month and 5-year visits, respectively. Any prescribed corrective lenses must be worn 
for at least 1 month prior to the 24 month and 5 year assessments.
8.3
Assessments upon Discontinuation
If a subject discontinues prior to the 5-year CA visit, every attempt will be made to complete the 
assessments scheduled for the subject’s next visit. 
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 Code of Federal Regulations (CFR) Part 
11 Guidance. The clinical trial database will include an audit trail to document any evidence of 
data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Global Drug Safety database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock. All statistical analyses 
will be performed by the Biometrics department at Shire. Statistical analyses will be performed 
using Version 9.1 or higher of SAS® (SAS Institute, Cary, NC 27513).
Continuous variables will be summarized using descriptive statistics including the number of 
observations, 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 2 possible 
treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3
or standard neonatal care).
For analysis purposes, baseline is defined as the first assessment either in the antecedent study 
(ROPP-2008-01) or in this study (SHP-607-201). As necessary, relevant data from Study 
ROPP-2008-01 may be extracted and summarized with the data from this study (SHP-607-201).
For consented patients, additional biomarker analysis may be performed on prior collected blood 
samples from Study ROPP-2008-01.
10.2
Determination of Sample Size
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study.
10.3
Method of Assigning Study Subjects to Treatment Groups
Not applicable.
10.4
Population Description
10.4.1
Analysis Populations
Enrolled Population- the Enrolled Population will consist of all subjects for whom written 
informed consent has been provided for this study. 
Safety Population- the Safety Population will consist of the subjects in the Enrolled Population
who have safety follow-up data in this long-term outcome study.
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10.4.2
Subject Disposition
Subjects who complete the study and subjects who prematurely discontinue from the study will 
be summarized by treatment group using descriptive statistics. In addition, for subjects who 
prematurely discontinue from the study, the reasons for discontinuation will be summarized by 
treatment group.
10.4.3
Protocol Violations and Deviations
Protocol violations and deviations will be listed. Details of the criteria for deviations and
violations will be provided in the SAP.
10.4.4
Demographics and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for the Enrolled Population. 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. Continuous variables such as age (including corrected age), weight, and 
length/height will be summarized using number of observations, mean, standard deviation, 
median, minimum and maximum values. Categorical variables, like gender and race, will be 
summarized using number of observations and percentages.
Medical history, including maternal and perinatal history, (as obtained from the antecedent 
study, ROPP-2008-01) will be summarized by treatment group using the number of observations 
and percentages of subjects reporting each category.
10.5
Efficacy Analysis
All efficacy analyses will be performed using the Enrolled Population.
10.5.1
Primary Efficacy Analysis
The primary efficacy endpoints consist of the following:

Visual Acuity:  Visual acuity will be categorized as the following: 
o
normal (measurable acuity ≥20/40), 
o
below normal (20/200≤measurable acuity <20/40), 
o
poor (measurable acuity ≤20/200)
o
blind/low vision (only the ability to detect the 2.2 cm wide stripes on the 
low-vision Teller acuity card and at any location in the visual field). 
The number and proportion of patients within each category listed above will be 
summarized by treatment group and visit. In addition, acuity results in the normal and 
below normal categories will be classified as favorable outcomes, and acuity results in 
the poor and blind/low-vision categories will be classified as unfavorable outcomes. 
Tabular summaries by treatment group and visit will include the frequency and the 
percentage for each visual acuity category. 
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In addition, shift tables of favorable outcomes from baseline (first assessment during 
this study) to each of the subsequent assessments, including the last assessment, will 
be presented by treatment group.

Ocular Alignment and Oculomotor Exam (Motility):  Findings from the ocular 
motility assessment will be either presence or absence of strabismus (esotropia, 
exotropia, hypertropia, or hypotropia). Tabular summaries by treatment group and 
visit will include the frequency and the percentage in each category. In addition, shift 
tables from baseline (first assessment during this study) to the last assessment will be 
provided by treatment group.

Nystagmus:  Presence or absence of nystagmus will be summarized by treatment 
group and visit

Refraction with Cycloplegia:  Findings from the refraction with cycloplegia will be 
summarized by treatment group and visit

Stereoacuity:  Presence or absence of stereopsis will be summarized by treatment 
group and visit
10.5.2
Secondary Efficacy Analysis

Growth Parameters (body weight, body length [and height], and head circumference):  
A standard Z-score, utilizing WHO child growth standards, will be calculated for each 
assessment by adjusting age- and sex- matched means and standard deviations (norm). 
The descriptive statistics of the Z-score for each of these parameters will be 
summarized at each assessment and the corresponding change from baseline. When 
appropriate, a 95% CI for the corresponding mean change within each group and the 
difference in the mean change between the 2 treatment groups and the corresponding 
95% CI will be presented as appropriate. If the parametric assumption for the 
distribution of the above endpoints cannot be justified, a non-parametric approach will 
be utilized to estimate the treatment difference (ie, median difference or 
Hodges-Lehmann estimator and the corresponding confidence intervals)

BSID-III and WPPSI:  The raw score, age equivalent scores, and standard scores for 
each domain within each questionnaire will be summarized by treatment group and 
visit using descriptive statistics.

ADHD-RS:  ADHD-RS total score and subscales (Hyperactivity/Impulsivity and 
Inattentiveness) will be summarized by treatment group and visit using descriptive 
statistics.

SCQ:  The SCQ subscales (communication and social) will be summarized by 
treatment group and visit using descriptive statistics

VABS-II:  The raw score, age equivalent scores, and standard scores for each domain 
of the scale will be summarized by treatment group and visit using descriptive 
statistics.

CBCL:  The raw score and change from baseline for each domain of the scale will be 
summarized by treatment group and visit using descriptive statistics.
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10.7
Analysis of Safety
Safety summaries will be based on all assessments post-baseline. The safety data will be 
assessed by AE monitoring, change in cardiac size, and kidney and spleen size over time. 
Adverse events will be summarized by MedDRA system organ class (SOC) and preferred term 
for each treatment group and overall, the number and percentage of subjects having any AE, 
having an AE in each SOC and having each individual AE. In addition, those events which 
resulted in death, or were otherwise classified as serious will be presented in a separate listing. In 
addition, the summary of AEs will be presented by severity and relationship to trial medication. 
The change in cardiac size and size of kidney and spleen will be assessed at the 6-month CA visit 
via echocardiogram and abdominal ultrasound, respectively.  These data will be analyzed as a 
binary response (ie, normal/abnormal) and summarized using frequency count.  The number and 
proportion of patients with each category (ie, normal/abnormal) for each of these safety 
endpoints will be summarized by treatment group.  
In addition, the 2-sided 95% CI for the proportion of patients with a normal status for each of the 
endpoints will be estimated by treatment group.
Physical examinations findings will be summarized descriptively. 
10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
If any baseline data are imbalanced and are considered to be clinically relevant, between-group 
comparisons for efficacy outcomes will be adjusted for covariates and detailed in the SAP. 
10.8.2
Handling of Dropouts or Missing Data
Handling of missing data rules will be described in the SAP.
10.8.3
Interim Analyses and Data Monitoring
No interim analysis is planned. However, a snapshot of the data will be reviewed after all data 
from all enrolled subjects in this study (after either completed 2-year follow-up [24-month visit]
assessments or have prematurely withdrawn from the study [before completing 2 years of follow 
up]) has been entered into the database, queried, and discrepancies resolved. A selective 
descriptive analysis of the data for this interim review may be performed and used to understand 
the progress of the study, completion of the data, safety monitoring, regulatory communication, 
or general planning purposes.
10.8.4
Multiple Comparisons/Multiplicity
Not applicable.
10.8.5
Sensitivity Analyses
Sensitivity analyses for the efficacy outcomes will be detailed in the SAP, as necessary.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 and Investigator Agreement. Curriculum vitae must be provided for the Investigators 
and subinvestigators listed on Form FDA 1572 or Investigator Agreement. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, and their study related duties and functions. 
The Investigator must maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC/REB approval of the protocol and the informed consent form. This approval 
must refer to the informed consent form and to the study title, study number, and version and 
date of issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC/REB at least once per year. The IRB/IEC/REB 
must be notified of completion of the study. Within 3 months of study completion or termination, 
a final report must be provided to the IRB/IEC/REB. A copy of these reports will be sent to the 
study clinical monitor. The Investigators must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. AEs 
which are reported to the US (FDA or other Regulatory agencies (Safety Reports) must be 
submitted promptly to the IRB/IEC/REB.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s) or legally 
authorized representative(s) must consent to participate after the nature, scope, and 
possible consequences of the clinical study have been explained in a form understandable to 
him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. 
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The informed consent (or assent) form must be in a language understandable to the subject or the 
subject’s parent(s) or legally authorized representative(s) and must specify who informed the 
subject, the subject’s parent(s), or the subject’s legally authorized representative(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the subject, the subject’s parent(s) or the subject’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the Sponsor. Only the subject number - will be recorded in 
the eCRF, and if the subject name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The subjects will be told that 
representatives of the Sponsor, a designated CRO, the IRB/IEC/REB, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to enable records to be 
identified.
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11.6
Study Monitoring
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed. Review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Electronic case report forms (eCRFs) are provided for each subject. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the Investigator to ensure that the following documents are available to Sponsor 
or their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and subinvestigator(s) (current, dated and signed within 
12 months of study initiation)

