Trial Outcomes & Findings for Long-term Safety and Efficacy Outcome Study Comparing Children Previously Enrolled in Study ROPP-2008-01 for the Prevention of Retinopathy of Prematurity (ROP) (NCT NCT02386839)

Last Updated: 2022-05-18

Results Overview

Standard age-appropriate methods were used to assess visual acuity (how well a participant sees at different distances) with teller acuity cards, LEA symbols test and Charts. It was categorized as 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). Corrected Age (weeks) was defined as Chronological Age (weeks) - 40 + Gestational Age (weeks) in this study.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

76 participants

Primary outcome timeframe

At 6 Months CA

Results posted on

2022-05-18

Participant Flow

This study was conducted at 16 sites from 26 March 2015 (first participant first visit) to 28 September 2021 (last participant last visit).

A total of 76 participants who previously treated with rhIGF 1/rhIGFBP-3 or Standard Neonatal Care in ROPP-2008-01 (NCT01096784) study were enrolled in this long-term safety and efficacy study.

Participant milestones

Participant milestones
Measure	Antecedent Standard of Care Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Overall Study STARTED	36	40
Overall Study COMPLETED	20	25
Overall Study NOT COMPLETED	16	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Antecedent Standard of Care Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Overall Study Death	1	0
Overall Study Withdrawal by Subject	9	10
Overall Study Lost to Follow-up	4	4
Overall Study Other (Site Terminated by Sponsor)	1	0
Overall Study Other (Covid 19 Pandemic)	0	1
Overall Study Other (unspecified)	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Antecedent Standard of Care n=36 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).	Total n=76 Participants Total of all reporting groups
Age, Continuous	7.15 Weeks STANDARD_DEVIATION 5.622 • n=5 Participants	6.73 Weeks STANDARD_DEVIATION 6.224 • n=7 Participants	6.93 Weeks STANDARD_DEVIATION 5.911 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	14 Participants n=7 Participants	27 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	26 Participants n=7 Participants	49 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	13 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	27 Participants n=7 Participants	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) White	26 Participants n=5 Participants	34 Participants n=7 Participants	60 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: At 6 Months CA

Population: Enrolled set included all participants for whom written informed consent was obtained for this long-term outcome study. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified categories.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=27 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=34 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Right Eye · Normal	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Right Eye · Below Normal	12 Participants	19 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Right Eye · Poor	12 Participants	13 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Left Eye · Normal	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Left Eye · Below Normal	14 Participants	18 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Left Eye · Poor	7 Participants	14 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Both Eyes · Normal	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Both Eyes · Below Normal	18 Participants	25 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected Age (CA) Participants With Both Eyes · Poor	9 Participants	9 Participants

PRIMARY outcome

Timeframe: At 12 Months CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=24 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=36 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Right Eye · Normal	0 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Right Eye · Below Normal	21 Participants	26 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Right Eye · Poor	0 Participants	5 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Left Eye · Normal	0 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Left Eye · Below Normal	20 Participants	25 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Left Eye · Poor	1 Participants	6 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Both Eyes · Normal	0 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Both Eyes · Below Normal	23 Participants	33 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA Participants With Both Eyes · Poor	1 Participants	2 Participants

PRIMARY outcome

Timeframe: At 20 Months CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=33 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Right Eye · Normal	0 Participants	2 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Right Eye · Below Normal	17 Participants	23 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Right Eye · Poor	2 Participants	4 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Left Eye · Normal	0 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Left Eye · Below Normal	18 Participants	24 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Left Eye · Poor	2 Participants	4 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Both Eyes · Normal	0 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Both Eyes · Below Normal	20 Participants	30 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA Participants With Both Eyes · Poor	3 Participants	2 Participants

PRIMARY outcome

Timeframe: At 24 Months CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=33 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Right Eye · Normal	0 Participants	2 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Right Eye · Below Normal	17 Participants	25 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Right Eye · Poor	3 Participants	4 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Left Eye · Normal	0 Participants	2 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Left Eye · Below Normal	17 Participants	24 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Left Eye · Poor	3 Participants	2 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Both Eyes · Normal	1 Participants	5 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Both Eyes · Below Normal	19 Participants	24 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA Participants With Both Eyes · Poor	3 Participants	4 Participants

PRIMARY outcome

Timeframe: At 4.75 Years CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=15 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=18 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Right Eye · Normal	11 Participants	15 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Right Eye · Below Normal	4 Participants	3 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Right Eye · Poor	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Left Eye · Normal	11 Participants	14 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Left Eye · Below Normal	4 Participants	4 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Left Eye · Poor	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Both Eyes · Normal	10 Participants	17 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Both Eyes · Below Normal	5 Participants	1 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA Participants With Both Eyes · Poor	0 Participants	0 Participants

PRIMARY outcome

Timeframe: At 5 Years CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=14 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Right Eye · Normal	9 Participants	11 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Right Eye · Below Normal	5 Participants	6 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Right Eye · Poor	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Left Eye · Normal	8 Participants	11 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Left Eye · Below Normal	6 Participants	6 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Left Eye · Poor	0 Participants	0 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Both Eyes · Normal	9 Participants	11 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Both Eyes · Below Normal	5 Participants	6 Participants
Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA Participants With Both Eyes · Poor	0 Participants	0 Participants

PRIMARY outcome

Timeframe: At 12 Months CA

Population: Enrolled set included all participants for whom written informed consent was obtained for this long-term outcome study. Here, "Overall Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Ocular alignment was assessed in primary gaze by comparing the position of the corneal light reflection in left eye and right eye (corneal light reflection assessment). Presence or absence of strabismus was 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 was recorded. Ocular motility referred to eye movements governed by the 6 extraocular muscles in each eye. It was assessed by examiner observation of the participants ability to abduct, adduct, supra, and inferoduct each eye. Ocular alignment and motility included the presence or absence of strabismus (classified as Esotropia \[inward turn of the eye\], Exotropia \[outward turn of the eye\], Hypertropia \[upward turn of the eye\], Hypotropia \[downward turn of the eye\]) was recorded. Number of participants with combined data for ocular alignment and oculomotor examination (motility) at 12 months CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=25 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=36 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Esotropia · Presence	1 Participants	4 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Esotropia · Absence	24 Participants	32 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Exotropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Exotropia · Absence	25 Participants	36 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Hypertropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Hypertropia · Absence	25 Participants	36 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Hypotropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA Participants with Hypotropia · Absence	25 Participants	36 Participants

