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Clinical Trial Results:
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated With rhIGF 1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or who Received Standard Neonatal Care

Summary
EudraCT number	2014-003556-31
Trial protocol	SE GB NL PL IT
Global end of trial date	28 Sep 2021

Results information
Results version number	v1(current)
This version publication date	18 Apr 2022
First version publication date	18 Apr 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SHP607-201

ISRCTN number

US NCT number

NCT02386839

WHO universal trial number (UTN)

Sponsor organisation name

Shire

Sponsor organisation address

300 Shire Way, Lexington, Massachusetts, United States, 02421

Public contact

Study Director, Shire, ClinicalTransparency@takeda.com

Scientific contact

Study Director, Shire, ClinicalTransparency@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000534-PIP03-17

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

28 Sep 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Sep 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate the long-term efficacy and safety outcomes following short-term exposure to rhIGF-1/rhIGFBP-3 versus standard neonatal care in Study ROPP-2008-01 (2007-007872-40).

Protection of trial subjects

This study was conducted in accordance with Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) Parts 50, 56, and 312 and the International Conference on Harmonisation (ICH) GCP guidelines. Compliance with these regulations and guidelines also constitutes compliance with the ethical principles described in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Italy: 38

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Sweden: 18

Country: Number of subjects enrolled

United States: 9

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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

Screening details

A total of 76 participants who previously treated with rhIGF 1/rhIGFBP-3 or Standard Neonatal Care in ROPP-2008-01 (2007-007872-40) study were enrolled in this long term safety and efficacy study.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Antecedent Standard of Care

Arm description

Participants who were treated with standard neonatal care in study ROPP-2008-01 (2007-007872-40).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Antecedent rhIGF-1/rhIGFBP-3

Arm description

Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (2007-007872-40).

Arm type

Experimental

Investigational medicinal product name

Mecasermin rinfabate

Investigational medicinal product code

Other name

rhIGF-1/rhIGFBP-3

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants who received "rhIGF-1/rhIGFBP-3" in study ROPP-2008-01 (2007-007872-40) were enrolled to this study. No investigational product was administered in this study.

Number of subjects in period 1	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Started	36	40
Completed	20	25
Not completed	16	15
Adverse event, serious fatal	1	-
Other (Due to Covid 19 Pandemic)	-	1
Withdrawal by Subject	9	10
Other (unspecified)	1	-
Lost to follow-up	4	4
Other (Site Terminated by Sponsor)	1	-

Baseline characteristics

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Reporting group title

Antecedent Standard of Care

Reporting group description

Participants who were treated with standard neonatal care in study ROPP-2008-01 (2007-007872-40).

Reporting group title

Antecedent rhIGF-1/rhIGFBP-3

Reporting group description

Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (2007-007872-40).

Reporting group values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3	Total
Number of subjects	36	40	76
Age Categorical
Units: Subjects
Age continuous
The age reported here is the corrected age. Corrected Age (weeks) was defined as Chronological Age (weeks) – 40 + Gestational Age (weeks) in this study.
Units: weeks
arithmetic mean (standard deviation)	7.15 ± 5.622	6.73 ± 6.224	-
Gender categorical
Units: Participants
Female	13	14	27
Male	23	26	49
Race (NIH/OMB)
Units: Subjects
Asian	4	0	4
Black or African American	5	1	6
White	26	34	60
Unknown or Not Reported	1	5	6
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	6	13	19
Not Hispanic or Latino	28	27	55
Unknown or Not Reported	2	0	2

End points

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Reporting group title

Antecedent Standard of Care

Reporting group description

Participants who were treated with standard neonatal care in study ROPP-2008-01 (2007-007872-40).

Reporting group title

Antecedent rhIGF-1/rhIGFBP-3

Reporting group description

Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (2007-007872-40).

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected age (CA)

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected age (CA) ^[1]

End point description

Standard age-appropriate methods were 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 greater than or equal to [>=] 20/40 or >=15 cycles/degree); below normal (20/200 less than or equal to [<=] measurable acuity less than [<] 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. Enrolled set included all participants for whom written informed consent was obtained for this long-term outcome study. Here, “number of subjects analyzed”= subjects evaluable for this endpoint and “n=number analyzed” evaluable at specific categories.

End point type

Primary

End point timeframe

At 6 Months CA

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	27	34
Units: Participants
Right Eye: Normal (n=24, 32)	0	0
Right Eye: Below Normal (n=24, 32)	12	19
Right Eye: Poor (n=24, 32)	12	13
Left Eye: Normal (n=21, 32)	0	0
Left Eye: Below Normal (n=21, 32)	14	18
Left Eye: Poor (n=21, 32)	7	14
Both Eyes: Normal (n=27, 34)	0	0
Both Eyes: Below Normal (n=27, 34)	18	25
Both Eyes: Poor (n=27, 34)	9	9

No statistical analyses for this end point

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA ^[2]

End point description

End point type

Primary

End point timeframe

At 12 Months CA

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	24	36
Units: Participants
Right Eye: Normal (n=21, 32)	0	1
Right Eye: Below Normal (n=21, 32)	21	26
Right Eye: Poor (n=21, 32)	0	5
Left Eye: Normal (n=21, 32)	0	1
Left Eye: Below Normal (n=21, 32)	20	25
Left Eye: Poor (n=21, 32)	1	6
Both Eyes: Normal (n=24, 36)	0	1
Both Eyes: Below Normal (n=24, 36)	23	33
Both Eyes: Poor (n=24, 36)	1	2

No statistical analyses for this end point

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA ^[3]

End point description

End point type

Primary

End point timeframe

At 20 Months CA

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	33
Units: Participants
Right Eye: Normal (n=19, 29)	0	2
Right Eye: Below Normal (n=19, 29)	17	23
Right Eye: Poor (n=19, 29)	2	4
Left Eye: Normal (n=20, 29)	0	1
Left Eye: Below Normal (n=20, 29)	18	24
Left Eye: Poor (n=20, 29)	2	4
Both Eyes: Normal (n=23, 33)	0	1
Both Eyes: Below Normal (n=23, 33)	20	30
Both Eyes: Poor (n=23, 33)	3	2