Copy of Investigator and subinvestigator(s) current medical license (indicating license 
number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC/REB clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written 
information to be provided regarding subject recruitment procedures

Copy of IRB/IEC/REB approved Subject Information/Informed Consent Form/any 
other written information/advertisement (with IRB approval stamp and date of 
approval)

Current list of IRB/IEC/REB Committee members/constitution (dated within 
12 months prior to study initiation)
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
Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
Given that any long-term safety signal observed in this study could impact the safety profile of 
rhIGF-1/rhIGFBP-3 as administered in premature neonates being enrolled in the antecedent 
study (ROPP-2008-01, Section D), the Data Monitoring Committee (DMC) for Study 
ROPP-2008-01 will review safety data from this long-term outcome study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC/REB and the appropriate regulatory authorities, where applicable, 
have given approval/favorable opinion. Modifications to the protocol will not be made without 
agreement of the Sponsor. Changes to the protocol will require written IRB/IEC/REB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC/REB may provide, if applicable 
regulatory authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval/favorable opinion of the IRB/IEC/REB. The 
Sponsor will submit all protocol modifications to the regulatory authorities, where applicable, in 
accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC/REB.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC/REB and submitted to the FDA or other applicable international regulatory authority 
before initiation, if applicable.
11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
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development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC/REB, or the Sponsor may request access to all source 
documents, eCRFs, and other study documentation for onsite audit or inspection. Direct access to 
these documents must be guaranteed by the Investigator, who must provide support at all times 
for these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. The Sponsor or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-Drug Dictionary (WHO-DD). Central reads 
will be employed as described in the study manual to aid in consistent measurement of 
abdominal ultrasound and echocardiogram parameters. 
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
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11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other study personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with the Sponsor, 
provided the Sponsor a copy of the draft document intended for publication, and obtained the 
Sponsor’s written consent for such publication. All information obtained during the conduct of 
this study will be regarded as confidential. 
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12
LIST OF REFERENCES
1. Maida JM, Mathers K, Alley CL. Pediatric ophthalmology in the developing world. Current 
opinion in ophthalmology 2008;19:403-8.
2. O'Connor AR, Stephenson TJ, Johnson A, et al. Visual function in low birthweight children. 
The British journal of ophthalmology 2004;88:1149-53.
3. Keith CG, Kitchen WH. Ocular morbidity in infants of very low birth weight. The British 
journal of ophthalmology 1983;67:302-5.
4. Laws D, Shaw DE, Robinson J, Jones HS, Ng YK, Fielder AR. Retinopathy of prematurity:  
a prospective study. Review at six months. Eye 1992;6:477-83.
5. O'Connor AR, Stephenson T, Johnson A, et al. Long-term ophthalmic outcome of low birth 
weight children with and without retinopathy of prematurity. Pediatr 2002;109:12-8.
6. Schaffer DB, Quinn GE, Johnson L. Sequelae of arrested mild retinopathy of prematurity. 
Archives of ophthalmology 1984;102:373-6.
7. Cats BP, Tan KE. Prematures with and without regressed retinopathy of prematurity:  
comparison of long-term (6-10 years) ophthalmological morbidity. Journal of pediatric 
ophthalmology and strabismus 1989;26:271-5.
8. Chard T. Insulin-like growth factors and their binding proteins in normal and abnormal 
human fetal growth. Growth Regul 1994;4:91-100.
9. Hansen-Pupp I, Lofqvist C, Polberger S, et al. Influence of insulin-like growth factor I and 
nutrition during phases of postnatal growth in very preterm infants. Pediatr Res 2011;69:448-
53.
10. Ohkawa N, Shoji H, Kitamura T, et al. IGF-I, leptin and active ghrelin levels in very low 
birth weight infants during the first 8 weeks of life. Acta Paediatr 2010;99:37-41.
11. Lofqvist C, Hellgren G, Niklasson A, Engstrom E, Ley D, Hansen-Pupp I. Low postnatal 
serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD). Acta Paediatr 
2012;101:1211-6.
12. Ishii DN, Glazner GW, Whalen LR. Regulation of peripheral nerve regeneration by insulin-
like growth factors. Annals of the New York Academy of Sciences 1993;692:172-82.
13. Lewis ME, Neff NT, Contreras PC, et al. Insulin-like growth factor-I:  potential for treatment 
of motor neuronal disorders. Experimental neurology 1993;124:73-88.
14. Pediatric Ophthalmology/Strabismus Preferred Practice Pattern Development Process and 
Participants. Pediatric Eye Evaluations:  American Academy of OphthalmologyPediatric 
Ophthalmology/Strabismus Preferred Practice Pattern Panel; 2012.
15. Wechsler D. Wechsler preschool and primary scale of intelligence 4th ed. Bloomington, MN:  
Pearson; 2012.
16. Wechsler D. Technical and Interpretive Manual Supplement:  Special Group Validity Studies 
With Other Measures 2012.
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17. Achenbach T, Rescorla L. Manual for the ASEBA preschool forms and profiles. Burlington, 
VT:  University of Vermont; 2000.
18. Vinall J, Miller SP, Synnes AR, Grunau RE. Parent behaviors moderate the relationship
between neonatal pain and internalizing behaviors at 18 months corrected age in children 
born very prematurely. Pain 2013;154:1831-9.
19. Scott MN, Taylor HG, Fristad MA, et al. Behavior disorders in extremely preterm/extremely 
low birth weight children in kindergarten. J Dev Behav Pediatr 2012;33:202-13.
20. Wu YC, Leng CH, Hsieh WS, et al. A randomized controlled trial of clinic-based and home-
based interventions in comparison with usual care for preterm infants:  Effects and mediators. 
Res Dev Disabil 2014;35:2384-93.
21. Ebesutani C, Bernstein A, Nakamura BJ, Chorpita BF, Higa-McMillan CK, Weisz JR. 
Concurrent Validity of the Child Behavior Checklist DSM-Oriented Scales:  Correspondence 
with DSM Diagnoses and Comparison to Syndrome Scales. Journal of psychopathology and 
behavioral assessment 2010;32:373-84.
22. DuPaul G, Power T, Anastopoulos A, Reed R. The ADHD rating scale IV:  checklists, norms 
and clinical interpretation. New York:  Guilford Press; 1998.
23. Rutter M, Bailey A, Lord C. Manual for the Social Communication Questionnaire2003.
24. Chandler S, Charman T, Baird G, et al. Validation of the social communication questionnaire 
in a population cohort of children with autism spectrum disorders. Journal of the American 
Academy of Child and Adolescent Psychiatry 2007;46:1324-32.
25. Gosselin J, Amiel-Tison C. Neurological Assessment from Birth to 6 Years. 2nd ed. 
Montreal:  CHU Sainte-Justine; 2011.
26. Matza LS, Swensen AR, Flood EM, Secnik K, Leidy NK. Assessment of health-related 
quality of life in children:  a review of conceptual, methodological, and regulatory issues. 
Value Health 2004;7:79-92.
27. Varni JW, Burwinkle TM, Lane MM. Health-related quality of life measurement in pediatric 
clinical practice:  an appraisal and precept for future research and application. Health Qual 
Life Outcomes 2005;3:34.
28. Constitution of the World Health Organization:  basic document. Geneva, Switzerland:  
World Health Organization; 1948.
29. Varni JW, Limbers CA. The pediatric quality of life inventory:  measuring pediatric health-
related quality of life from the perspective of children and their parents. Pediatr Clin North 
Am 2009;56:843-63.
30. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL Infant Scales:  feasibility, internal 
consistency reliability, and validity in healthy and ill infants. Quality of life research :  an 
international journal of quality of life aspects of treatment, care and rehabilitation 
2011;20:45-55.
31. Varni JW, Seid M, Kurtin PS. PedsQL 4.0:  reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical 
care 2001;39:800-12.
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APPENDICES
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Appendix 1
Study Schedule of Events
Procedures
Initial Study 
Visite
Months (CA)k
Years (CA)k
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Informed Consent
•
Eligibility Criteria
•
Demographics
•
Visual acuitya
•
•
•
•
•
•
Corrective lens determinationh
•
•g
•g
Ocular alignment and motility
•
•
•
Refraction with cycloplegiah
•
Stereoacuity
•
Length
•
•
•
Height
•
Weight
•
•
•
•
Head Circumference
•
•
•
BSID-III
•
•
WPPSI
•
CBCL
•
•
VABS-II
•
•
•
•
ADHD-RS
•
SCQ
•
Physical Examination including 
tonsil examination 
•
•
•
•
Blood Pressure, Heart Rate, and 
Respiratory Rate
•
Cerebral Palsy Assessment
•
Hearing Assessment Historyb
•
•
Pulmonary Morbidity Assessment 
1
•
•
Pulmonary Morbidity Assessment 
2  (clinical site visit)
•
•
Pulmonary Morbidity Assessment 
(phone interview)
•
•
•
•
•
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SHP-607-201 Protocol Amendment 4
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018
Procedures
Initial Study 
Visite
Months (CA)k
Years (CA)k
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
Survival assessment
•
•
•
•
•
•
•
•
•
•
HRQoLc
•
• i
• i
•i
•
•
• i
HCRU
•
• i
• i
•i
•
•
• i
HSCS-PS
•i
•
•
• i
HUI2/3
•
Abdominal Ultrasound
•
Echocardiogram
•
Assessment of Participation in 
Other Clinical 
Studies
•
•
•
•
•
•
•
•
•
•
Medications
•
•
•
•
•
•
•
•
•
•
Adverse eventsd
•j
•
•
•
•
•
•
•
•
•
•
Abbreviations:  ADHD-RS = Attention-Deficit/Hyperactivity Disorder Rating Scale; BSID-III = Bayley Scales of Infant and Toddler Development-Third 
Edition, CBCL = Child Behavior Checklist; CA = corrected age; HCRU = health care resource use; HRQoL = health-related quality of life; HSCS-PS = Health 
Status Classification System; HUI2/HUI3=Health Utilities Index Mark 2 and Mark 3; mth(s) = months; PedsQL = Pediatric Quality of Life Inventory; 
SCQ = Social Communication Questionnaire; VABS-II = Vineland Adaptive Behavior Scales, Second Edition; wks = weeks; WPPSI = Wechsler Preschool and 
Primary Scale of Intelligence
a
The tools used to assess visual acuity will change as the subject ages during their participation in the study. The tools that will be used in this study and are 
summarized by applicable study visit in Table A1.
b
Historical hearing test data may be recorded at any time during the study prior to the 6-month visit.
c
HRQoL will be assessed via the validated PedsQL™ scales appropriate for the child’s age of development as specified in the Study Operations Manual.
d
Adverse event collection will include an assessment of the specified targeted medical events.
e
The Initial Visit may be performed prior to 40 weeks CA for any subject who discontinued from Study ROPP-2008-01 and, for all subjects, any time after 
40 weeks CA. If the Initial Visit does not occur at or before 40 weeks CA, the subject may still be enrolled until 2 years CA +3 months. Subjects are no 
longer eligible to participate in this study after they turn 2 years CA +3 months.
f
Visits at 3 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted by telephone.
g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments.
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SHP-607-201 Protocol Amendment 4
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018
Procedures
Initial Study 
Visite
Months (CA)k
Years (CA)k
40 weeks
(CA)/term 
equivalent
3f
± 2 
wks
6 
± 1 mth
12
± 3 
mths
20 
-1 mthg
24
± 3 mth
30f
± 3 mth
3f
± 
3 mths
3.5f
± 
3 mth
4f
± 3 mths
4.5f
± 3 mth
4.75
-1 mthg
5
+ 6 
mths
h
Refraction with cycloplegia will be performed as part of the corrective lens determination procedure.
i
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through clinical site staff if 
there are time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through clinical site staff 
and may be performed at any time within the visit window.
j
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201):  any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
k
Multiple visits and/or phone contacts are allowed to complete all assessments, if needed.
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SHP-607-201 Protocol Amendment 4
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018
Table A1
Summary of Visual Acuity Assessments 
Visual Acuity 
Assessment Tool
Description
Unit of Measure
Applicable 
Age/Study 
Visit (CA)
Teller acuity cards
Resolution acuity –
discrimination of a grating 
optotype from a background with 
the same mean luminance
cycles per degree
6 months
12 months
LEA Symbols Test 
Recognition acuity - tests 
recognition of 4 optotypes
Snellen fraction
(eg, 20/20)
24 monthsa
LEA Symbols 
(ETDRS-style) chart
Distance visual acuity test
Snellen fraction
(eg, 20/20)
5 yearsa
Abbreviations:  CA = corrected age; ETDRS = Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA 
Symbols Test and LEA Symbols Chart, respectively. If during this attempt, the examiner determines 
that it will not be possible to perform an accurate assessment with the relevant LEA tool, visual acuity 
should be assessed with the Teller acuity cards.
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SHP-607-201 Protocol Amendment 4
Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
09 Apr 2018
Description of Change
Section(s) Affected by
Clarified that multiple visits and/or phone contacts are allowed 
to complete all assessments, if needed.
Section 8.2
Appendix 1
A description of the Health Status Classification 
System-Preschool (HSCS-PS) statistical analysis was added.
Section 10.6
Removed language stating that a full 2-year clinical study report 
based on the data at the interim analysis will be completed.
Section 10.8.3
Administrative errors were corrected throughout the protocol.
All sections
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT02386839 
Study Title: 
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 
Previously Treated with rhIGF-1/rhIGFBP-3 for the Prevention of 
Retinopathy of Prematurity (ROP) or Who Received Standard Neonatal 
Care 
Study Number: 
SHP607-201 
SAP Version and Date: 
Version 1.0: 01 September 2020 