PRIMARY outcome

Timeframe: At 24 Months CA

Ocular alignment was assessed in primary gaze by comparing the position of the corneal light reflection in left eye and right eye (corneal light reflection assessment). Presence or absence of strabismus was 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 was recorded. Ocular motility referred to eye movements governed by the 6 extraocular muscles in each eye. It was assessed by examiner observation of the participants ability to abduct, adduct, supra, and inferoduct each eye. Ocular alignment and motility included the presence or absence of strabismus (classified as Esotropia, Exotropia, Hypertropia, Hypotropia) was recorded. Number of participants with combined data for ocular alignment and oculomotor examination (motility) assessed by corneal light reflex and by the cover test at 24 months CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=34 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Esotropia · Presence	1 Participants	5 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Esotropia · Absence	22 Participants	29 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Exotropia · Presence	0 Participants	1 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Exotropia · Absence	23 Participants	33 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Hypertropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Hypertropia · Absence	23 Participants	34 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Hypotropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA Participants with Hypotropia · Absence	23 Participants	34 Participants

PRIMARY outcome

Timeframe: At 5 Years CA

Ocular alignment was assessed in primary gaze by comparing the position of the corneal light reflection in left eye and right eye (corneal light reflection assessment). Presence or absence of strabismus was 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 was recorded. Ocular motility referred to eye movements governed by the 6 extraocular muscles in each eye. It was assessed by examiner observation of the participants ability to abduct, adduct, supra, and inferoduct each eye. Ocular alignment and motility included the presence or absence of strabismus (classified as Esotropia, Exotropia, Hypertropia, Hypotropia) was recorded. Number of participants with combined data for ocular alignment and oculomotor examination (motility) assessed by corneal light reflex and by the cover test at 5-Years CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=14 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Esotropia · Presence	1 Participants	1 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Esotropia · Absence	13 Participants	16 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Exotropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Exotropia · Absence	14 Participants	17 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Hypertropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Hypertropia · Absence	14 Participants	17 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Hypotropia · Presence	0 Participants	0 Participants
Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA Participants with Hypotropia · Absence	14 Participants	17 Participants

PRIMARY outcome

Timeframe: At 12 Months CA

Population: Enrolled set included of all participants for whom written informed consent was obtained for this long-term outcome study. Here, "Overall Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Nystagmus was observed during the ocular alignment assessments. Presence and absence of nystagmus was reported at 12 Months CA.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=25 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=36 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Nystagmus at 12 Months CA Participants with presence of nystagmus	1 Participants	2 Participants
Number of Participants With Nystagmus at 12 Months CA Participants with absence of nystagmus	24 Participants	34 Participants

PRIMARY outcome

Timeframe: At 24 Months CA

Nystagmus was observed during the ocular alignment assessments. Presence and absence of nystagmus was reported at 24 Months CA.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=34 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Nystagmus at 24 Months CA Participants with presence of nystagmus	0 Participants	2 Participants
Number of Participants With Nystagmus at 24 Months CA Participants with absence of nystagmus	23 Participants	32 Participants

PRIMARY outcome

Timeframe: At 5 Years CA

Nystagmus was observed during the ocular alignment assessments. Presence and absence of nystagmus was reported at 5 Years CA.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=14 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Nystagmus at 5 Years CA Participants with presence of nystagmus	0 Participants	2 Participants
Number of Participants With Nystagmus at 5 Years CA Participants with absence of nystagmus	14 Participants	15 Participants

PRIMARY outcome

Timeframe: At 6 Months CA

Refraction was a measure of the lens power required for a focused image on the retina. Refraction with cycloplegia was measured and recorded in diopters for each eye individually (left eye and right eye). Refraction with cycloplegia performed as part of the corrective lens determination procedure included measurements of sphere, cylinder, axis, and prism for each individual eye (left eye and right eye). For sphere, the negative values are summarized as 'nearsighted', and the positive values (including sphere of 0.00) are summarized as 'farsighted'.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=25 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=34 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Right Eye: Sphere (Nearsighted)	-1.833 Diopter Standard Deviation 1.0916	-1.417 Diopter Standard Deviation 1.4216
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Right Eye: Sphere (Farsighted)	1.976 Diopter Standard Deviation 1.2572	1.838 Diopter Standard Deviation 1.3256
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Right Eye: Cylinder	0.875 Diopter Standard Deviation 0.8534	0.932 Diopter Standard Deviation 0.8801
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Right Eye: Axis	116.4 Diopter Standard Deviation 58.03	106.0 Diopter Standard Deviation 52.87
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Left Eye: Sphere (nearsighted)	-1.750 Diopter Standard Deviation 0.9747	-1.250 Diopter Standard Deviation 0.9014
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Left Eye: Sphere (farsighted)	2.034 Diopter Standard Deviation 1.2731	1.831 Diopter Standard Deviation 1.3494
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Left Eye: Cylinder	0.820 Diopter Standard Deviation 0.6395	0.962 Diopter Standard Deviation 0.8341
Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA Left Eye: Axis	120.3 Diopter Standard Deviation 52.27	108.8 Diopter Standard Deviation 54.18