No statistical analyses for this end point

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA ^[4]

End point description

End point type

Primary

End point timeframe

At 24 Months CA

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	33
Units: Participants
Right Eye: Normal (n=20, 31)	0	2
Right Eye: Below Normal (n=20, 31)	17	25
Right Eye: Poor (n=20, 31)	3	4
Left Eye: Normal (n=20, 28)	0	2
Left Eye: Below Normal (n=20, 28)	17	24
Left Eye: Poor (n=20, 28)	3	2
Both Eyes: Normal (n=23, 33)	1	5
Both Eyes: Below Normal (n=23, 33)	19	24
Both Eyes: Poor (n=23, 33)	3	4

No statistical analyses for this end point

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA ^[5]

End point description

Standard age-appropriate methods were 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 greater than or equal to [>=] 20/40 or >=15 cycles/degree); below normal (20/200 less than or equal to [<=] measurable acuity less than [<] 20/40 or 3 cycles/degree <= measurable acuity <15 cycles/degree); poor (measurable acuity <=20/200 or <=3 cycles/degree). Teller acuity card and at any location in the visual field). Corrected Age (weeks) was defined as Chronological Age (weeks) – 40 + Gestational Age (weeks) in this study. Enrolled set included all participants for whom written informed consent was obtained for this long-term outcome study. Here, “number of subjects analyzed”= subjects evaluable for this endpoint and “n=number analyzed” evaluable at specific categories.

End point type

Primary

End point timeframe

At 4.75 Years CA

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	15	18
Units: Participants
Right Eye: Normal (n=15, 18)	11	15
Right Eye: Below Normal (n=15, 18)	4	3
Right Eye: Poor (n=15, 18)	0	0
Left Eye: Normal (n=15, 18)	11	14
Left Eye: Below Normal (n=15, 18)	4	4
Left Eye: Poor (n=15, 18)	0	0
Both Eyes: Normal (n=15, 18)	10	17
Both Eyes: Below Normal (n=15, 18)	5	1
Both Eyes: Poor (n=15, 18)	0	0

No statistical analyses for this end point

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA

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End point title

Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA ^[6]

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 5 Years CA

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	14	17
Units: Participants
Right Eye: Normal (n=14, 17)	9	11
Right Eye: Below Normal (n=14, 17)	5	6
Right Eye: Poor (n=14, 17)	0	0
Left Eye: Normal (n=14, 17)	8	11
Left Eye: Below Normal (n=14, 17)	6	6
Left Eye: Poor (n=14, 17)	0	0
Both Eyes: Normal (n=14, 17)	9	11
Both Eyes: Below Normal (n=14, 17)	5	6
Both Eyes: Poor (n=14, 17)	0	0

No statistical analyses for this end point

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA

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End point title

Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA ^[7]

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 12 Months CA

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	25	36
Units: Participants
Esotropia: Presence	1	4
Esotropia: Absence	24	32
Exotropia: Presence	0	0
Exotropia: Absence	25	36
Hypertropia: Presence	0	0
Hypertropia: Absence	25	36
Hypotropia: Presence	0	0
Hypotropia: Absence	25	36

No statistical analyses for this end point

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA

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End point title

Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA ^[8]

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 24 Months CA

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	34
Units: Participants
Esotropia: Presence	1	5
Esotropia: Absence	22	29
Exotropia: Presence	0	1
Exotropia: Absence	23	33
Hypertropia: Presence	0	0
Hypertropia: Absence	23	34
Hypotropia: Presence	0	0
Hypotropia: Absence	23	34

No statistical analyses for this end point

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA

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End point title

Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA ^[9]

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 5-Years CA

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	14	17
Units: Participants
Esotropia: Presence	1	1
Esotropia: Absence	13	16
Exotropia: Presence	0	0
Exotropia: Absence	14	17
Hypertropia: Presence	0	0
Hypertropia: Absence	14	17
Hypotropia: Presence	0	0
Hypotropia: Absence	14	17

No statistical analyses for this end point

Primary: Number of Participants With Nystagmus at 12 Months CA

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End point title

Number of Participants With Nystagmus at 12 Months CA ^[10]

End point description

Nystagmus was observed during the ocular alignment assessments. Number of participants with presence and absence of nystagmus was reported at 12 Months CA. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 12 Months CA

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	25	36
Units: Participants
Nystagmus: Presence	1	2
Nystagmus: Absence	24	34

No statistical analyses for this end point

Primary: Number of Participants With Nystagmus at 24 Months CA

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End point title

Number of Participants With Nystagmus at 24 Months CA ^[11]

End point description

Nystagmus was observed during the ocular alignment assessments. Number of participants with presence and absence of nystagmus was reported at 24 Months CA. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 24 Months CA

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	34
Units: Participants
Nystagmus: Presence	0	2
Nystagmus: Absence	23	32

No statistical analyses for this end point

Primary: Number of Participants With Nystagmus at 5 Years CA

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End point title

Number of Participants With Nystagmus at 5 Years CA ^[12]

End point description

Nystagmus was observed during the ocular alignment assessments. Presence and absence of nystagmus was reported at 5 Years CA. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 5 Years CA

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	14	17
Units: Participants
Nystagmus: Presence	0	2
Nystagmus: Absence	14	15

No statistical analyses for this end point

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA

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End point title

Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA ^[13]

End point description

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 are summarized as ‘farsighted’. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific categories. Here, '99999' = mean and SD was not estimated.