STATISTICAL ANALYSIS PLAN
Protocol No.:
SHP-607-201
Protocol Title:
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 
Previously Treated with rhIGF-1/rhIGFBP-3 for the Prevention of 
Retinopathy of Prematurity (ROP) or Who Received Standard 
Neonatal Care
Drug:
SHP607, Mecasermin rinfabate (rhIGF-1/rhIGFBP-3)
Sponsor: 
Premacure AB, A Member of the Shire Group of Companies
300 Shire Way
Lexington, MA 02421 USA
Version No. and Date
Version 1.0, 1 September 2020
Version 
No:
Document History
Description of Update
Author(s)
Effective Date
1.0
Final
1 September 2020
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
TABLE OF CONTENTS
LIST OF TABLES...........................................................................................................................5
LIST OF FIGURES .........................................................................................................................5
LIST OF APPENDICES..................................................................................................................5
ABBREVIATIONS .........................................................................................................................6
1.
INTRODUCTION....................................................................................................................8
2.
OBJECTIVES AND ENDPOINTS..........................................................................................9
2.1
Objectives...................................................................................................................9
2.1.1
Primary Objectives...................................................................................................9
2.1.2
Secondary Objectives...............................................................................................9
2.1.3
Exploratory Objective..............................................................................................9
2.2
Endpoints....................................................................................................................9
2.2.1
Primary Efficacy Endpoints.....................................................................................9
2.2.2
Secondary Efficacy Endpoints...............................................................................10
2.2.3
Exploratory 
 Endpoint ..............................................................................10
2.2.4
Health Economic Outcome Research Endpoints...................................................10
2.2.5
Safety Endpoints....................................................................................................11
3.
STUDY DESIGN ...................................................................................................................12
3.1
General Description..................................................................................................12
3.2
Randomization .........................................................................................................13
3.3
Masking....................................................................................................................13
3.4
Sample Size and Power Considerations...................................................................13
4.
STATISTICAL ANALYSIS SETS........................................................................................14
4.1
Enrolled Set..............................................................................................................14
4.2
Safety Set..................................................................................................................14
5.
STUDY SUBJECTS...............................................................................................................15
5.1
Disposition of Subjects.............................................................................................15
5.2
Demographic and Other Baseline Characteristics....................................................15
5.3
Medical History........................................................................................................15
5.4
Concomitant Medication..........................................................................................16
5.5
Exposure to Investigational Product ........................................................................16
5.6
Protocol Violations and Deviations..........................................................................16
6.
EFFICACY ANALYSES.......................................................................................................17
6.1
Analyses of Primary Efficacy Endpoints .................................................................17
6.1.1
Visual Acuity .........................................................................................................17
6.1.2
Ocular Alignment and Oculomotor Exam (Motility) ............................................17
6.1.3
Nystagmus..............................................................................................................18
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
6.1.4
Refraction with Cycloplegia ..................................................................................18
6.1.5
Stereoacuity............................................................................................................18
6.1.6
Sensitivity Analyses of Primary Efficacy Endpoints.............................................18
6.2
Analyses of Secondary Efficacy Endpoints .............................................................18
6.2.1
Growth Parameters.................................................................................................18
6.2.2
Cognitive Development .........................................................................................19
6.2.2.1
Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III)...............................................................................................19
6.2.2.2
Wechsler Preschool and Primary Scale of Intelligence, Fourth 
Edition (WPPSI-IV) ...............................................................................19
6.2.3
Physical Development ...........................................................................................21
6.2.4
Child Behavior.......................................................................................................21
6.2.4.1
Attention Deficit/Hyperactivity Disorder Rating Scale, Version IV 
(ADHD-RS-IV)......................................................................................21
6.2.4.2
Social Communication Questionnaire (SCQ) ........................................22
6.2.4.3
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)..........22
6.2.4.4
Child Behavior Checklist (CBCL) 1½-5................................................22
6.2.5
Pulmonary Morbidity Assessment.........................................................................23
6.2.6
Survival..................................................................................................................24
6.3
Analyses of Exploratory 
 Endpoint.............................................................24
6.4
Subgroup Analyses...................................................................................................24
7.
SAFETY ANALYSIS ............................................................................................................25
7.1
Adverse Events.........................................................................................................25
7.2
Cardiac Size..............................................................................................................27
7.3
Kidney and Spleen Size............................................................................................27
7.4
Physical Examination...............................................................................................27
7.5
Blood Pressure, Heart Rate, and Respiratory Rate...................................................28
8.
OTHER ANALYSES .............................................................................................................29
8.1
Pediatric Quality of Life Inventory (PedsQL)..........................................................29
8.2
Health Utility............................................................................................................29
8.2.1
Health Status Classification System-Preschool (HSCS-PS)..................................29
8.2.2
Health Utilities Index Mark 2 and Mark 3 (HUI2/3).............................................29
8.3
Health Care Resource Use (HCRU).........................................................................30
9.
INTERIM ANALYSIS...........................................................................................................31
10. DATA HANDLING CONVENTIONS..................................................................................32
10.1
General Data Reporting Conventions ......................................................................32
10.2
Definition of Visit Windows....................................................................................32
10.3
Repeated or Unscheduled Assessments ...................................................................32
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
10.4
Handling of Missing, Unused, and Spurious Data...................................................32
10.4.1 Missing Severity Assessment for Adverse Events.................................................32
10.4.2 Missing Relationship for Adverse Events..............................................................32
11. ANALYSIS SOFTWARE......................................................................................................33
12. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ..................................................34
13. REFERENCES .......................................................................................................................35
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Page 5
Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
LIST OF TABLES
Table 6-1
Test Framework for Ages 4:0–7:7.................................................................21
LIST OF FIGURES
Figure 3-1
Overview of Study Design ............................................................................13
LIST OF APPENDICES
Appendix 1
Study Schedule of Events..............................................................................36
Appendix 2
WHO Child Growth Standards......................................................................40
Appendix 3
SCQ Items Listed Under the Domains ..........................................................43
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Page 6
Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
ABBREVIATIONS
ADHD
attention-deficit hyperactivity disorder
ADHD-RS
Attention-Deficit/Hyperactivity Disorder Rating Scale
AE
adverse event 
AESI
adverse event of special interest
ASD
Autism Spectrum Disorder
ATC
Anatomic Therapeutic Chemical
BPD
bronchopulmonary dysplasia
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition
CA
corrected age
CBCL
Child Behavior Checklist 
CI
confidence interval
CRF
case report form
eCRF
electronic case report form
EOS
end of study
ER
emergency room
GA
gestational age
HCRU
health care resource use
HRQoL
health-related quality of life
HSCS-PS
Health Status Classification System-Preschool
HUI
Health Utilities Index
HUI2/3
Health Utilities Index Mark 2 and Mark 3
IGF
insulin-like growth factor
IGFBP-3
insulin-like growth factor binding protein-3
IP
investigational product
IVH
intraventricular hemorrhage
KM
Kaplan-Meier
LV
left ventricle
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
magnetic resonance imaging
OD
right eye
OS
left eye
OU
both eyes
PCS
potentially clinically significant
PedsQL
Pediatric Quality of Life Inventory
PMA
post menstrual age
PT
preferred term 
PVL
periventricular leukomalacia
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System 
SCQ
Social Communication Questionnaire
SD
standard deviation 
SOC
system organ class
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPPSI
Wechsler Preschool and Primary Scale of Intelligence
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Page 8
Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
1.
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the study protocol amendment 4, dated 
09 April 2018. Specifications for tables, figures, and listings are contained in a separate 
document. 
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020