PRIMARY outcome

Timeframe: At 12 Months CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=30 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Right Eye: Sphere (Nearsighted)	-1.564 Diopter Standard Deviation 1.8752	-2.438 Diopter Standard Deviation 1.4773
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Right Eye: Sphere (Farsighted)	2.042 Diopter Standard Deviation 1.1796	1.491 Diopter Standard Deviation 1.0908
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Right Eye: Cylinder	0.783 Diopter Standard Deviation 0.7163	0.926 Diopter Standard Deviation 0.6423
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Right Eye: Axis	86.0 Diopter Standard Deviation 62.82	105.7 Diopter Standard Deviation 50.53
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Right Eye: Prism	0.00 Diopter Standard Deviation 0.000	0.00 Diopter Standard Deviation 0.000
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Left Eye: Sphere (Nearsighted)	-2.875 Diopter Standard Deviation 1.9203	-2.500 Diopter Standard Deviation 1.7048
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Left Eye: Sphere (Farsighted)	1.857 Diopter Standard Deviation 1.3171	1.606 Diopter Standard Deviation 1.1962
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Left Eye: Cylinder	0.663 Diopter Standard Deviation 0.6334	0.851 Diopter Standard Deviation 0.6795
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Left Eye: Axis	107.3 Diopter Standard Deviation 60.19	112.6 Diopter Standard Deviation 55.11
Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA Left Eye: Prism	0.00 Diopter Standard Deviation 0.000	0.00 Diopter Standard Deviation 0.000

PRIMARY outcome

Timeframe: At 20 Months CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=31 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Right Eye: Sphere (Nearsighted)	-2.350 Diopter Standard Deviation 2.4083	-1.700 Diopter Standard Deviation 1.6808
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Right Eye: Sphere (Farsighted)	1.903 Diopter Standard Deviation 0.9931	1.278 Diopter Standard Deviation 0.8996
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Right Eye: Cylinder	0.750 Diopter Standard Deviation 0.6755	0.778 Diopter Standard Deviation 0.6841
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Right Eye: Axis	105.0 Diopter Standard Deviation 62.33	122.8 Diopter Standard Deviation 58.69
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Right Eye: Prism	0.00 Diopter Standard Deviation 0.000	0.00 Diopter Standard Deviation 0.000
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Left Eye: Sphere (Nearsighted)	-3.500 Diopter Standard Deviation 1.8028	-2.600 Diopter Standard Deviation 1.9733
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Left Eye: Sphere (Farsighted)	1.800 Diopter Standard Deviation 1.2237	1.389 Diopter Standard Deviation 1.1080
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Left Eye: Cylinder	0.900 Diopter Standard Deviation 0.8288	0.681 Diopter Standard Deviation 0.5665
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Left Eye: Axis	117.8 Diopter Standard Deviation 53.82	110.1 Diopter Standard Deviation 53.56
Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA Left Eye: Prism	0.00 Diopter Standard Deviation 0.000	0.00 Diopter Standard Deviation 0.000

PRIMARY outcome

Timeframe: At 4.75 Years CA

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=17 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Right Eye: Sphere (Nearsighted)	-8.500 Diopter Standard Deviation NA SD is not evaluable for single participants mean data point	-0.500 Diopter Standard Deviation NA SD is not evaluable for single participants mean data point
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Right Eye: Sphere (Farsighted)	1.691 Diopter Standard Deviation 1.1094	1.383 Diopter Standard Deviation 1.5465
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Right Eye: Cylinder	0.593 Diopter Standard Deviation 0.6505	0.603 Diopter Standard Deviation 0.6254
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Right Eye: Axis	99.1 Diopter Standard Deviation 69.95	119.0 Diopter Standard Deviation 56.05
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Right Eye: Prism	0.02 Diopter Standard Deviation 0.075	0.00 Diopter Standard Deviation 0.000
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Left Eye: Sphere (Nearsighted)	-6.500 Diopter Standard Deviation NA SD is not evaluable for single participants mean data point	-0.750 Diopter Standard Deviation NA SD is not evaluable for single participants mean data point
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Left Eye: Sphere (Farsighted)	1.853 Diopter Standard Deviation 1.2376	1.517 Diopter Standard Deviation 1.9966
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Left Eye: Cylinder	0.717 Diopter Standard Deviation 0.7126	0.574 Diopter Standard Deviation 0.5574
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Left Eye: Axis	88.6 Diopter Standard Deviation 65.64	114.2 Diopter Standard Deviation 55.17
Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA Left Eye: Prism	0.02 Diopter Standard Deviation 0.056	0.00 Diopter Standard Deviation 0.000

PRIMARY outcome

Timeframe: At 5 Years CA

Stereoacuity, a measure of depth perception, was assessed using the Lang Stereotest. Number of participants with presence and absence of stereopsis (the ability to perceive depth and 3-dimensional structure) was reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=14 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA Participants with presence of stereopsis	13 Participants	16 Participants
Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA Participants with absence of stereopsis	1 Participants	1 Participants

PRIMARY outcome

Timeframe: From start of study up to end of study (up to 6.5 years)

Population: Safety Set included all participants in the Enrolled Set who have safety follow-up data in this long-term outcome study.

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=36 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Adverse Events (AEs)	11 Participants	9 Participants

SECONDARY outcome

Timeframe: Baseline, 6 Months CA, 12 Months CA, 24 Months CA and 5 Years CA

Body weight collected using calibrated scales (type of scale was dependent upon participant's age). Measure recorded to the nearest 0.1 kilogram (kg). Z-score based on participants chronological age and utilizing World Health Organization child growth standards by adjusting age and sex- matched means and standard deviations (norm). Z-score is standard score that gives idea of how far from the mean a data point is. If Z-score is 0, it indicates that the data point's score is identical to the mean score. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Baseline is first assessment in the antecedent study (ROPP-2008-01 \[NCT01096784\]). Change from baseline in body weight Z-score at 6-month, 12-month, 24-month and 5-year CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=28 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline in Body Weight Z-score Change at 6 Months CA	4.40 Z-score Standard Deviation 1.323	4.30 Z-score Standard Deviation 1.146
Change From Baseline in Body Weight Z-score Change at 12 Months CA	5.08 Z-score Standard Deviation 1.300	4.88 Z-score Standard Deviation 1.026
Change From Baseline in Body Weight Z-score Change at 24 Months CA	5.17 Z-score Standard Deviation 0.885	4.99 Z-score Standard Deviation 0.983
Change From Baseline in Body Weight Z-score Change at 5 Years CA	5.80 Z-score Standard Deviation 1.149	5.60 Z-score Standard Deviation 1.660