End point type

Primary

End point timeframe

At 6 Months CA

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	25	34
Units: Diopter
arithmetic mean (standard deviation)
Right Eye: Sphere (Nearsighted) (n=6, 34)	-1.833 ± 1.0916	-1.417 ± 1.4216
Right Eye: Sphere (Farsighted) (n=21, 34)	1.976 ± 1.2572	1.838 ± 1.3256
Right Eye: Cylinder (n=24, 33)	0.875 ± 0.8534	0.932 ± 0.8801
Right Eye: Axis (n=25, 33)	116.4 ± 58.03	106.0 ± 52.87
Right Eye: Prism (n=0, 0)	99999 ± 99999	99999 ± 99999
Left Eye: Sphere (Nearsighted) (n=6, 3)	-1.750 ± 0.9747	-1.250 ± 0.9014
Left Eye: Sphere (Farsighted) (n=22, 34)	2.034 ± 1.2731	1.831 ± 1.3494
Left Eye: Cylinder (n=25, 33)	0.820 ± 0.6395	0.962 ± 0.8341
Left Eye: Axis (n=25, 33)	120.3 ± 52.27	108.8 ± 54.18
Left Eye: Prism (n=0, 0)	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA

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End point title

Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA ^[14]

End point description

End point type

Primary

End point timeframe

At 12 Months CA

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	30
Units: Diopter
arithmetic mean (standard deviation)
Right Eye: Sphere (Nearsighted) (n=7, 4)	-1.564 ± 1.8752	-2.438 ± 1.4773
Right Eye: Sphere (Farsighted) (n=18, 27)	2.042 ± 1.1796	1.491 ± 1.0908
Right Eye: Cylinder (n=23, 27)	0.783 ± 0.7163	0.926 ± 0.6423
Right Eye: Axis (n=23, 30)	86.0 ± 62.82	105.7 ± 50.53
Right Eye: Prism (n=15, 25)	99999 ± 99999	99999 ± 99999
Left Eye: Sphere (Nearsighted) (n=4, 5)	-2.875 ± 1.9203	-2.500 ± 1.7048
Left Eye: Sphere (Farsighted) (n=21, 26)	1.857 ± 1.3171	1.606 ± 1.1962
Left Eye: Cylinder (n=23, 27)	0.663 ± 0.6334	0.851 ± 0.6795
Left Eye: Axis (n=22, 27)	107.3 ± 60.19	112.6 ± 55.11
Left Eye: Prism (n=15, 25)	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA

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End point title

Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA ^[15]

End point description

End point type

Primary

End point timeframe

At 20 Months CA

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	31
Units: Diopter
arithmetic mean (standard deviation)
Right Eye: Sphere (Nearsighted) (n=5, 5)	-2.350 ± 2.4083	-1.700 ± 1.6808
Right Eye: Sphere (Farsighted) (n=18, 27)	1.903 ± 0.9931	1.278 ± 0.8996
Right Eye: Cylinder (n=21, 27)	0.750 ± 0.6755	0.778 ± 0.6841
Right Eye: Axis (n=23, 31)	105.0 ± 62.33	122.8 ± 58.69
Right Eye: Prism (n=15, 22)	99999 ± 99999	99999 ± 99999
Left Eye: Sphere (Nearsighted) (n=3, 5)	-3.500 ± 1.8028	-2.600 ± 1.9733
Left Eye: Sphere (Farsighted) (n=20, 27)	1.800 ± 1.2237	1.389 ± 1.1080
Left Eye: Cylinder (n=20, 29)	0.900 ± 0.8288	0.681 ± 0.5665
Left Eye: Axis (n=21, 28)	117.8 ± 53.82	110.1 ± 53.56
Left Eye: Prism (n=16, 23)	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA

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End point title

Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA ^[16]

End point description

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 are summarized as ‘farsighted’.Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific categories. Here, '99999' = mean and SD was not estimated because “n” was 1 for this category.

End point type

Primary

End point timeframe

At 4.75 Years CA

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	17	17
Units: Diopter
arithmetic mean (standard deviation)
Right Eye: Sphere (Nearsighted) (n=1, 1)	-8.500 ± 99999	-0.500 ± 99999
Right Eye: Sphere (Farsighted) (n=17, 15)	1.691 ± 1.1094	1.383 ± 1.5465
Right Eye: Cylinder (n=16, 17)	0.593 ± 0.6505	0.603 ± 0.6254
Right Eye: Axis (n=17, 17)	99.1 ± 69.95	119.0 ± 56.05
Right Eye: Prism (n=17, 14)	0.02 ± 0.075	0.00 ± 0.000
Left Eye: Sphere (Nearsighted) (n=1, 1)	-6.500 ± 99999	-0.750 ± 99999
Left Eye: Sphere (Farsighted) (n=17, 15)	1.853 ± 1.2376	1.517 ± 1.9966
Left Eye: Cylinder (n=15, 17)	0.717 ± 0.7126	0.574 ± 0.5574
Left Eye: Axis (n=16, 17)	88.6 ± 65.64	114.2 ± 55.17
Left Eye: Prism (n=15, 13)	0.02 ± 0.056	99999 ± 99999

No statistical analyses for this end point

Primary: Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA

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End point title

Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA ^[17]

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

At 5 Years CA

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	14	17
Units: Participants
Participants with presence of stereopsis	13	16
Participants with absence of stereopsis	1	1

No statistical analyses for this end point

Primary: Number of Participants With Adverse Events (AEs)

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End point title

Number of Participants With Adverse Events (AEs) ^[18]

End point description

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

End point type

Primary

End point timeframe

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

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed for this endpoint.

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	36	40
Units: Participants	11	9

No statistical analyses for this end point

Secondary: Change From Baseline in Body Weight Z-score

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End point title

Change From Baseline in Body Weight Z-score

End point description

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 [2007-007872-40]).). Change from baseline in body weight Z-score at 6-month, 12-month, 24-month and 5-year CA were reported. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific time points..

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	28	39
Units: Z-score
arithmetic mean (standard deviation)
Change at 6 Months CA (n=28, 39)	4.40 ± 1.323	4.30 ± 1.146
Change at 12 Months CA (n=26, 36)	5.08 ± 1.300	4.88 ± 1.026
Change at 24 Months CA (n=25, 36)	5.17 ± 0.885	4.99 ± 0.983
Change at 5 Years CA (n=19, 24)	5.80 ± 1.149	5.60 ± 1.660

No statistical analyses for this end point

Secondary: Change From Baseline in Height Z-score

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End point title

Change From Baseline in Height Z-score

End point description

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). Baseline was defined as the first assessment in the antecedent study (ROPP-2008-01 [2007-007872-40]). 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. Change from baseline in Height Z-score at 6-month, 12-month, 24-month and 5-year CA were reported. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	28	39
Units: Z-Score
arithmetic mean (standard deviation)
Change at 6 Months CA (n=28, 39)	6.36 ± 1.711	6.19 ± 1.215
Change at 12 Months CA (n=26, 36)	6.79 ± 1.747	7.25 ± 1.155
Change at 24 Months CA (n=25, 36)	7.30 ± 2.029	7.78 ± 1.376
Change at 5 Years CA (n=19, 24)	7.84 ± 1.856	8.17 ± 1.505