Ocular alignment and ocular motor examination in primary gaze and in as many of 
9 positions of gaze as possible as assessed by corneal light reflex and by the cover test

Assessment of nystagmus by observation

Refraction as assessed by retinoscopy with cycloplegia

Stereoacuity as assessed with the Lang Stereotest
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are:

Growth parameters including body weight, body length (or height), and head 
circumference

Cognitive development as assessed by the following standardized, age-appropriate tools:
o
Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
o
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

Physical development as assessed by the following standardized, age-appropriate tools:
o
Neurological examination (as part of physical examination) for assessment of 
cerebral palsy
o
Hearing assessment

Child behavior as assessed by the following:
o
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
o
Child Behavior Checklist (CBCL; 1 ½ to 5)
o
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) for the 
assessment of symptoms of attention-deficit/hyperactivity disorder (ADHD)
o
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum 
Disorder (ASD)

Pulmonary morbidity data (eg, hospitalizations, emergency room [ER] visits, pulmonary 
medications)

Survival as assessed by death during the study due to any cause
2.2.3
Exploratory 
 Endpoint
2.2.4
Health Economic Outcome Research Endpoints 
The health economic outcome research endpoints of this study are:

Health Related Quality of Life (HRQoL) as assessed by the Pediatric Quality of Life 
Inventory (PedsQL™) Scales appropriate for the child’s age of development with the 
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
Total Scale Score and 5 domains within Physical Health (Physical Functioning and 
Physical Symptoms) and Psychosocial Health Scores (Emotional, Social, and Cognitive 
Functioning, respectively) 

Health status (eg, health utility) as measured by the Health Status Classification 
System-Preschool (HSCS-PS) and the Health Utilities Index Mark 2 (HUI2) and Mark 3 
(HUI3)

Resource use associated with inpatient visits, outpatient visits, medical utilization, and 
pharmacy utilization as measured by Health Care Resource Use (HCRU) 
2.2.5
Safety Endpoints
The safety endpoints of this study are:

Adverse events (AEs), as follows:
o
those considered related to rhIGF-1/rhIGFBP-3 (as administered in 
Study ROPP-2008-01, Section D)
o
those considered related to procedures performed in this study 
(Study SHP-607-201)
o
specified targeted medical events regardless of causality
o
fatal serious adverse events (SAEs) regardless of causality

Cardiac size as assessed by echocardiogram

Kidney and spleen size and any other gross abnormalities as assessed by abdominal 
ultrasound