SECONDARY outcome

Timeframe: Baseline, 6 Months CA, 12 Month CA, 24 Months CA and 5 Years CA

Height was measured using Z-score. Z-score was calculated based on the participants chronological age and utilizing World Health Organization child growth standards by adjusting age and sex- matched means and standard deviations (norm). Z-score is a standard score that gives an idea of how far from the mean a data point is. If a Z-score is 0, it indicates that the data point's score is identical to the mean score. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Baseline was defined as the first assessment in the antecedent study (ROPP-2008-01 \[NCT01096784\]). Change from baseline in Height Z-score at 6-month, 12-month, 24-month and 5-year CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=28 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline in Height Z-score Change at 6 Months CA	6.36 Z-Score Standard Deviation 1.711	6.19 Z-Score Standard Deviation 1.215
Change From Baseline in Height Z-score Change at 12 Months CA	6.79 Z-Score Standard Deviation 1.747	7.25 Z-Score Standard Deviation 1.155
Change From Baseline in Height Z-score Change at 24 Months CA	7.30 Z-Score Standard Deviation 2.029	7.78 Z-Score Standard Deviation 1.376
Change From Baseline in Height Z-score Change at 5 Years CA	7.84 Z-Score Standard Deviation 1.856	8.17 Z-Score Standard Deviation 1.505

SECONDARY outcome

Timeframe: Baseline, 6 Months CA, 12 Months CA and 24 Months CA

Head circumference measured for all participants using a "lasso" type, non-stretchable measuring tape such as the Lasso-o tape. Z-score calculated based on participants chronological age and utilizing World Health Organization child growth standards by adjusting age, sex matched means and standard deviations (norm).Z-score is standard score that gives idea of how far from mean a data point is. If a Z-score is 0, it indicates that data point's score is identical to mean score. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Baseline was defined as the first assessment in the antecedent study (ROPP-2008-01 \[NCT01096784\]). Change from baseline in Head Circumference Z-score at 6, 12 and 24-months reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=28 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline in Head Circumference Z-score Change at 6 Months CA	7.61 Z-score Standard Deviation 1.535	7.12 Z-score Standard Deviation 1.576
Change From Baseline in Head Circumference Z-score Change at 12 Months CA	8.29 Z-score Standard Deviation 1.472	7.83 Z-score Standard Deviation 1.567
Change From Baseline in Head Circumference Z-score Change at 24 Months CA	8.44 Z-score Standard Deviation 1.415	8.05 Z-score Standard Deviation 1.692

SECONDARY outcome

Timeframe: Baseline (12 Months CA), 24 Months CA

BSID-III was to assess cognitive, motor, and language skills, and applicable to children aged 1-42 months. There are 5 subscales, cognitive subscale (Ranges: 55-145) stands alone while 2 language subscales (expressive and receptive) combine to make a total language score (Ranges: 47-153) and 2 motor subtests (fine and gross motor) form combined motor scale (Ranges: 46-154). Higher scores represent greater cognitive, language and motor abilities. Positive value indicates improvement and negative value indicate worsening in cognitive development. The 12 Months CA considered as baseline for this outcome measure. Composite scores derived from various sums of subtest scaled scores and scaled to a metric with a mean of 100 and a standard deviation of 15 and range from 40 to 160. Higher values denote stronger skills and abilities in the domain, indicating better outcomes.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=32 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline (12 Months CA) in Cognitive Development as Assessed by Bayley Scales of Infant and Toddler Development (BSID-III) Composite Scores at 24 Months CA Cognitive Composite Scores: Change at 24 Months CA	7.0 Score on a scale Standard Deviation 18.45	6.6 Score on a scale Standard Deviation 21.27
Change From Baseline (12 Months CA) in Cognitive Development as Assessed by Bayley Scales of Infant and Toddler Development (BSID-III) Composite Scores at 24 Months CA Language Composite Scores: Change at 24 Months CA	2.4 Score on a scale Standard Deviation 18.73	-0.9 Score on a scale Standard Deviation 15.79
Change From Baseline (12 Months CA) in Cognitive Development as Assessed by Bayley Scales of Infant and Toddler Development (BSID-III) Composite Scores at 24 Months CA Motor Composite Scores: Change at 24 Months CA	12.2 Score on a scale Standard Deviation 23.54	10.8 Score on a scale Standard Deviation 18.25

SECONDARY outcome

Timeframe: At 5 Years CA

The WPPSI-IV is a measure of general cognitive development in children that has components of both verbal and non-verbal tasks. 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. The test framework of the WPPSI-IV is organized into five Primary Index sub scales: Verbal Comprehension, Visual Spatial, Fluid Reasoning, Working Memory, and Processing Speed. The Full Scale includes all of the sub scales at the Primary Index scale level, as well as any additional supplemental subtests that may be used to derive the Full Scale IQ. Composite scores are derived from the sum of sub scaled scores with a mean of 100 and a standard deviation of 15. Composite score for Full Scale IQ and subscales (Verbal Comprehension, Visual Spatial, Fluid Reasoning, Working Memory, and Processing Speed) ranges from 40 (extremely low) to 160 (very superior). Data for Full scale IQ was reported here.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=11 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=14 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Cognitive Development as Assessed by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) Full Scale at 5 Years CA	97.3 Scores on a scale Standard Deviation 17.28	91.6 Scores on a scale Standard Deviation 14.17

SECONDARY outcome

Timeframe: From start of study drug administration up to end of study (up to 6.5 years)

Population: Safety Set included all participants in the Enrolled Set who have safety follow-up data in this long-term outcome study.