No statistical analyses for this end point

Secondary: Change From Baseline in Head Circumference Z-score

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End point title

Change From Baseline in Head Circumference Z-score

End point description

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 defined as first assessment in antecedent study (ROPP-2008-01 [2007-007872-40]).Change from baseline in Head Circumference Z-score at 6, 12 and 24-months reported. Enrolled set.Here,“number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	28	39
Units: Z-score
arithmetic mean (standard deviation)
Change at 6 Months CA (n=28, 39)	7.61 ± 1.535	7.12 ± 1.576
Change at 12 Months CA (n=26, 36)	8.29 ± 1.472	7.83 ± 1.567
Change at 24 Months CA (n=25, 35)	8.44 ± 1.415	8.05 ± 1.692

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

The 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). Positive value indicate improvement and negative value indicates 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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline (12 Months CA), 24 Months CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	32
Units: Score on a scale
arithmetic mean (standard deviation)
Cognitive Composite Scores (n=23,32)	7.0 ± 18.45	6.6 ± 21.27
Language Composite Scores (n=23,32)	2.4 ± 18.73	-0.9 ± 15.79
Motor Composite Scores (n=23,32)	12.2 ± 23.54	10.8 ± 18.25

No statistical analyses for this end point

Secondary: Cognitive Development as Assessed by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) Full Scale at 5 Years CA

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End point title

Cognitive Development as Assessed by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) Full Scale at 5 Years CA

End point description

WPPSI-IV is measure of general cognitive development in children that has components of both verbal and nonverbal tasks. It is applicable to children aged 2 years +6 months to 7 years +7 months, is used to assess child's cognitive skills. Its test framework is organized into five Primary Index sub scales: Verbal Comprehension,Visual Spatial,Fluid Reasoning,Working Memory and Processing Speed. The Full Scale includes all sub scales at the Primary Index scale level, as well as any supplemental subtests that may be used to derive the Full Scale IQ. Composite scores 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). Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

At 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	11	14
Units: Scores on a scale
arithmetic mean (standard deviation)	97.3 ± 17.28	91.6 ± 14.17

No statistical analyses for this end point

Secondary: Number of Participants With Abnormal Physical Examination

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End point title

Number of Participants With Abnormal Physical Examination

End point description

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. Number of participants with abnormal physical examination were reported. Safety set included all participants in the Enrolled Set who have safety follow-up data in this long-term outcome study.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	36	40
Units: Participants	13	18

No statistical analyses for this end point

Secondary: Number of Participants Diagnosed With Cerebral Palsy (CP) by Neurological Examination at 24 Months CA

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End point title

Number of Participants Diagnosed With Cerebral Palsy (CP) by Neurological Examination at 24 Months CA

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

At 24 Months CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	25	37
Units: Participants	1	5

No statistical analyses for this end point

Secondary: Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II)

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End point title

Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II)

End point description

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 four domains (Communication, Daily Living Skills, Socialization, and Motor skills) 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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	22	30
Units: Score on a scale
arithmetic mean (standard deviation)
Change at 12 Months CA (n=22, 30)	-0.3 ± 14.50	-1.5 ± 12.41
Change at 24 Months CA (n=20, 30)	7.8 ± 16.47	0.8 ± 14.89
Change at 5 Years CA (n=13, 15)	-3.2 ± 20.92	-3.9 ± 19.86

No statistical analyses for this end point

Secondary: Number of Participants With Normal and Abnormal Hearing Screening Status

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End point title

Number of Participants With Normal and Abnormal Hearing Screening Status

End point description

Number of participants with any hearing status (normal and abnormal) were reported. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

At 6 Months CA and 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	21	28
Units: Participants
At 6 Months CA: Normal Hearing (21, 28)	20	24
At 6 Months CA: Abnormal Hearing (21, 28)	1	4
At 5 Years CA: Normal Hearing (17, 21)	15	20
At 5 Years CA: Abnormal Hearing (17, 21)	2	1

No statistical analyses for this end point

Secondary: Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories

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End point title

Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories

End point description

CBCL(1½ to 5) a parent-reported outcome measure to assess behavioral, emotional, and social functioning of children aged 18-60 months. It composed of 99 items rated on Likert scale and include 7 syndrome scale under 2 domains (Internalizing and Externalizing Problems): Internalizing include syndromes of Emotionally Reactive,Anxious/Depressed,Somatic Complaints,and Withdrawn. Externalizing include syndrome of Aggressive Behavior and Attention Problem. The 2 domains of all 7 scales combined to form total score range of 23 to 100. For each question, raw scores of all subscales converted to standardized T-scores. Higher T score indicate more behavior problems. For Internalization, Externalization and Total Behavior Problem, T-scores of less than 60 are non-clinical,60-63 are borderline,and 64 or more considered clinical. Enrolled set.Here,“number of subjects analysed”=subjects evaluable for this endpoint and“n=number analysed” evaluable at specific categories. Here, “M”=Months, “Y”=Years.