Physical examination including tonsil examination

Blood pressure, heart rate, and respiratory rate
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
3.
STUDY DESIGN
3.1
General Description
This is a Phase II, multicenter, long-term developmental outcome study enrolling subjects who 
were randomized in Section D of Study ROPP-2008-01 to receive either rhIGF-1/rhIGFBP-3 
(treated) or standard neonatal care (control). Enrolled subjects in this study will be followed 
through age 5 years CA. This study will enroll both subjects who were in the treated (received 
rhIGF-1/rhIGFBP-3) and control (received standard neonatal care) groups of 
Study ROPP-2008-01 (Section D) to enable assessment of rhIGF-1/rhIGFBP-3 long-term 
efficacy and safety outcomes versus standard neonatal care. No investigational product will be 
administered in this study. In the descriptions of summary statistics, treatment groups refer to the 
2 treatment assignments in the antecedent study, ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 
or standard neonatal care).
In this study, the Initial Visit will occur at 40 weeks corrected age (CA; ie, term equivalent) or 
upon discontinuation from Study ROPP-2008-01, or may occur any time until 2 years CA 
+3 months. Subjects are no longer eligible to participate in this study after they turn 2 years CA 
+3 months. Subjects in Study ROPP-2008-01 are premature infants enrolling at gestational age 
(GA) of 23 weeks+0 days to 27 weeks +6 days. 
Time points for assessments have been chosen based on standard premature infant follow-up 
periods and represent important developmental ages for premature infant follow-up. Both 
telephone and clinical site visits are included to help maintain contact with subjects throughout 
the 5-year duration of the study.
Subjects will be evaluated at appropriate follow-up site locations with expertise in the 
assessment of the developmental outcomes of premature infants. Pediatric ophthalmology 
expertise will also be required.
The overall study design is outlined in Figure 3-1.
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
Figure 3-1
Overview of Study Design
CA=corrected age
Note: Visits conducted by telephone are indicated with a diamond shape. Visits conducted at the study site are 
indicated with rectangles. Visit windows are provided in Appendix 1.
3.2
Randomization
Not applicable. 
3.3
Masking 
Not applicable. 
3.4
Sample Size and Power Considerations
No formal sample size calculation was performed for this study because this is a follow-up study 
to Section D of Study ROPP-2008-01. Any subjects enrolled in Study ROPP-2008-01 are 
eligible to enroll in this study. There are up to 120 subjects who will be eligible to enroll in this 
long-term developmental outcome study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
4.
STATISTICAL ANALYSIS SETS
4.1
Enrolled Set
The Enrolled Set will consist of all subjects for whom written informed consent has been 
provided for this long-term outcome study.
4.2
Safety Set  
The Safety Set will consist of all subjects in the Enrolled Set who have safety follow-up data in 
this long-term outcome study.
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Statistical Analysis Plan
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01 Sep 2020
5.
STUDY SUBJECTS
5.1
Disposition of Subjects
This section describes subject disposition for both the analysis sets and the study status.
The number of subjects included in each defined analysis set will be summarized by treatment 
group and overall. Percentages will be provided using the Enrolled Set as the denominator.
The number and percentage of subjects who completed through the study visits (3-month, 
6-month, 12-month, 24-month and 5-year CA visits), who completed the study, and who 
prematurely discontinued from the study will be presented for each treatment group and overall 
for the Enrolled Set. Primary reasons for premature discontinuation as recorded on the Study 
Completion page of the eCRF will be summarized (number and percentage) by treatment group 
and overall. All subjects who prematurely discontinued will be listed for the Enrolled Set.
A by-subject listing of study completion information, including the reason for premature study 
discontinuation, where applicable, will be presented.
5.2
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the Enrolled Set.
Continuous variables will be summarized using descriptive statistics, including number of 
observations, mean, standard deviation, median, minimum and maximum values. Categorical 
variables will be summarized using number of subjects and percentages.
The following demographic and baseline characteristics will be summarized: chronological age 
(weeks) at enrollment, CA at enrollment (weeks), GA at birth (weeks), GA group (<26 weeks, 
≥26 weeks), sex, ethnicity, race, weight at birth (kg), body length at birth (cm), head 
circumference at birth (cm), way of delivery (Vaginal, Caesarean Section), bronchopulmonary 
dysplasia (BPD) status (None/Mild, Moderate/Severe), intraventricular hemorrhage (IVH) status 
(Grade 0-II, Grade III-IV), and periventricular leukomalacia (PVL, severe or cystic). The history 
of BPD, IVH, and PVL status will be obtained from the antecedent study (ROPP-2008-01). CA 
(weeks) is calculated as [chronological age (weeks) – 40 + GA (weeks)]. 
A listing will be presented to show all the demographic and baseline characteristics for each 
subject in the Enrolled Set. 
5.3
Medical History
Medical history, including maternal and perinatal medical history, will be obtained from the 
antecedent study (ROPP-2008-01) and summarized by medication for each treatment group and 
overall for the Enrolled Set. In addition, medical history will be provided in data listings for the 
Enrolled Set.
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
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5.4
Concomitant Medication
Concomitant medications will be coded using WHO-Drug Dictionary (WHO-DD) dated 
June 2013. All medications administered to the subjects collected from the time of informed 
consent through the 5-year CA visit (or until the subject withdraws or is discontinued) are 
considered as concomitant medications. The therapeutic class is coded using the highest 
anatomic therapeutic chemical (ATC) level that is available (eg, ATC level 3 will be used if 
ATC level 4 is not applicable).
Concomitant medications will be summarized by the number and proportion of subjects in each 
treatment group and overall by therapeutic class and preferred term for the Enrolled Set. Multiple 
medication usage by a subject in the same category will be counted only once.
All concomitant medications will be listed for the Enrolled Set.
5.5
Exposure to Investigational Product
Exposure to investigational product is not applicable as no investigational product is 
administered in this study.
5.6
Protocol Violations and Deviations
Protocol violations and deviations will be recorded by the site separately from the clinical 
database. All protocol violations and deviations will be summarized by category and site for each 
treatment group and overall, for the Enrolled Set. A by-subject listing will be provided for 
protocol violations and deviations for the Enrolled Set.
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
01 Sep 2020
6.
EFFICACY ANALYSES
All efficacy analyses will be based on the Enrolled Set and summarized by treatment group 
unless stated otherwise. Baseline is defined as the first assessment in this study (SHP-607-201) 
unless stated otherwise.  
All efficacy analyses will be conducted according to the antecedent treatment assigned in Study 
ROPP-2008-01, Section D (rhIGF-1/rhIGFBP-3 or standard neonatal care).
Continuous variables will be summarized using descriptive statistics, including number of 
subjects, mean, standard deviation, median, minimum, and maximum values. Categorical 
variables will be summarized using number of subjects and percentages.
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects, unless stated otherwise. All confidence intervals will be 2-sided 95% confidence 
intervals, unless stated otherwise.
6.1
Analyses of Primary Efficacy Endpoints
6.1.1
Visual Acuity 
Visual acuity will be measured at the 6-month, 12-month, 20-month, 24-month, 4.75-year and 
5-year CA visits. It will be assessed by an age-appropriate method summarized in Table A1 and 
categorized as the following: 

normal (measurable acuity ≥20/40 or ≥15 cycles/degree)

below normal (20/200 ≤ measurable acuity <20/40 or 3 cycles/degree ≤measurable acuity 
<15 cycles/degree)

poor (measurable acuity ≤ 20/200 or ≤3 cycles/degree)