Physical examination includes general appearance; head and neck, eyes, ears, nose and throat; chest and lungs; endocrine, cardiovascular system, abdomen, genitourinary, skin and musculoskeletal system.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=36 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Abnormal Physical Examination	13 Participants	18 Participants

SECONDARY outcome

Timeframe: At 24 Months CA

A comprehensive neurological examination for the diagnosis of CP was conducted. The Amiel-Tison neurological examination framework was utilized for this assessment and it was conducted by trained medical professionals. Number of Participants diagnosed with CP by neurological examination at 24 Months CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=25 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=37 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants Diagnosed With Neurological Examination for Cerebral Palsy (CP) by Neurological Examination at 24 Months CA	1 Participants	5 Participants

SECONDARY outcome

Timeframe: At 6 Months CA and 5 Years CA

Number of participants with any hearing status (normal and abnormal) were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=21 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=28 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Normal and Abnormal Hearing Screening Status At 6 Months CA · Normal Hearing	20 Participants	24 Participants
Number of Participants With Normal and Abnormal Hearing Screening Status At 6 Months CA · Abnormal Hearing	1 Participants	4 Participants
Number of Participants With Normal and Abnormal Hearing Screening Status At 5 Years CA · Normal Hearing	15 Participants	20 Participants
Number of Participants With Normal and Abnormal Hearing Screening Status At 5 Years CA · Abnormal Hearing	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (6 Months CA), 12 Months CA, 24 Months CA, and 5 Year CA

The VABS-II was used to measure the personal and social skills of participants serially over time. This test measures the following 4 key domains: Communication, Daily Living Skills, Socialization, and Motor skills. The domains have the same range and directionality as the adaptive behavior composite score (20-160). Higher scores indicate higher level of cognitive ability. A positive change value indicates improvement and negative value indicates worsening in adaptive functioning. The 6 months CA was considered as baseline for this outcome measure. Change from baseline (6 Months CA) in child behavior as assessed by VABS-II adaptive behavior composite was reported here.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=22 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=30 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II) Change at 12 Months CA: Adaptive Behavior Composite	-0.3 Score on a scale Standard Deviation 14.50	-1.5 Score on a scale Standard Deviation 12.41
Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II) Change at 24 Months CA: Adaptive Behavior Composite	7.8 Score on a scale Standard Deviation 16.47	0.8 Score on a scale Standard Deviation 14.89
Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II) Change at 5 Years CA: Adaptive Behavior Composite	-3.2 Score on a scale Standard Deviation 20.92	-3.9 Score on a scale Standard Deviation 19.86

SECONDARY outcome

Timeframe: At 24 Months CA and 5 Years CA

The CBCL (1 ½ to 5) was parent-reported outcome measure used to assess behavioral, emotional, and social functioning of toddlers and preschool children aged 18-60 months. It is composed of 99 items rated on Likert scale and includes 7 syndrome scales under 2 domains (Internalizing and Externalizing Problems): Internalizing includes syndromes of Emotionally Reactive, Anxious/Depressed, Somatic Complaints, and Withdrawn. Externalizing includes syndromes of Aggressive Behavior and Attention Problems. The 2 domains of all 7 scales were combined to form total score range of 23 to 100. For each question, raw scores of all subscales are converted to standardized T-scores. Higher T score indicates more behavior problems. For Internalization, Externalization and Total Behavior Problem, T-scores of less than 60 are considered non-clinical, 60-63 are borderline, and 64 or more are considered clinical.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=23 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=34 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Internalizing · Borderline	0 Participants	0 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Internalizing · Clinical	0 Participants	2 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Internalizing · Non-Clinical	15 Participants	15 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Internalizing · Borderline	1 Participants	2 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Internalizing · Clinical	3 Participants	3 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Externalizing · Non-Clinical	21 Participants	32 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Externalizing · Borderline	1 Participants	0 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Externalizing · Clinical	1 Participants	2 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Externalizing · Non-Clinical	16 Participants	17 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Externalizing · Borderline	0 Participants	2 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Externalizing · Clinical	3 Participants	1 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Total Behavior Problems · Non-Clinical	22 Participants	31 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Total Behavior Problems · Borderline	1 Participants	3 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Total Behavior Problems · Clinical	0 Participants	0 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Total Behavior Problems · Non-Clinical	14 Participants	17 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Total Behavior Problems · Borderline	3 Participants	2 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 5 Years CA: Total Behavior Problems · Clinical	2 Participants	1 Participants
Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories At 24 Months CA: Internalizing · Non-Clinical	23 Participants	32 Participants

SECONDARY outcome

Timeframe: At 5 Years CA

The ADHD-RS measures the behaviors of children with Attention-Deficit/Hyperactivity Disorder (ADHD). It consisted of 18 items designed to reflect current symptomatology of ADHD based on DSM-IV criteria. Each item was 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. Higher scores represent greater severity of ADHD symptoms.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=18 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=20 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Child Behavior as Assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Based on Total Score	11.9 Score on scale Standard Deviation 9.30	8.3 Score on scale Standard Deviation 10.10

SECONDARY outcome

Timeframe: At 5 Years CA

The SCQ is a brief instrument evaluate communication skills and social functioning in children used for screening for autism or autism spectrum disorders (ASD). The SCQ has 40 dichotomous (yes, no) items, and each item scored 1 point for "abnormal behavior" and 0 point for "absence of abnormal behavior/normal behavior." It yields total score ranging from 0 to 39, higher scores represent more social communication impairment. The first item, "Is she/he now able to talk using short phrases or sentences?", is not scored, but determines if six items relating to abnormal language are assigned. Only "verbal" children (children with "yes" response to first question) are assigned the six items relating to abnormal language and can score a total of 0 to 39 points; "non-verbal" children (children with "no" response to first question) are not assigned six items in relation to abnormal language and score a total of 0 to 33 points where higher scores represent more social communication impairment.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=19 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=20 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Child Behavior as Assessed by Social Communication Questionnaire (SCQ)	5.9 Score on scale Standard Deviation 6.80	5.2 Score on scale Standard Deviation 7.88