End point type

Secondary

End point timeframe

At 24 Months CA and 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	23	34
Units: Participants
24 M: Internalizing:NonClinical(n=23,34)	23	32
24 M: Internalizing:Borderline(n=23,34)	0	0
24 M: Internalizing:Clinical(n=23,34)	0	2
5 Y: Internalizing:NonClinical(n=19, 20)	15	15
5 Y: Internalizing:Borderline(n=19,20)	1	2
5 Y: Internalizing:Clinical(n=19,20)	3	3
24 M: Externalizing:NonClinical(n=23,34)	21	32
24 M: Externalizing:Borderline(n=23,34)	1	0
24 M: Externalizing:Clinical(n=23,34)	1	2
5 Y: Externalizing:NonClinical(n=19, 20)	16	17
5 Y: Externalizing:Borderline(n=19, 20)	0	2
5 Y: Externalizing:Clinical(n=19, 20)	3	1
24 M: Total Behavior Problems:Clinical(n=23,34)	22	31
24 M: Total Behavior Problems:NonClinical(n=23,34)	1	3
24 M: Total Behavior Problems:Borderline(n=23,34)	0	0
5 Y: Total Behavior Problems:Clinical(n=19,20)	14	17
5 Y: Total Behavior Problems:NonClinical(n=19,20)	3	2
5 Y: Total Behavior Problems:Borderline(n=19,20)	2	1

No statistical analyses for this end point

Secondary: Child Behavior as Assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Based on Total Score

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End point title

Child Behavior as Assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Based on Total Score

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

At 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	18	20
Units: Score on scale
arithmetic mean (standard deviation)	11.9 ± 9.30	8.3 ± 10.10

No statistical analyses for this end point

Secondary: Number of Participants With Pulmonary Morbidity

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End point title

Number of Participants With Pulmonary Morbidity

End point description

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. Enrolled set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific categories. Here, “M”=Months, “Y”=Yes and “N”=No.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	28	39
Units: Participants
6M:Same home with participant smoke:Y(n=28,39)	6	7
6M:Same home with participant smoke:N(n=28,39)	22	32
6M:Asthma,wheeze,BPDexacerbation flare:Y(n=28,39)	8	4
6M:Asthma,wheeze,BPDexacerbation flare:N(n=28,39)	20	35
6M:Bronchiolitis,bronchitis,pneumonia:Y(n=28,39)	4	5
6M:Bronchiolitis,bronchitis,pneumonia:N(n=28,39)	24	34
6M:Used oxygen at home:Y(n=28,39)	8	5
6M:Used oxygen at home:N(n=28,39)	20	34
6M:Emergency respiratory problem:Y(n=28,39)	5	7
6M:Emergency respiratory problem:N(n=28,39)	23	32
6M:Hospitalovernightrespiratoryproblem:Y(n=28,39)	5	7
6M:Hospitalovernightrespiratoryproblem:N(n=28,39)	23	32
12M:Same home with participant smoke:Y(n=26,35)	3	5
12M:Same home with participant smoke:N(n=26,35)	23	30
12M:Asthma,wheeze,BPDexacerbation flare:Y(n=26,35)	4	7
12M:Asthma,wheeze,BPDexacerbation flare:N(n=26,35)	22	28
12M:Bronchiolitis,bronchitis,pneumonia:Y(n=26,35)	1	5
12M:Bronchiolitis,bronchitis,pneumonia:N(n=26,35)	25	30
12M:Used oxygen at home:Y(n=26,35)	2	0
12M:Used oxygen at home:N(n=26,35)	24	35
12M:Emergency respiratory problem:Y(n=26,35)	3	7
12M:Emergency respiratory problem:N(n=26,35)	23	28
12M:Hospitalovernightrespiratoryproblem:Y(n=26,35)	1	4
12M:Hospitalovernightrespiratoryproblem:N(n=26,35)	25	31
24M:Same home with participant smoke:Y(n=25,36)	3	3
24M:Same home with participant smoke:N(n=25,36)	22	33
24M:Asthma,wheeze,BPDexacerbation flare:Y(n=25,36)	4	8
24M:Asthma,wheeze,BPDexacerbation flare:N(n=25,36)	21	28
24M:Bronchiolitis,bronchitis,pneumonia:Y(n=25,36)	2	1
24M:Bronchiolitis,bronchitis,pneumonia:N(n=25,36)	23	25
24M:Used oxygen at home:Y(n=25,36)	1	0
24M:Used oxygen at home:N(n=25,36)	24	36
24M:Emergency respiratory problem:Y(n=25,36)	5	5
24M:Emergency respiratory problem:N(n=25,36)	20	31
24M:Hospitalovernightrespiratoryproblem:Y(n=25,36)	2	0
24M:Hospitalovernightrespiratoryproblem:N(n=25,36)	23	36

No statistical analyses for this end point

Secondary: Child Behavior as Assessed by Social Communication Questionnaire (SCQ) Based on Total Score

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End point title

Child Behavior as Assessed by Social Communication Questionnaire (SCQ) Based on Total Score

End point description

SCQ instrument to evaluate communication skills and social functioning in child with autism or autism spectrum disorders (ASD). The SCQ has 40 dichotomous (yes, no) items. Each scored item receives a value of 1 point for “abnormal behavior” and 0 point for “absence of abnormal behavior/normal behavior.” The SCQ yields a total score ranging from 0 to 39, with higher scores representing more social communication impairment. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint

End point type

Secondary

End point timeframe

At 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	19	20
Units: Score on scale
arithmetic mean (standard deviation)	5.9 ± 6.80	5.2 ± 7.88

No statistical analyses for this end point

Secondary: Number of Participants With Survival Status

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End point title

Number of Participants With Survival Status

End point description

Survival status was assessed by number participants who died and were censored during the study. Safety set included all participants in the Enrolled Set who have safety follow-up data in this long-term outcome study.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	36	40
Units: Participants
Participants who Died	1	0
Participants who were Censored	35	40

No statistical analyses for this end point

Secondary: Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale

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End point title

Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale

End point description

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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	28	38
Units: Score on scale
arithmetic mean (standard deviation)
Change at 6 Months CA: Total Score (n=28, 38)	-1.10 ± 10.056	-0.60 ± 11.088
Change at 12 Months CA: Total Score (n=25, 36)	-0.16 ± 12.875	-0.57 ± 11.902
Change at 24 Months CA: Total Score (n=3, 7)	7.84 ± 7.339	-4.82 ± 14.205

No statistical analyses for this end point

Secondary: Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score

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End point title

Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score

End point description

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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	19	22
Units: Score on scale
arithmetic mean (standard deviation)
Change at 3 Years CA: Total Score (n=19, 22)	0.62 ± 12.220	-1.13 ± 8.533
Change at 4 Years CA: Total Score (n=19, 18)	1.50 ± 14.376	-3.46 ± 7.917
Change at 5 Years CA: Total Score (n=16, 15)	-4.96 ± 15.561	-4.49 ± 8.225