blind/low vision (only the ability to detect the 2.2 cm wide stripes on the low-vision 
Teller acuity card and at any location in the visual field).
Acuity results will be further classified as favorable outcomes (normal, below normal) and 
unfavorable outcomes (poor, blind/low vision). The number and proportion of subjects within 
each category listed above will be summarized for the left eye (OS), right eye (OD), and both 
eyes (OU) by treatment group and visit. In addition, a shift table of favorable outcomes from 
baseline (first assessment during this study) to each of the subsequent assessments, including the 
last assessment, will be presented by treatment group for OS, OD and OU.
The measurement results will be presented in a by-subject listing. 
6.1.2
Ocular Alignment and Oculomotor Exam (Motility)
Ocular alignment and motility will be assessed at the 12-month, 24-month and 5-year CA visits. 
Findings from the ocular motility assessment will be either presence or absence of strabismus 
(esotropia, exotropia, hypertropia or hypotropia). Tabular summaries by treatment group and
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visit will include the frequency and the percentage in each category. In addition, a shift table 
from baseline (first assessment during this study) to each of the subsequent assessments, 
including the last assessment will be provided by treatment group for each category.
All the assessment results will be presented in a by-subject listing. 
6.1.3
Nystagmus
The assessment of nystagmus will be recorded at the 12-month, 24-month and 5-year CA visits 
during the ocular alignment assessments. The presence or absence of nystagmus will be 
summarized by treatment group and visit and presented in a by-subject listing.  
6.1.4
Refraction with Cycloplegia
Refraction with cycloplegia will be performed at the 6-month, 12-month, 20-month and 
4.75-year CA visits as part of the corrective lens determination procedure. Descriptive statistics 
will be presented for each measurement (sphere, cylinder, axis, prism) and each eye individually 
(OS and OD) by treatment group and visit. 
All measurement results will be presented in a by-subject listing. 
6.1.5
Stereoacuity
Stereoacuity will be performed at the 5-year CA visit. Presence or absence of stereopsis will be 
summarized by treatment group and presented in a by-subject listing. 
6.1.6
Sensitivity Analyses of Primary Efficacy Endpoints
Not applicable. 
6.2
Analyses of Secondary Efficacy Endpoints 
6.2.1
Growth Parameters
For growth parameters, baseline is defined as the first assessment in the antecedent study 
(ROPP-2008-01). Body weight will be collected at the 6-month, 12-month, 24-month and 5-year 
CA visits. Body length will be collected at the 6-month, 12-month and 24-month CA visits, and 
height will be collected at the 5-year CA visit. Head circumference will be collected at the 
6-month, 12-month and 24-month CA visits. For height and length, 2 measures should be taken 
and recorded. The average height and length will be used in the analysis.
A standard Z-score for each growth parameter (body weight, body length/height, and head 
circumference) will be calculated at each time point by adjusting age- and sex- matched means 
and standard deviations (norm) utilizing WHO child growth standards. Refer to Appendix 2 for 
reference files and the detailed calculation on the Z-score. 
Descriptive statistics of the observed value and Z-score for each growth parameter and the 
corresponding change from baseline at each post-baseline visit and the last visit will be 
summarized by treatment group. A 95% confidence interval (CI) for the corresponding mean 
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change within each treatment group, the difference between two treatment groups and the 
corresponding 95% CI will also be presented. 
The Shapiro-Wilk test will be used to test the normality of the change from baseline for each of 
the above parameters. If the normality assumption can be satisfied, the mean change will be 
utilized to measure the treatment difference at each post-baseline visit, and the associated 95% 
CI will be estimated from the two-sample t-test. Otherwise, the median difference will be 
utilized, and the associated 95% CI will be estimated from the Hodges-Lehmann estimator.
All the growth parameters with Z-scores will be provided in a data listing. The growth 
parameters and the corresponding Z-scores against scheduled visits will be plotted by treatment 
group. 
6.2.2
Cognitive Development 
Cognitive development will be assessed by the BSID-III and WPPSI. All the questionnaire 
assessments and results will be provided in the data listings. 
6.2.2.1
Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III)
The BSID-III will be performed at the 12-month and 24-month CA visits. There are 3 domains 
of development (cognitive, language and motor) and 5 subtests. The cognitive subtest stands 
alone while the 2 language subtests (expressive and receptive communication) combine to make 
a total language score and the 2 motor subtests (fine and gross motor) form a combined motor 
scale. The cognitive and language composite scores <85 and the motor composite scores <70 are 
classified as moderate to severe developmental delay. 
The raw score and scale score for each subtest will be summarized by treatment group using 
descriptive statistics of the observed value at each visit and change from the 12-month CA visit. 
The composite score for each domain will be summarized in the same manner. In addition, the
number and percentage of subjects with the developmental status (no/mild delay, 
moderate/severe delay) classified by the composite score will be summarized by treatment group 
and visit. 
6.2.2.2
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition
(WPPSI-IV)
The WPPSI-IV will be performed at the 5-year CA visit. It is composed of 15 subtests: Block 
Design, Information, Matrix Reasoning, Bug Search, Picture Memory, Similarities, Picture 
Concepts, Cancellation, Zoo Locations, Object Assembly, Vocabulary, Animal Coding, 
Comprehension, Receptive Vocabulary, and Picture Naming. 
For children aged 4 years through 7 years 7 months (4:0–7:7), the test framework of the 
WPPSI-IV (Table 6-1) is organized into five Primary Index scales, with each scale composed of 
two core subtests: Verbal Comprehension (Information and Similarities), Visual Spatial (Block 
Design and Object Assembly), Fluid Reasoning (Matrix Reasoning and Picture Concepts), 
Working Memory (Picture Memory and Zoo Locations), and Processing Speed (Bug Search and 
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Cancellation). The Full Scale includes all of the subtests in each scale at the Primary Index scale 
level, as well as any additional supplemental subtests that may be used to derive the Full Scale 
IQ. At the Full Scale level, there are six core subtests (Information, Similarities, Block Design, 
Matrix Reasoning, Picture Memory, and Bug Search) and seven supplemental subtests 
(Vocabulary, Comprehension, Object Assembly, Picture Concepts, Zoo Locations, Cancellation, 
and Animal Coding). The sum of scaled scores will be used to derive the composite score for 
each Primary Index scale and the Full Scale.
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Table 6-1
Test Framework for Ages 4:0–7:7
Full Scale
Verbal Comprehension
Visual Spatial
Fluid Reasoning
Working Memory
Processing Speed
Information
Block Design
Matrix Reasoning
Picture Memory
Bug Search
Similarities
Object Assembly*
Picture Concepts*
Zoo Locations*
Cancellation*
Vocabulary*
Animal Coding* 
Comprehension*
Primary 
Index 
Scale
Verbal Comprehension
Visual Spatial
Fluid Reasoning
Working Memory
Processing Speed
Information
Block Design
Matrix Reasoning
Picture Memory
Bug Search
Similarities
Object Assembly
Picture Concepts
Zoo Locations
Cancellation
*Supplemental subtest 
The total raw score and scaled score for each subtest will be summarized by treatment group 
using descriptive statistics. The sum of scaled scores and the composite score for each Primary 
Index scale and the Full Scale will also be summarized by treatment group using descriptive 
statistics. The mean of the scaled score for each subtest will be plotted by treatment group. 
6.2.3
Physical Development 
The cerebral palsy will be assessed at the 24-month CA visit. Descriptive statistics will be 
summarized for cerebral palsy assessment details as collected in the Cerebral Palsy CRF page by 
treatment group. 
The hearing assessments will be recorded at the 6-month (historical hearing test data may be 
recorded at any time prior to the 6-month visit) and 5-year CA visits. The number and proportion 
of subjects with hearing screening status (normal, abnormal) will be summarized by treatment 
group. 
All the assessment results will be presented in the data listings. 
6.2.4
Child Behavior 
Child behavior will be assessed by the ADHD-RS, SCQ, VABS-II, and CBCL. All the 
questionnaire assessments and results will be provided in the data listings. 
6.2.4.1
Attention Deficit/Hyperactivity Disorder Rating Scale, Version IV
(ADHD-RS-IV)
The ADHD-RS-IV will be performed at the 5-year CA visit. It consists of 18 items designed to 
reflect current symptomatology of ADHD based on DSM-IV criteria. Each item is scored on a 
4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with 
total scores ranging from 0 to 54. The 18 items are grouped into 2 subscales: 
hyperactivity/impulsivity (even numbered items, ranging from 0 to 27) and inattentiveness (odd 
numbered items, ranging from 0 to 27). The total score and subscale scores
(hyperactivity/impulsivity and inattentiveness) will be summarized by treatment group using 
descriptive statistics.
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6.2.4.2
Social Communication Questionnaire (SCQ)
The SCQ (Lifetime version) will be performed at the 5-year CA visit. It has 40 dichotomous 
(yes, no) items, and each scored item receives a value of 1 point for “abnormal behavior” and 
0 point for “absence of abnormal behavior/normal behavior.” It yields a total score ranging from 
0 to 39, with higher scores representing more social communication impairment. The first item, 
“Is she/he now able to talk using short phrases or sentences?”, is not scored, but rather 
determines whether six items relating to abnormal language are assigned. Only “verbal” children 
(ie, children with a “yes” response to the first question) are assigned the six items relating to 
abnormal language and can score a total of 0 to 39 points; “non-verbal” children (ie, children 
with a “no” response to the first question) are not assigned the six items in relation to abnormal 
language and can score a total of 0 to 33 points. These items focus on three areas of functioning:
Reciprocal Social Interaction; Communication; and Restricted, Repetitive, and Stereotyped 
Patterns of Behavior. Refer to Appendix 3 for SCQ items listed under each domain. 
The total score and the domain (Reciprocal Social Interaction, Communication, and 
Repetition/Stereotyped Behavior) scores will be summarized by treatment group using 
descriptive statistics.
6.2.4.3
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
The VABS-II (Sparrow et al., 2005) will be performed at the 6-month, 12-month, 24-month, and 
5-year CA visits. These scales are organized into three domains and three subdomains within 
each domain: Communication (Receptive, Expressive, and Written), Daily Living Skills 
(Personal, Domestic, and Community), and Socialization (Interpersonal Relationships, Play and 
Leisure Time, and Coping Skills). In addition, the VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index. The Motor Skills domain with Gross and Fine subdomains 
will be assessed, if applicable. The four domains combine to form the Adaptive Behavior 
Composite. Standard scores and adaptive levels will be used to interpret domains and Adaptive 
Behavior Composite, while raw scores, v-scaled scores, adaptive levels, and age equivalents will 
be used to interpret subdomains.
The following descriptive summaries will be provided by treatment group and visit for each 
domain and/or subdomain, if applicable:

Descriptive statistics of raw scores, v-scaled scores, and age equivalents for subdomains

Descriptive statistics of standard scores for domains and Adaptive Behavior Composite