SECONDARY outcome

Timeframe: At 6 Months CA, 12 Months CA and 24 Months CA

Pulmonary morbidity was assessed with questions related to family history and smoking status as well as diagnosis of select pulmonary symptoms, conditions and related hospitalizations. Anyone living in the same home with participant smoke, Participants had asthma, wheezing, bronchopulmonary dysplasia (BPD) exacerbation or flare-up, Participants had bronchiolitis, bronchitis, or pneumonia diagnosed, Participants had to use oxygen at home, Participants had to visit emergency room or urgent care for respiratory problem, and Participants had to stay in a hospital overnight for respiratory problem were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=28 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to use oxygen at home · No	24 Participants	36 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Anyone living in the same home with participant smoke · Yes	6 Participants	7 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Anyone living in the same home with participant smoke · No	22 Participants	32 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · Yes	8 Participants	4 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · No	20 Participants	35 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · Yes	4 Participants	5 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · No	24 Participants	34 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to use oxygen at home · Yes	8 Participants	5 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to use oxygen at home · No	20 Participants	34 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to visit emergency room or urgent care for respiratory problem · Yes	5 Participants	7 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to visit emergency room or urgent care for respiratory problem · No	23 Participants	32 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to stay in a hospital overnight for respiratory problem · Yes	5 Participants	7 Participants
Number of Participants With Pulmonary Morbidity At 6 Months CA: Had to stay in a hospital overnight for respiratory problem · No	23 Participants	32 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Anyone living in the same home with participant smoke · Yes	3 Participants	5 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Anyone living in the same home with participant smoke · No	23 Participants	30 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · Yes	4 Participants	7 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · No	22 Participants	28 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · Yes	1 Participants	5 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · No	25 Participants	30 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to use oxygen at home · Yes	2 Participants	0 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to use oxygen at home · No	24 Participants	35 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to visit emergency room or urgent care for respiratory problem · Yes	3 Participants	7 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to visit emergency room or urgent care for respiratory problem · No	23 Participants	28 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to stay in a hospital overnight for respiratory problem · Yes	1 Participants	4 Participants
Number of Participants With Pulmonary Morbidity At 12 Months CA: Had to stay in a hospital overnight for respiratory problem · No	25 Participants	31 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Anyone living in the same home with participant smoke · Yes	3 Participants	3 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Anyone living in the same home with participant smoke · No	22 Participants	33 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · Yes	4 Participants	8 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had asthma, wheezing, BPD exacerbation or flare-up · No	21 Participants	28 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · Yes	2 Participants	1 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had bronchiolitis, bronchitis, or pneumonia diagnosed · No	23 Participants	35 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to use oxygen at home · Yes	1 Participants	0 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to visit emergency room or urgent care for respiratory problem · Yes	5 Participants	5 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to visit emergency room or urgent care for respiratory problem · No	20 Participants	31 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to stay in a hospital overnight for respiratory problem · Yes	2 Participants	0 Participants
Number of Participants With Pulmonary Morbidity At 24 Months CA: Had to stay in a hospital overnight for respiratory problem · No	23 Participants	36 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to end of study (up to 6.5 years)

Population: Safety set included all participants in the Enrolled Set who have safety follow-up data in this long-term outcome study.

Survival status was assessed by number participants who died and were censored during the study.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=36 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Survival Status Participants who were Censored	35 Participants	40 Participants
Number of Participants With Survival Status Participants who Died	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (3 Months CA) up to 6 Months CA, 12 Months CA and 24 Months CA

The PedsQL was a generic health related quality of life instrument designed specifically for a pediatric population. PedsQL infant scale encompasses 5 dimensions of functioning (Physical Functioning, Physical Symptoms, Emotional Functioning, Social Functioning, and Cognitive Functioning). The infant for ages 1-12 months (36 Items); for ages 13-24 months (45 Items) rated on a 5-point Likert scale (0 to 4). Overall total scores were calculated as average of all dimensional sub-score items of Infant scale, ranging from 0 to 100 where 0=100 (Never), 1=75 (almost never), 2=50 (sometimes), 3=25 (often), and 4=0 (almost always). Higher scores indicate improved quality of life. A negative value indicates decreased quality of life. The 3 months CA was considered as baseline for this outcome measure.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=28 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=38 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale Change at 6 Months CA: Total Score (Infant scale)	-1.10 Score on scale Standard Deviation 10.056	-0.60 Score on scale Standard Deviation 11.088
Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale Change at 12 Months CA: Total Score (Infant scale)	-0.16 Score on scale Standard Deviation 12.875	-0.57 Score on scale Standard Deviation 11.902
Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale Change at 24 Months CA: Total Score (Infant scale)	7.84 Score on scale Standard Deviation 7.339	-4.82 Score on scale Standard Deviation 14.205

SECONDARY outcome

Timeframe: Baseline (24 Months CA), up to 3 Years CA, 4 Years CA and 5 Years CA

The PedsQL was a generic health related quality of life instrument designed specifically for a pediatric population. The GCS encompasses 4 dimensions of functioning (physical, emotional, social, school). The GCS that apply to toddler for 2-4 years of age (21 Items) rated on a 5-point Likert scale (0 to 4); and Young Child for 5-7 years of age (23 Items) rated on a 3-point Likert scale (0, 2, 4). Overall total scores were calculated as average of all dimensional sub-score items of GCS (Toddler and young children's) ranging from 0 to 100 where 0=100 (Never), 1=75 (almost never), 2=50 (sometimes), 3=25 (often), and 4=0 (almost always). Higher scores indicate improved quality of life. A negative value indicates decreased quality of life. The 24 month CA was considered as baseline for this outcome measure.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=19 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=22 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score Change at 3 Years CA: Total Score	0.62 Score on scale Standard Deviation 12.220	-1.13 Score on scale Standard Deviation 8.533
Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score Change at 4 Years CA: Total Score	1.50 Score on scale Standard Deviation 14.376	-3.46 Score on scale Standard Deviation 7.917
Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score Change at 5 Years CA: Total Score	-4.96 Score on scale Standard Deviation 15.561	-4.49 Score on scale Standard Deviation 8.225