No statistical analyses for this end point

Secondary: Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS)

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End point title

Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS)

End point description

HSCS-PS: validated instrument for age 2.5 - 5 years, 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); mild problem (scoring 1 on scale of 0 to 3, or 1 to 2 on scale of 0 to 5 for any attribute);moderate/severe problem (scoring > 1 on 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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific timepoints.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	24	35
Units: Participants
24M:Neurosensory:No Problem(n=24,35)	21	30
24M:Neurosensory:Mild(n=24,35)	3	4
24M:Neurosensory:Moderate/severe(n=24,35)	0	1
24M:Motor:No Problem(n=24,35)	19	21
24M:Motor:Mild(n=24,35)	3	9
24M:Motor:Moderate/severe(n=24,35)	2	5
24M:Learning/Remembering:No Problem(n=24,35)	10	10
24M:Learning/Remembering: Mild(n=24,35)	6	13
24M:Learning/Remembering: Moderate/severe(n=24,35)	8	12
24M:Quality of life:No Problem(n=24,35)	11	21
24M:Quality of life: Mild(n=24,35)	11	11
24M:Quality of life: Moderate/severe(n=24,35)	2	3
3Y:Neurosensory:No Problem(n=24,33)	20	28
3Y:Neurosensory:Mild(n=24,33)	2	3
3Y:Neurosensory:Moderate/severe(n=24,33)	2	2
3Y:Motor:No Problem(n=24,33)	16	16
3Y:Motor:Mild(n=24,33)	4	13
3Y:Motor:Moderate/severe(n=24,33)	4	4
3Y:Learning/Remembering:No Problem(n=24,33)	13	17
3Y:Learning/Remembering: Mild(n=24,33)	6	11
3Y:Learning/Remembering: Moderate/severe(n=24,33)	5	5
3Y:Quality of life:No Problem(n=24,33)	13	21
3Y:Quality of life: Mild(n=24,33)	9	8
3Y:Quality of life: Moderate/severe(n=24,35)	2	4
4Y:Neurosensory:No Problem(n=23,27)	21	23
4Y:Neurosensory:Mild(n=23,27)	2	4
4Y:Neurosensory:Moderate/severe(n=23,27)	0	0
4Y:Motor:No Problem(n=23,27)	16	16
4Y:Motor:Mild(n=23,27)	5	8
4Y:Motor:Moderate/severe(n=23,27)	2	3
4Y:Learning/Remembering:No Problem(n=23,27)	16	12
4Y:Learning/Remembering: Mild(n=23,27)	4	11
4Y:Learning/Remembering: Moderate/severe(n=23,27)	3	4
4Y:Quality of life:No Problem(n=23,27)	13	17
4Y:Quality of life: Mild(n=23,27)	8	9
4Y:Quality of life: Moderate/severe(n=23,27)	2	1
5Y:Neurosensory:No Problem(n=19,20)	16	17
5Y:Neurosensory:Mild(n=19,20)	3	3
5Y:Neurosensory:Moderate/severe(n=19,20)	0	0
5Y:Motor:No Problem(n=19,20)	13	14
5Y Motor:Mild(n=19,20)	5	5
5Y:Motor:Moderate/severe(n=19,20)	1	1
5Y:Learning/Remembering:No Problem(n=19,20)	10	12
5Y:Learning/Remembering: Mild(n=19,20)	7	7
5Y:Learning/Remembering: Moderate/severe(n=19,20)	2	1
5Y:Quality of life:No Problem(n=19,20)	11	15
5Y:Quality of life: Mild(n=19,20)	8	4
5Y:Quality of life: Moderate/severe(n=19,20)	0	1

No statistical analyses for this end point

Secondary: Health Status Measured by the Health Utilities Index (HUI) Mark 2 and 3

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End point title

Health Status Measured by the Health Utilities Index (HUI) Mark 2 and 3

End point description

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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

At 5 Years CA

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	19	20
Units: Score on scale
arithmetic mean (standard deviation)
HUI2 Overall Utility Score	0.929 ± 0.1246	0.867 ± 0.2115
HUI3 Overall Utility Score	0.893 ± 0.1960	0.852 ± 0.2665

No statistical analyses for this end point

Secondary: Health Care Resource Use (HCRU)

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End point title

Health Care Resource Use (HCRU)

End point description

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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	29	39
Units: Visits
arithmetic mean (standard deviation)
At 3 Months CA (n=29, 39)	9.8 ± 6.48	8.3 ± 7.67
At 6 Months CA (n=28, 37)	15.5 ± 16.06	10.3 ± 9.40
At 12 Months CA (n=25, 36)	25.0 ± 23.81	22.5 ± 33.95
At 24 Months CA (n=25, 35)	20.1 ± 31.95	30.0 ± 40.92
At 3 Years CA (n=24, 31)	22.8 ± 41.38	34.8 ± 55.25
At 4 Years CA (n=20, 23)	21.8 ± 39.00	41.2 ± 69.93
At 5 Years CA (n=16, 15)	15.7 ± 39.80	32.7 ± 51.22

No statistical analyses for this end point

Secondary: Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department

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End point title

Health Care Resource Utilization (HCRU): Number of Visits to Emergency Department

End point description

Number of visits to the 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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific categories. Here, '99999' = SD was not estimated.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	15	17
Units: Visits
arithmetic mean (standard deviation)
At 3 Months CA (n=6, 7)	2.5 ± 1.87	1.6 ± 1.13
At 6 Months CA (n=5, 10)	2.2 ± 2.17	1.3 ± 0.67
At 12 Months CA (n=9, 13)	1.6 ± 0.73	2.2 ± 1.14
At 24 Months CA (n=15, 17)	2.1 ± 1.39	1.4 ± 0.61
At 3 Years CA (n=11, 14)	2.5 ± 2.38	1.6 ± 0.84
At 4 Years CA (n=7, 6)	1.9 ± 1.46	1.7 ± 0.82
At 5 Years CA (n=3, 1)	1.7 ± 0.58	1 ± 99999