The number and percentage of subjects by percentile-based adaptive skill level (low, 
moderately low, adequate, moderately high, and high) for domains, subdomains and 
Adaptive Behavior Composite 
6.2.4.4
Child Behavior Checklist (CBCL) 1½-5
The CBCL (Achenbach et al., 2000) is a parent-reported outcome measure used to assess 
behavioral, emotional, and social functioning of toddlers and preschool children aged 
18-60 months. The CBCL will be performed at the 24-month and 5-year CA visits. It is 
composed of 7 syndromes: Emotionally Reactive, Anxious/Depressed, Somatic Complaints, 
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Withdrawn, Sleep Problems, Attention Problems, and Aggressive Behavior. These preschool 
syndromes are submitted to a second-order factor analysis, two broad-band problems, labeled 
“Internalizing” and “Externalizing”. The former includes the syndromes of Emotionally 
Reactive, Anxious/Depressed, Somatic Complaints, and Withdrawn, while the latter includes 
syndromes of Aggressive Behavior and Attention Problems. The syndrome of Sleep Problems 
stands alone.
The CBCL raw scores are converted to the standardized T-scores, which have a normative group 
mean of 50 and standard deviation of 10. Descriptive statistics of the observed value at each visit 
and change from the 24-month CA visit will be summarized for the seven syndrome scales, 
Internalizing, Externalizing, and Total Problems by treatment group using the raw score and 
normalized T score, respectively.  
For each syndrome, Internalizing, Externalizing, and Total Problems, scores can be interpreted as 
falling in the non-clinical, borderline, or clinical range. The non-clinical T-score range for all 
syndromes is 65 or less, the borderline clinical range is from 66 to 70, while the clinical range is 
71 or greater; For Internalizing, Externalizing, and Total Problems, the cut-off point for the 
non-clinical range is a T score less than 60, borderline is from 60 to 63, and the clinical range is 
64 or greater.
The number and proportion of subjects within each category listed above will be summarized for 
each syndrome, Internalizing, Externalizing, and Total Problems by treatment group and visit.
6.2.5
Pulmonary Morbidity Assessment
Pulmonary morbidity is assessed with questions related to family history and smoking status as 
well as diagnosis of select pulmonary symptoms, conditions and related hospitalizations. 
Pulmonary morbidity assessment will be performed as outlined in the Study Schedule of Events 
(see Appendix 1) with both clinical site visits and phone interviews. Different questionnaires will 
be provided for different type of visits. Items below will be summarized by treatment group and 
visit using descriptive statistics: 

Had asthma, wheezing, BPD exacerbation, or flare-up (yes/no)

Had bronchiolitis, bronchitis, or pneumonia diagnosed (yes/no)

Had to use oxygen at home (yes/no)

Had to visit ER or urgent care (yes/no)

Had to stay in a hospital overnight (yes/no)
Questionnaires of pulmonary morbidity assessment for clinical visits and phone interviews will 
be presented in the data listings separately. 
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7.
SAFETY ANALYSIS 
The safety analysis will be performed using the Safety Set. Safety data include AEs, abdominal 
ultrasound, echocardiogram, physical examination including tonsil examination, blood pressure, 
heart rate, and respiratory rate. Safety summaries will be based on all assessments post-baseline.
All safety analyses will be conducted according to the treatment the subject actually received in 
Study ROPP-2008-01 (Section D).
7.1
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 16.0. AEs and SAEs will be collected and recorded throughout the study, from the time 
of informed consent is signed through the last visit. Ongoing targeted medical events regardless 
of causality, and ongoing study drug-related AEs (including SAEs) collected as part of Study 
ROPP-2008-01 (Section D) will be recorded as AEs in this study. 
For the purposes of this study only the following adverse events will be collected:

Those considered related to investigational product (rhIGF-1/rhIGFBP-3 as
administered in Study ROPP -2008-01, Section D)

Those considered related to procedures performed in this study (SHP-607-201)

AEs related to ROP

AEs related to congenital malformations not identified at birth which may impact
neurocognitive development

Additional illnesses present at the time when informed consent is given are to be
regarded as AEs

Specified targeted medical events (protocol Section 7.9.1.4) regardless of causality
If it is determined that any of the specified targeted medical events have been experienced by a 
subject, they will be recorded as AEs or SAEs, as appropriate, regardless of relationship to 
investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP-2008-01, 
Section D). The targeted medical events are identified based on a list of pre-specified preferred 
terms and are further classified into the following Adverse Events of Special Interest (AESI) 
class:

Cardiac size increase (including cardiomegaly, cardiac hypertrophy, cardiac septal 
hypertrophy, ventricular hypertrophy, atrial hypertrophy, left ventricular hypertrophy, 
right ventricular hypertrophy, left atrial hypertrophy, right atrial hypertrophy, 
cardiomyopathy, cardiomyopathy neonatal, hypertrophic cardiomyopathy)

Tonsillar hypertrophy (including tonsillar hypertrophy, adenoidal hypertrophy, thymus 
enlargement, hypoacusis, snoring, ear tube insertion, tonsillectomy, adenoidectomy, sleep 
apnoea syndrome)
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
Intracranial hypertension (including intracranial pressure increased, benign intracranial 
hypertension, fontanelle bulging, delayed fontanelle closure)

Hypoglycemia (including hypoglycaemia, hypoglycaemia neonatal, blood glucose 
decreased)
An overall summary of the number of subjects as well as the number of events in each treatment 
group and overall will be presented, including the number and percentage of subjects with:

Any AE

Any SAE 

Any severe AE

Any AE related to IP as administered in Study ROPP-2008-01 (Section D)

Any SAE related to IP as administered in Study ROPP-2008-01 (Section D)

Any severe AE related to IP as administered in Study ROPP-2008-01 (Section D)

Any AE related to procedures performed in this study (SHP-607-201)

Any SAE related to procedures performed in this study (SHP-607-201)

Any severe AE related to procedures performed in this study (SHP-607-201)

Any AE leading to death

Any AESI
The number and percentage of subjects reporting AEs, as well as the number of events (except 
for tables by the maximum severity), in each treatment group and overall will be tabulated, 
respectively, in following ways:

By system organ class (SOC) and preferred term (PT) for all AEs

By the maximum severity, SOC and PT for all AEs 

By SOC and PT for all AEs considered related to IP as administered in 
Study ROPP-2008-01 (Section D)

By SOC and PT for all AEs considered related to study procedures

By SOC and PT for all AEs leading to death

By SOC and PT for all SAEs

By AESI class and PT for AESI

By AESI class and PT for serious AESI
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In tables by severity or relationship, missing severity or missing relationship imputation will be 
applied, and handling of those missing cases are detailed in Section 10.4.1 and Section 10.4.2, 
respectively. If a subject had multiple occurrences of the same AEs, the subject will be counted 
only once per SOC and once per PT at the maximum severity. 
All AEs will be presented in a data listing. Separate data listings will be presented for AEs 
related to the antecedent IP, AEs related to study procedures, AEs leading to death, SAEs and 
AESI.
7.2
Cardiac Size
Echocardiographic examination will be performed for the evaluation of cardiac size at the 
6-month CA visit. The following measurements will be summarized by treatment group using 
descriptive statistics.

Interventricular septal thickness 

Posterior wall thickness 

Intracavity volume (both in end diastole and end systole)
The measurement results will be summarized by treatment group using descriptive statistics. 
By-subject listings with the echocardiogram measurement results will be presented. 
7.3
Kidney and Spleen Size
An abdominal ultrasound will be performed to assess the size of the kidneys and spleen at the 
6-month CA visit. 
The measurements of the length of each kidney (left, right) and spleen will be summarized by 
treatment group using descriptive statistics. The measurement results will be categorized into a 
binary response (normal, abnormal) and summarized within each category by the number and 
proportion of subjects in each treatment group. A 2-sided 95% CI will be estimated for subjects 
with a normal status using the Wald test. 
A by-subject listing with the measurement results by abdominal ultrasound and status of 
normality will be presented. 
7.4
Physical Examination
Any abnormal findings from physical examination (including tonsil examination) will be 
summarized by treatment group and visit.
All the physical exam results will be listed by subject in a data listing.
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7.5
Blood Pressure, Heart Rate, and Respiratory Rate
Blood pressure, heart rate and respiratory rate will be summarized by treatment group and visit 
using descriptive statistics and listed by subject in a data listing.
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8.
OTHER ANALYSES
The Enrolled Set will be used for health economics and outcomes research analyses. All the 
analyses will be conducted and summarized by the treatment assigned in Study ROPP-2008-01 
(Section D). All the questionnaire assessments and results will be presented in the data listings.
8.1
Pediatric Quality of Life Inventory (PedsQL)
The PedsQL will be performed at the 3-month, 6-month, 12-month, 24-month, 3-year, 4-year and 
5-year CA visits. The infant scales that apply to ages less than 24 months include Physical 
Functioning, Physical Symptoms, Emotional Functioning, Social Functioning, and Cognitive 
Functioning. The generic core scales that apply to toddlers (ages 24 months to 4 years) and 
young children (ages 5 to 7 years) include Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning. The scale scores, the summary scores (Physical Health 
Summary Score and Psychosocial Health Summary Score), and the total score will be 
summarized by treatment group using descriptive statistics of the observed value at each visit 
and change from the first assessment for both infants (ages less than 24 months) and 
toddlers/young children (ages 24 months to 7 years), separately. 
8.2
Health Utility
8.2.1
Health Status Classification System-Preschool (HSCS-PS)
The HSCS-PS will be performed at the 24-month, 3-year, 4-year and 5-year CA visits. The 
instrument is composed of 12 domains (Vision, Hearing, Speech, Mobility, Dexterity, Self-care, 
Emotion, Learn/Remember, Think/Problem Solve, Pain, General Health, and Behavior). Each 
domain has up to 6 levels (0-5) to indicate the health status (with higher numbers indicating 
better status). Descriptive statistics will be presented for each domain by treatment group and 
visit. 
These domains will be grouped into four categories: Neurosensory (Vision and Hearing), Motor 
(Mobility, Dexterity, and Self-care), Learning/Remembering (Speech, Learn/Remember, and 
Think/Problem Solve) and Quality of Life (Emotion, Pain, General Health, and Behavior). For 
each category, the data will be recorded into the following levels: no problem (scoring 0 on any 
attribute); a mild problem (scoring 1 on a scale of 0 to 3, or 1 to 2 on a scale of 0 to 5 for any 
attribute); or a moderate or severe problem (scoring >1 on a scale of 0 to 3, or >2 on a scale of 0 
to 5 for any attribute). The number and percentage of subjects in each level for each category 
will be summarized by treatment group and visit. 
8.2.2
Health Utilities Index Mark 2 and Mark 3 (HUI2/3)
The HUI2/3 will be performed at the 5-year CA visit. The HUI2 classification system scores 
6 attributes: Sensation, Mobility, Cognition, Self-Care, Emotion, and Pain. The HUI3 
classification system comprises 8 attributes: Vision, Hearing, Speech, Cognition, Ambulation, 
Dexterity, Emotion, and Pain. Each attribute has up to 6 levels to indicate the severity (with 
higher numbers indicating worse levels). Single-attribute scores of morbidity are defined on a 
scale such the worst level has a score of 0.00 and the best level has a score of 1.00.
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The number and percentage of subjects in each level for each attribute will be summarized by 
treatment group. The utility score for each attribute and the overall utility score will be 
summarized by treatment group using descriptive statistics.
8.3
Health Care Resource Use (HCRU)
The HCRU will be performed at the 3-month, 6-month, 12-month, 24-month, 3-year, 4-year and 
5-year CA visits. The following items will be summarized descriptively by treatment group and 
visit:

