IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

Phase 2

Completed

Conditions: Retinopathy of Prematurity (ROP)

Interventions: Drug: rhIGF-I/rhIGFBP-3

Registration Number: NCT01096784

Lead Sponsor: Shire

Brief Summary: To compare the severity of retinopathy of prematurity (ROP) among treated infants with an untreated control population, matched for gestational age at birth while confirming the dose of rhIGF-1/rhIGFBP-3 is safe and efficacious.

Detailed Description: When preterm infants are deprived of their natural intrauterine environment they lose access to important factors, normally found in utero, such as proteins, growth factors, and cytokines. It has been demonstrated that insulin-like growth factor-1 (IGF-1) is one such factor. In utero these biological factors are introduced to the fetus via placental absorption or ingestion from amniotic fluid. Deprivation of such factors is likely to cause inhibition or improper stimulation of important pathways, which in the case of the eye may cause abnormal retinal vascular growth, the hallmark of retinopathy of prematurity (ROP).

Retinopathy of prematurity is the major cause of blindness in children in the developed and developing world, despite the availability of current treatment of late-stage ROP. As developing countries provide more neonatal and maternal intensive care, which increases the survival of preterm born infants, the incidence of ROP is increasing.

This phase 2 study was originally designed in 3 sections, Sections A, B, and C which are now complete. The protocol was amended and patients enrolled from this point forward will be enrolled into Section D.

In Study Section D, a total of 120 subjects (GA of 23 weeks + 0 days to 27 weeks + 6 days) will be randomly assigned with 1:1 allocation ratio to either treatment with rhIGF-1/rhIGFBP-3 or to receive standard neonatal care (Control Group) to obtain at least 80 evaluable subjects. Duration of infusion will last at longest from Study Day 0 (day of birth) up to and including PMA 29 weeks + 6 days, when the subject's endogenous production of IGF-1 is considered sufficient to maintain physiologic serum IGF-1 levels. After discontinuation of study drug infusion, each subject will be followed to PMA 40 weeks ± 4 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 121

Inclusion Criteria

Signed informed consent from parents/guardians;
Subject must be between GA of 26 weeks + 0 days and 27 weeks + 6 days (Study Section A) or between GA of 23 weeks + 0 days and 27 weeks + 6 days (Study Sections B, C, and D), inclusive

Exclusion Criteria

Subjects born small for gestational age (SGA), ie, body weight at birth <-2 standard deviation score (SDS) (Study Section A only)
Detectable gross malformation
Known or suspected chromosomal abnormality, genetic disorder, or syndrome, according to the Investigator's opinion
Persistent blood glucose level <2.5 mmol/L or >10 mmol/L at Study Day 0 (day of birth) to exclude severe congenital abnormalities of glucose metabolism
Anticipated need of administration of erythropoietin (rhEPO) during treatment with study drug.
Any maternal diabetes requiring insulin during the pregnancy
Clinically significant neurological disease according to the Investigator's opinion(Stage 1 IVH allowed)
Any other condition or therapy that, in the Investigator's opinion, may pose a risk to the subject or interfere with the subject's ability to be compliant with this protocol or interfere with interpretation of results
Monozygotic twins
Subject participating or plans to participate in a clinical study of another investigational study drug

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
rhIGF-I/rhIGFBP-3	rhIGF-I/rhIGFBP-3	Continuous IV Infusion

Primary Outcome Measures

Name	Time	Method
Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population	End of study	ROP was measured by central exams with fundus photography. Maximum severity of ROP stage across all retinal examinations included International Classification of Retinopathy of Prematurity, a 5 stage system, for the classification of ROP with 7 different outcomes of the ROP stage in each retinal examination: 0, 1, 2, 3, 3+, 4, and 5. This is an ordinal scale with higher numbers indicating a more severe outcome. The maximum severity of ROP across all time points was assessed from 31 PMA weeks up to 40 PMA Weeks +/- 4 days (end of study).