No statistical analyses for this end point

Secondary: Health Care Resource Utilization (HCRU): Duration of Hospitalization

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End point title

Health Care Resource Utilization (HCRU): Duration of Hospitalization

End point description

The participants, 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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	9	12
Units: Days
arithmetic mean (standard deviation)
At 3 Months CA (n=9, 11)	12.9 ± 31.27	5.5 ± 4.55
At 6 Months CA (n=9, 12)	6.4 ± 4.56	7.4 ± 5.98
At 12 Months CA (n=5, 9)	7.2 ± 7.76	9.0 ± 11.87
At 24 Months CA (n=7, 4)	4.1 ± 5.01	2.5 ± 1.73
At 3 Years CA (n=4, 5)	4.3 ± 3.30	4.8 ± 6.87
At 4 Years CA (n=2, 3)	3.5 ± 3.54	4.0 ± 3.61
At 5 Years CA (n=0, 0)	0.00 ± 0.000	0.00 ± 0.000

No statistical analyses for this end point

Secondary: Health Care Resource Utilization (HCRU): Number of Participants who Required Prescription Eyeglasses and Educational Support

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End point title

Health Care Resource Utilization (HCRU): Number of Participants who Required Prescription Eyeglasses and Educational Support

End point description

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. Enrolled set. Here,“number of subjects analysed”= subjects evaluable for this endpoint. and “n=number analysed” evaluable at specific time points.

End point type

Secondary

End point timeframe

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

End point values	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Number of subjects analysed	32	39
Units: Participants
3 Months:Used Eyeglasses:Yes(n=32,39)	0	0
3 Months:Used Eyeglasses:No(n=32,39)	32	39
6 Months:Used Eyeglasses:Yes(n=28,39)	0	0
6 Months:Used Eyeglasses:No(n=28,39)	28	39
12 Months:Used Eyeglasses:Yes(n=26,36)	0	1
12 Months:Used Eyeglasses:No(n=26,36)	26	35
24 Months:Used Eyeglasses:Yes(n=25,36)	1	2
24 Months:Used Eyeglasses:No(n=25,36)	24	34
3 Years:Used Eyeglasses:Yes(n=24,33)	3	7
3 Years:Used Eyeglasses:No(n n=24,33)	21	26
4 Years:Used Eyeglasses:Yes(n=23,27)	2	5
4 Years:Used Eyeglasses:No(n=23,27)	21	22
5 Years:Used Eyeglasses:Yes(n=19,20)	3	4
5 Years:Used Eyeglasses:No(n=19,20)	16	16
3 Months:Educational Support:Yes(n=32,39)	0	0
3 Months:Educational Support:No(n=32,39)	32	39
6 Months:Educational Support:Yes(n=28,39)	0	1
6 Months:Educational Support:No(n=28,39)	28	38
12 Months:Educational Support:Yes(n=26,36)	0	1
12 Months:Educational Support:No(n=26,36)	26	35
24 Months:Educational Support:Yes(n=25,36)	0	0
24 Months:Educational Support:No(n=25,36)	25	36
3 Years:Educational Support:Yes(n=24,33)	1	4
3 Years:Educational Support:No(n=24,33)	23	29
4 Years:Educational Support:Yes(n=23,27)	5	3
4 Years:Educational Support:No(n=23,27)	18	24
5 Years:Educational Support:Yes(n=19,20)	3	5
5 Years:Educational Support:No(n=19,20)	16	15

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Antecedent Standard of Care

Reporting group description

Participants who were treated with standard neonatal care in study ROPP-2008-01 (2007-007872-40).

Reporting group title

Antecedent rhIGF-1/rhIGFBP-3

Reporting group description

Participants who were treated with rhIGF-1/rhIGFBP-3 in study ROPP-2008-01 (2007-007872-40).

Serious adverse events	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 36 (8.33%)	2 / 40 (5.00%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	0	0
General disorders and administration site conditions
Sudden infant death syndrome
subjects affected / exposed	1 / 36 (2.78%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy
subjects affected / exposed	1 / 36 (2.78%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	2 / 36 (5.56%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Antecedent Standard of Care	Antecedent rhIGF-1/rhIGFBP-3
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 36 (13.89%)	2 / 40 (5.00%)
Respiratory, thoracic and mediastinal disorders
Tonsillar hypertrophy
subjects affected / exposed	5 / 36 (13.89%)	2 / 40 (5.00%)
occurrences all number	5	2

More information

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Were there any global substantial amendments to the protocol? Yes

19 Feb 2016

Protocol Amendment 1: Removed the Refraction with Cycloplegia assessment performed at the 24-month and the 5-year visits. Added the 20-month visit with the following assessments: visual acuity, corrective lens determination (including refraction with cycloplegia), assessment of participation in other clinical studies. Added the 4.75-year visit with the following assessments: visual acuity and corrective lens determination (including refraction with cycloplegia). Clarified the term “Pulmonary Morbidity Assessment” throughout the protocol for consistency by replacing "Questionnaire” with “Assessment.” Updated list of Target Medical Events to be captured in the study to ensure all events with a potential impact to the primary and secondary endpoint are tracked. AEs related to investigational product (rhIGF-1/rhIGFBP-3 as administered in Study ROPP 2008 01, Section D). AEs related to procedures performed in this study (Study SHP 607 201). Specified targeted medical events regardless of causality. Only the following SAEs will be collected (Fatal SAEs regardless of causality, SAEs related to ROP, SAEs related to congenital malformations not identified at birth which may impact neurocognitive development, Captured SAEs from the end-of–study visit in ROPP-2008-01 Section D and the start of the SHP-607-201 study for safety purpose, Added “When possible, subject’s parents or legally authorized representative(s) should be consented at the end of study visit for the ROPP-2008-01. However, SAEs that the subject experiences between ROPP-2008-001 end-of-study visit and the start of the SHP-607-201, will be reported by the Investigator.” Added “SAEs that the subject experiences between ROPP-2008-001 end-of-study visit and the start of the SHP-607-201 will be reported by the Investigator.”