The number of visits to health care providers (including Pediatrician, General Practitioner 
or Family Doctor, Pediatric Ophthalmologist or Ophthalmologist, Pediatric 
Pulmonologist or Pulmonologist, Physical Therapist, Occupational Therapist, 
Developmental Therapist, Speech Therapist, and Other) in private office/clinic and 
hospital outpatient

The number of visits to the Emergency Department / Urgent Center / Casualty / Accident 
or Emergency

The duration of hospitalization (days)

Use of prescription eyeglasses (yes/no)

Receive educational support (yes/no)
The duration/number of visits will be calculated as the sum of all durations/number of visits at 
each visit window. Subjects who were not hospitalized/made no visits at the corresponding visit 
window will not be counted.   
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9.
INTERIM ANALYSIS 
No formal interim analysis is planned. A snapshot of the data was reviewed after all enrolled 
subjects in this study completed 2-year follow-up (24-month visit) assessments or prematurely 
withdrew from the study before completing 2 years of follow up, and after data were entered into 
the database, queried, and discrepancies resolved. 
A selective descriptive analysis of the data with focus on the 24-month CA visit for this interim 
review was performed and used to understand the progress of the study, completion of the data, 
safety monitoring, regulatory communication, and general planning purposes.
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10.
DATA HANDLING CONVENTIONS 
10.1
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, minimum and maximum. Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in each category. 
Unless specified otherwise, median and mean will use 1 decimal place beyond the precision of 
data used for the measurement; standard deviation and standard error of the mean will use 
2 decimal places beyond the precision; minimum and maximum values will use the same number 
of decimal places as the precision. P-values will be rounded to 3 decimal places and presented as 
<0.001 for values less than 0.001.
10.2
Definition of Visit Windows 
Assessments will be assigned to visits based on the completed CRF page. 
10.3
Repeated or Unscheduled Assessments 
If End-of-Study (EOS) assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics if 
needed. However, all assessments will be presented in the data listings.
10.4
Handling of Missing, Unused, and Spurious Data 
10.4.1
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE, a severity of “Severe” will be assigned. The imputed values for 
severity assessment will be used for incidence summaries, while the actual values will be used in 
data listings.
10.4.2
Missing Relationship for Adverse Events 
If the relationship to investigational product (as administered in Study ROPP-2008-01, 
Section D) is missing for an AE, a causality of “Related” will be assigned. If the relationship to 
study procedure performed in this study (SHP-607-201) is missing for an AE starting on or after 
the date of informed consent, a causality of “Related” will be assigned. The imputed values for 
relationship will be used for incidence summaries, while the actual values will be presented in 
data listings.
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11.
ANALYSIS SOFTWARE 
Statistical analyses will be performed using Version 9.4 (or newer) of SASon a suitably 
qualified environment. 
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13.
REFERENCES
Achenbach T, Rescorla L. Manual for the ASEBA preschool forms and profiles. Burlington, VT: 
University of Vermont; 2000.Johnson S, Moore T, Marlow N. Using the Bayley-III to assess 
neurodevelopmental delay: which cut-off should be used? Pediatr Res. 2014; 75(5): 670-674.
Marvin AR, Marvin DJ, Lipkin PH, Law JK. Analysis of Social Communication Questionnaire 
(SCQ) Screening for Children Less Than Age 4. Curr Dev Disord Rep. 2017; 4(4): 137-144. 
Rutter M, Bailey A, Lord C. Manual for the Social Communication Questionnaire. 2003.
Schiariti V, Klassen AF, Houbé JS, Synnes A, Lisonkova S, Lee SK. Perinatal characteristics 
and parents' perspective of health status of NICU graduates born at term. J Perinatol. 2008; 
28(5): 368-376. 
Sparrow SS, Cicchetti, DV, Balla, DA. The Vineland Adaptive Behavior Scales, 2nd edition 
(VABS-II). NCS Pearson Inc. 2005.
Wechsler D. Wechsler preschool and primary scale of intelligence 4th ed. Bloomington, MN: 
Pearson; 2012.
World Health Organization. WHO Child Growth Standards: Length/Height-for-Age, Weight-for-
Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and 
Development. Geneva: World Health Organization; 2006: 301-304.
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Appendix 1
Study Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For non-commercial use only


For non-commercial use only


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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
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g
The 20-month visit and the 4.75-year (4 years, 9 months) visit must occur at least 1 month prior to the 24-month and 5-year visits, respectively. Any 
prescribed corrective lenses must be worn for at least 1 month prior to the 24-month and 5-year assessments. 
h
Refraction with cycloplegia will be performed as part of the corrective lens determination procedure.
i
The HRQoL, HCRU, and HSCS-PS assessments for the 6-month, 12-month, 24-month and 5-year visits may be performed through clinical site staff if there 
are time constraints during the on-site visit. At the 3-month, 3-year, and 4-year visits, these assessments will be performed through clinical site staff and may 
be performed at any time within the visit window.
j
The following, collected as part of the ROPP-2008-01 study, will be used as part of this study (SHP-607-201): any ongoing targeted medical events 
regardless of causality and any ongoing study drug-related AEs, including SAEs.
k
Multiple visits and/or phone contacts are allowed to complete all assessments, if needed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
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Table A1
Summary of Visual Acuity Assessments
CA=corrected age; ETDRS=Early Treatment of Diabetic Retinopathy Study
a
At ages 24 months and 5 years CA an attempt should be made to assess visual acuity by the LEA Symbols Test 
and LEA Symbols Chart, respectively. If during this attempt, the examiner determines that it will not be 
possible to perform an accurate assessment with the relevant LEA tool, visual acuity should be assessed with 
the Teller acuity cards.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For non-commercial use only


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Statistical Analysis Plan
Protocol: SHP-607-201 Version 1
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Appendix 3
SCQ Items Listed Under the Domains
Reciprocal Social Interaction domain
9. Inappropriate facial expression
10. Use of other’s body to communicate
19. Friends
26. Eye gaze
27. Social smiling
28. Showing and directing attention
29. Offering to share
30. Seeking to share enjoyment
31. Offering comfort
32. Quality of social overtures
33. Range of facial expression
36. Interest in children
37. Response to other children’s approaches
39. Imaginative play with peers
40. Group play
Communication domain
2. Conversation
3. Stereotyped utterances
4. Inappropriate questions
5. Pronoun reversal
6. Neologisms
20. Social chat
21. Imitation
22. Pointing to express interest
23. Gestures
24. Nodding to mean yes
25. Head shaking to mean no
34. Imitative social play
35. Imaginative play
Restricted, Repetitive, and Stereotyped Patterns of Behavior domain
7. Verbal rituals
8. Compulsions and rituals
11. Unusual preoccupations
12. Repetitive use of objects
13. Circumscribed interests
14. Unusual sensory interests
15. Hand and finger mannerisms
16. Complex body mannerisms
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