Secondary Outcome Measures

Name	Time	Method
Time to Discharge From Neonatal Intensive Care (TDNIC)	Day 0 to 40 Weeks Post Menstrual Age (EOS)
Rate of Change in Body Weight	Day 0 to 40 Weeks Post Menstrual Age (EOS)	The rate of change is the rate of specific body weight change per day in kilogram (kg).
Number of Participants With Bronchopulmonary Dysplasia (BPD)	At 36 Weeks Post Menstrual Age	Severity of BPD as mild, moderate and severe were based on the National Institute of Child Health and Human Development (NICHD) guidelines for preterm infants born at gestational age (GA) less than (\<) 32 weeks. Mild: oxygen requirement during the first 28 days but in room air at PMA 36 weeks or discharge to home, whichever comes first. Moderate BPD: oxygen requirement during the first 28 days and oxygen \<30 percent (%) at PMA 36 weeks or discharge to home, whichever comes first. Severe BPD: oxygen requirement during the first 28 days and oxygen greater than equal (≥)30% through head hood or nasal canula, or continuous positive airway pressure, or mechanical ventilation, or high flow nasal cannula ≥2 L/min at PMA 36 weeks or discharge to home, whichever comes first.
Rate of Change in Length	Day 0 to 40 Weeks Post Menstrual Age (EOS)	The rate of change is the length change per day in centimeter (cm).
Brain Development Assessed by Brain Volume at 40 Weeks PMA/EOS	40 Weeks PMA/ (EOS) +/- 4 days	Brain volume was measured using cerebral magnetic resonance imaging (MRI). Brain volume included cerebrospinal volume, gray matter volume, white matter volume, and total cerebellar volume
Percentage of Participants With Maximum Severity of ROP Stage Greater Than or Equal to 3 at Any Time During the Study	Day 0 to 40 Weeks Post Menstrual Age (EOS)	ROP was measured by central exams with fundus photography. Maximum severity of ROP stage across all retinal examinations included International Classification of Retinopathy of Prematurity, a 5 stage system, for the classification of ROP with 7 different outcomes of the ROP stage in each retinal examination: 0, 1, 2, 3, 3+, 4, and 5. This is an ordinal scale with higher numbers indicating a more severe outcome.
Rate of Change in Head Circumference	Day 0 to 40 Weeks Post Menstrual Age (EOS)	The rate of change is the head circumference change per day in centimetre (cm).
Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP)	Every 1-2 weeks starting at 31 weeks PMA/ EOS +/- 4 days	Integration of the maximum severity of ROP stage and the duration of the time interval with respect to each retinal examination. AUC for the maximum severity of ROP was calculated using the trapezoidal rule. The area between each 2 visits was calculated by multiplying the average of the maximum severities of the 2 visits by the difference in days and analyzed using the van Elteren test. ROP is classified according to the International Classification and is subdivided into 5 stages (1-5) with higher values representing greater severity.
Percentage of Participants With Intraventricular Hemorrhage (IVH)	Day 0 to 40 Weeks Post Menstrual Age (EOS)	Development of intraventricular hemorrhage was assessed by cerebral ultrasound and coded as a binary endpoint (presence or absence of IVH).
Serum Concentrations of Acid Labile Sub-unit (ALS) After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3	Day 7 and Week 40 Post Menstrual Age
Percentage of Serum IGF-1 Concentrations Falling Within Target Range After Infusion of rhIGF-1/rhIGFBP-3	Day 0 to 40 Weeks Post Menstrual Age (EOS)	Serum samples were collected from treated and control participants for quantification of IGF-1 using validated immunoassays. Target range of serum IGF-1 was 28-109 mcg/L. The percentage of serum IGF-1 levels across treated participants that fall within the range was reported.
Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3	Day 0 and Week 40 Post Menstrual Age
Number of Participants With Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE)	Day 0 to 40 Weeks Post Menstrual Age (EOS)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product.

Trial Locations

Locations (24): Georgia Regents Medical Center
🇺🇸
Augusta, Georgia, United States
Vidant Medical Center
🇺🇸
Greenville, North Carolina, United States
West Virginia University Hospital
🇺🇸
Morgantown, West Virginia, United States
U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico
🇮🇹
Genova, Italy
D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi
🇮🇹
Firenze, Italy
UCL EGA Institute for Women's Health
🇬🇧
London, United Kingdom
VU medical Center
🇳🇱
Amsterdam, Netherlands
Instytut Centrum Zdrowia Matki Polki
🇵🇱
Lódz, Poland
Karolinska Universtitetssjukhuset i Huddinge
🇸🇪
Stockholm, Sweden
University of Padua
🇮🇹
Padua, Italy
Dipartimento per la Tutella della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente-U.O.C. Neonatologia-Poli. Gemelli
🇮🇹
Rome, Italy
University Hospital
🇬🇧
Coventry, United Kingdom
Alder Hey Children's NHS Foundation Trust
🇬🇧
Liverpool, United Kingdom
Skånes University Hospital Lund
🇸🇪
Lund, Sweden
Addenbrookes Hospital
🇬🇧
Cambridge, United Kingdom
St Peter's Hospital; Ashford & S
🇬🇧
Chertsey, United Kingdom
Norfolk and Norwich University
🇬🇧
Norwich, United Kingdom
St. Mary's Hospital
🇬🇧
Manchester, United Kingdom
University of South Alabama Children's and Women's Hospital
🇺🇸
Mobile, Alabama, United States
Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani
🇵🇱
Poznan, Poland
Univ of California Irvine Med Center
🇺🇸
Irvine, California, United States
University of Wisconsin - Madison
🇺🇸
Madison, Wisconsin, United States
Univ of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States