21 Feb 2017

Protocol Amendment 2: Added pulmonary morbidity assessments to be conducted during phone interviews at the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year CA visits, Provided the pulmonary morbidity assessments at clinical site visits for the 6-month,12-month, 24-month, and 5-year CA visits and phone interviews for the 30-month, 3-year, 3.5-year, 4-year, and 4.5-year CA visits, Added cerebral MRI to the 5-year CA visit, Added hearing assessment history at the 5-year CA visits, Added blood pressure, heart rate, and respiratory rate measurements at the 5-year CA Visit, Clarified that if informed consent is not obtained at or before the 3-month visit in Study ROPP-2008-01 for inclusion in this study (SHP607-201), the subject may still be enrolled until they turn 2 years +3 months CA, Clarified that for subjects enrolled between the ages of 9 months CA and 2 years +3 months CA, missed procedures such as neurocognitive assessments, abdominal ultrasounds, and echocardiograms are not required, Clarified that for consented patients, additional biomarker analysis may be performed on prior collected blood samples from Study ROPP-2008-01.

11 May 2017

Protocol Amendment 3: Added hearing assessment history to the 6-month CA visit. Added language explaining that cerebral magnetic resonance imagining (MRI) procedures are optional. Language was also added explaining that the nature, scope, risks, benefits, and potential sedation associated with cerebral MRI will be explained to the subject and subject’s parent(s) or legally authorized representative(s). Added cerebral MRI to the 5-year CA visit. Added medications, survival assessment, assessment of participation in other clinical studies and adverse events, including targeted medical events to the 30 months, 3.5 years, 4.5 years CA visits conducted by telephone. Clarified that age equivalent scores and standard scores will be summarized for Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), and Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Removed the pulmonary morbidity assessments from the appendices as they will be provided in the Study Operations Manual. Administrative errors were corrected throughout the protocol.

09 Apr 2018

Protocol Amendment 4: Updated Medical Monitor and Shire Global Drug Safety contact information. Added pulmonary function testing to be performed at selected sites that have access to personnel with expertise in performing pediatric spirometry. Added assessment of Health Utilities Index Mark 2 and Mark 3 (HUI2/3) to the 5 year CA visit. Removed assessment of optical coherence tomography (OCT) at the 5 year CA visit. Updated the status of Section D of Study ROPP-2008-01 since the study has now been completed. Clarified that if the Initial Visit does not occur at or before 40 weeks CA, the subject may still be enrolled until they turn 2 years CA +3 months. Removed language stating that any abnormal change in physical examination findings will be recorded as an adverse event (AE).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated With rhIGF 1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or who Received Standard Neonatal Care

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected age (CA)

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 6 Months Corrected age (CA)

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 12 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 20 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 24 Months CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 4.75 Years CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA

Primary: Number of Participants With Visual Acuity as Assessed by an Age-appropriate Method at 5 Years CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 12 Months CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 24 Months CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA

Primary: Number of Participants With Oculomotor Examination (Motility) and Ocular Alignment (Assessed by Corneal Light Reflex and Cover Test) at 5-Years CA

Primary: Number of Participants With Nystagmus at 12 Months CA

Primary: Number of Participants With Nystagmus at 12 Months CA

Primary: Number of Participants With Nystagmus at 24 Months CA

Primary: Number of Participants With Nystagmus at 24 Months CA

Primary: Number of Participants With Nystagmus at 5 Years CA

Primary: Number of Participants With Nystagmus at 5 Years CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 6 Months CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 12 Month CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 20 Month CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA

Primary: Refraction With Cycloplegia as Assessed by Retinoscopy at 4.75 Years CA

Primary: Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA

Primary: Number of Participants With Stereoacuity as Assessed With the Lang Stereotest At 5 Years CA

Primary: Number of Participants With Adverse Events (AEs)

Primary: Number of Participants With Adverse Events (AEs)

Secondary: Change From Baseline in Body Weight Z-score

Secondary: Change From Baseline in Body Weight Z-score

Secondary: Change From Baseline in Height Z-score

Secondary: Change From Baseline in Height Z-score

Secondary: Change From Baseline in Head Circumference Z-score

Secondary: Change From Baseline in Head Circumference Z-score

Secondary: 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

Secondary: 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

Secondary: Cognitive Development as Assessed by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) Full Scale at 5 Years CA

Secondary: Cognitive Development as Assessed by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) Full Scale at 5 Years CA

Secondary: Number of Participants With Abnormal Physical Examination

Secondary: Number of Participants With Abnormal Physical Examination

Secondary: Number of Participants Diagnosed With Cerebral Palsy (CP) by Neurological Examination at 24 Months CA

Secondary: Number of Participants Diagnosed With Cerebral Palsy (CP) by Neurological Examination at 24 Months CA

Secondary: Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II)

Secondary: Change From Baseline (6 Months CA) in Child Behavior as Assessed by Vineland Adaptive Behaviour Scales (VABS-II)

Secondary: Number of Participants With Normal and Abnormal Hearing Screening Status

Secondary: Number of Participants With Normal and Abnormal Hearing Screening Status

Secondary: Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories

Secondary: Number of Participants With Child Behaviour as Assessed by Child Behaviour Checklist (CBCL) Based on T-Score Clinical Categories

Secondary: Child Behavior as Assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Based on Total Score

Secondary: Child Behavior as Assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) Based on Total Score

Secondary: Number of Participants With Pulmonary Morbidity

Secondary: Number of Participants With Pulmonary Morbidity

Secondary: Child Behavior as Assessed by Social Communication Questionnaire (SCQ) Based on Total Score

Secondary: Child Behavior as Assessed by Social Communication Questionnaire (SCQ) Based on Total Score

Secondary: Number of Participants With Survival Status

Secondary: Number of Participants With Survival Status

Secondary: Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale

Secondary: Change From Baseline (3 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Infant Scale

Secondary: Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score

Secondary: Change From Baseline (24 Months CA) in Pediatric Quality of Life Inventory (PedsQL™) Scale: Generic Core Scale (GCS) Total Score

Secondary: Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS)

Secondary: Number of Participants With Health Status Measured by the Health Status Classification System-Preschool (HSCS-PS)

Clinical Trial Results:
Long-term Outcome of Children Enrolled in Study ROPP-2008-01 Previously Treated With rhIGF 1/rhIGFBP-3 for the Prevention of Retinopathy of Prematurity (ROP) or who Received Standard Neonatal Care