SECONDARY outcome

Timeframe: At 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA

HSCS-PS was a validated instrument used via parent proxy within age 2.5 - 5 years. The instrument is composed of 12 domains (Vision, Hearing, Speech, Mobility, Dexterity, Self-care, Emotion, Learn/Remember, Think/Problem Solve, Pain, General Health, Behavior) with up to 6 levels (0-5). The 12 dimensions grouped into 4 categories: neurosensory (vision and hearing), motor (mobility, dexterity, and self-care), learning/remembering (speech, learn/remember, think/problem solve), and quality of life (emotion, pain, general health, behavior). For each category, data were recorded into 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);moderate/severe problem (scoring \> 1 on a scale of 0 to 3, or \>2 on a scale of 0 to 5 for any attribute). Higher numbers indicating better child's health status.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=24 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=35 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Learning/Remembering · No Problem	13 Participants	17 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Learning/Remembering · Mild	6 Participants	11 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Learning/Remembering · Moderate/Severe	5 Participants	5 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Quality of Life · No Problem	13 Participants	21 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Quality of Life · Mild	9 Participants	8 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Quality of Life · Moderate/Severe	2 Participants	4 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Neurosensory · No Problem	21 Participants	23 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Neurosensory · Mild	2 Participants	4 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Neurosensory · Moderate/Severe	0 Participants	0 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Motor · No Problem	16 Participants	16 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Motor · Mild	5 Participants	8 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Motor · Moderate/Severe	2 Participants	3 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Learning/Remembering · No Problem	16 Participants	12 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Learning/Remembering · Mild	4 Participants	11 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Learning/Remembering · Moderate/Severe	3 Participants	4 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Quality of Life · No Problem	13 Participants	17 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Quality of Life · Mild	8 Participants	9 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 4 Years CA: Quality of Life · Moderate/Severe	2 Participants	1 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Neurosensory · No Problem	16 Participants	17 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Neurosensory · Mild	3 Participants	3 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Neurosensory · Moderate/Severe	0 Participants	0 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Motor · No Problem	13 Participants	14 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Motor · Mild	5 Participants	5 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Motor · Moderate/Severe	1 Participants	1 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Learning/Remembering · No Problem	10 Participants	12 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Learning/Remembering · Mild	7 Participants	7 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Learning/Remembering · Moderate/Severe	2 Participants	1 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Quality of Life · No Problem	11 Participants	15 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Quality of Life · Mild	8 Participants	4 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 5 Years CA: Quality of Life · Moderate/Severe	0 Participants	1 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Neurosensory · No Problem	21 Participants	30 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Neurosensory · Mild	3 Participants	4 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Neurosensory · Moderate/Severe	0 Participants	1 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Motor · No Problem	19 Participants	21 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Motor · Mild	3 Participants	9 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Motor · Moderate/Severe	2 Participants	5 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Learning/Remembering · No Problem	10 Participants	10 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Learning/Remembering · Mild	6 Participants	13 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Learning/Remembering · Moderate/Severe	8 Participants	12 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Quality of Life · No Problem	11 Participants	21 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Quality of Life · Mild	11 Participants	11 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 24 Months CA: Quality of Life · Moderate/Severe	2 Participants	3 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Neurosensory · No Problem	20 Participants	28 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Neurosensory · Mild	2 Participants	3 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Neurosensory · Moderate/Severe	2 Participants	2 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Motor · No Problem	16 Participants	16 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Motor · Mild	4 Participants	13 Participants
Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS) At 3 Years CA: Motor · Moderate/Severe	4 Participants	4 Participants

SECONDARY outcome

Timeframe: At 5 Years CA

The 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 score includes 6 attributes: Sensation, Mobility, Cognition, Self-Care, Emotion, and Pain with up to 5 levels of severity (higher numbers indicate worse level of severity). The HUI3 score includes 8 attributes: Vision, Hearing, Speech, Cognition, Ambulation, Dexterity, Emotion, and Pain with up to 6 levels to indicate the severity (with higher numbers indicating worse levels). HUI2/3 single-attribute scores of morbidities 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. HUI mark 2 and 3 Overall utility score was reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=19 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=20 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Health Status Measured by the Health Utilities Index (HUI) Mark 2 and 3 HUI2 Overall Utility Score	0.929 Score on scale Standard Deviation 0.1246	0.867 Score on scale Standard Deviation 0.2115
Health Status Measured by the Health Utilities Index (HUI) Mark 2 and 3 HUI3 Overall Utility Score	0.893 Score on scale Standard Deviation 0.1960	0.852 Score on scale Standard Deviation 0.2665

SECONDARY outcome

Timeframe: At 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA

The total number of private office/hospital outpatient visits of health care resource at 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=29 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Health Care Resource Use (HCRU) At 3 Months CA: Total Health Care Resource Use	9.8 Visits Standard Deviation 6.48	8.3 Visits Standard Deviation 7.67
Health Care Resource Use (HCRU) At 6 Months CA: Total Health Care Resource Use	15.5 Visits Standard Deviation 16.06	10.3 Visits Standard Deviation 9.40
Health Care Resource Use (HCRU) At 12 Months CA: Total Health Care Resource Use	25.0 Visits Standard Deviation 23.81	22.5 Visits Standard Deviation 33.95
Health Care Resource Use (HCRU) At 24 Months CA: Total Health Care Resource Use	20.1 Visits Standard Deviation 31.95	30.0 Visits Standard Deviation 40.92
Health Care Resource Use (HCRU) At 3 Years CA: Total Health Care Resource Use	22.8 Visits Standard Deviation 41.38	34.8 Visits Standard Deviation 55.25
Health Care Resource Use (HCRU) At 4 Years CA: Total Health Care Resource Use	21.8 Visits Standard Deviation 39.00	41.2 Visits Standard Deviation 69.93
Health Care Resource Use (HCRU) At 5 Years CA: Total Health Care Resource Use	15.7 Visits Standard Deviation 39.80	32.7 Visits Standard Deviation 51.22

SECONDARY outcome

Timeframe: At 3 Months CA, 6 Months CA, 12 Months CA , 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA

Number of visits to emergency department at 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=15 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=17 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 3 Months CA: Emergency Department Visits	2.5 Visits Standard Deviation 1.87	1.6 Visits Standard Deviation 1.13
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 6 Months CA: Emergency Department Visits	2.2 Visits Standard Deviation 2.17	1.3 Visits Standard Deviation 0.67
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 12 Months CA: Emergency Department Visits	1.6 Visits Standard Deviation 0.73	2.2 Visits Standard Deviation 1.14
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 24 Months CA: Emergency Department Visits	2.1 Visits Standard Deviation 1.39	1.4 Visits Standard Deviation 0.61
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 3 Years CA: Emergency Department Visits	2.5 Visits Standard Deviation 2.38	1.6 Visits Standard Deviation 0.84
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 4 Years CA: Emergency Department Visits	1.9 Visits Standard Deviation 1.46	1.7 Visits Standard Deviation 0.82
Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department At 5 Years CA: Emergency Department Visits	1.7 Visits Standard Deviation 0.58	1 Visits Standard Deviation NA SD is not evaluable for single mean data point.

SECONDARY outcome

Timeframe: At 3 Months CA, 6 Months CA, 12 Months CA , 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA

The participant's duration of hospitalizations at 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=9 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=12 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 4 Years CA	3.5 Days Standard Deviation 3.54	4.0 Days Standard Deviation 3.61
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 3 Months CA	12.9 Days Standard Deviation 31.27	5.5 Days Standard Deviation 4.55
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 6 Months CA	6.4 Days Standard Deviation 4.56	7.4 Days Standard Deviation 9.58
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 12 Months CA	7.2 Days Standard Deviation 7.76	9.0 Days Standard Deviation 11.87
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 24 Months CA	4.1 Days Standard Deviation 5.01	2.5 Days Standard Deviation 1.73
Health Care Resource Utilization (HCRU): Duration of Hospitalization At 3 Years CA	4.3 Days Standard Deviation 3.30	4.8 Days Standard Deviation 6.87

SECONDARY outcome

Timeframe: At 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA

Number of participants who required prescription eyeglasses and educational support at 3 Months CA, 6 Months CA, 12 Months CA, 24 Months CA, 3 Years CA, 4 Years CA and 5 Years CA were reported.

Outcome measures

Outcome measures
Measure	Antecedent Standard of Care n=32 Participants Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=39 Participants Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Months CA: Used Prescription Eyeglasses · Yes	0 Participants	0 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Months CA: Used Prescription Eyeglasses · No	32 Participants	39 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 6 Months CA: Used Prescription Eyeglasses · Yes	0 Participants	0 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 6 Months CA: Used Prescription Eyeglasses · No	28 Participants	39 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 12 Months CA: Used Prescription Eyeglasses · Yes	0 Participants	1 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 12 Months CA: Used Prescription Eyeglasses · No	26 Participants	35 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 24 Months CA: Used Prescription Eyeglasses · Yes	1 Participants	2 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 24 Months CA: Used Prescription Eyeglasses · No	24 Participants	34 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Years CA: Used Prescription Eyeglasses · Yes	3 Participants	7 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Years CA: Used Prescription Eyeglasses · No	21 Participants	26 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 4 Years CA: Used Prescription Eyeglasses · Yes	2 Participants	5 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 4 Years CA: Used Prescription Eyeglasses · No	21 Participants	22 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 5 Years CA: Used Prescription Eyeglasses · Yes	3 Participants	4 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 5 Years CA: Used Prescription Eyeglasses · No	16 Participants	16 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Months CA: Received Educational Support · Yes	0 Participants	0 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Months CA: Received Educational Support · No	32 Participants	39 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 6 Months CA: Received Educational Support · Yes	0 Participants	1 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 6 Months CA: Received Educational Support · No	28 Participants	38 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 12 Months CA: Received Educational Support · Yes	0 Participants	1 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 12 Months CA: Received Educational Support · No	26 Participants	35 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 24 Months CA: Received Educational Support · Yes	0 Participants	0 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 24 Months CA: Received Educational Support · No	25 Participants	36 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Years CA: Received Educational Support · Yes	1 Participants	4 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 3 Years CA: Received Educational Support · No	23 Participants	29 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 4 Years CA: Received Educational Support · Yes	5 Participants	3 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 4 Years CA: Received Educational Support · No	18 Participants	24 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 5 Years CA: Received Educational Support · Yes	3 Participants	5 Participants
Health Care Resource Utilization (HCRU): Number of Participants Who Required Prescription Eyeglasses and Educational Support At 5 Years CA: Received Educational Support · No	16 Participants	15 Participants

Adverse Events

Antecedent Standard of Care

Serious events: 3 serious events

Other events: 5 other events

Deaths: 1 deaths

Antecedent rhIGF-1/rhIGFBP-3

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Antecedent Standard of Care n=36 participants at risk Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 participants at risk Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
General disorders Sudden infant death syndrome	2.8% 1/36 • Number of events 1 • From start of study up to end of the study (up to 6.5 years)	0.00% 0/40 • From start of study up to end of the study (up to 6.5 years)
Respiratory, thoracic and mediastinal disorders Adenoidal hypertrophy	2.8% 1/36 • Number of events 1 • From start of study up to end of the study (up to 6.5 years)	0.00% 0/40 • From start of study up to end of the study (up to 6.5 years)
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	5.6% 2/36 • Number of events 2 • From start of study up to end of the study (up to 6.5 years)	5.0% 2/40 • Number of events 2 • From start of study up to end of the study (up to 6.5 years)

Other adverse events

Other adverse events
Measure	Antecedent Standard of Care n=36 participants at risk Participants who were treated with standard neonatal care in study ROPP-2008-01 (NCT01096784).	Antecedent rhIGF-1/rhIGFBP-3 n=40 participants at risk Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (NCT01096784).
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	13.9% 5/36 • Number of events 5 • From start of study up to end of the study (up to 6.5 years)	5.0% 2/40 • Number of events 2 • From start of study up to end of the study (up to 6.5 years)

Additional Information

Study Director

Shire (Note: This product was divested to Oak Hill Bio in 2022)

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER