IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

Study Overview
=================
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.

Official Title
-----------------
Determination of the rhIGF-1/rhIGFBP-3 Dose, Administered as a Continuous Infusion, Required to Establish and Maintain Longitudinal Serum IGF-1 Levels Within Physiological Levels in Premature Infants, to Prevent Retinopathy of Prematurity A Phase 2, Randomized Controlled, Assessor-blind, Dose Confirming, Pharmacokinetic, Safety and Efficacy, Multicenter Study

Conditions
-----------------
Retinopathy of Prematurity (ROP)

Intervention / Treatment
-----------------
* Drug: rhIGF-I/rhIGFBP-3


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 1 Day

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: rhIGF-I/rhIGFBP-3<br>Continuous IV Infusion | Drug: rhIGF-I/rhIGFBP-3<br>* Continuous intravenous infusion<br>* Other names: Mecasermin Rinfabate;|
| No Intervention: Control<br>The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3 | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population | 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). | End of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Discharge From Neonatal Intensive Care (TDNIC) |  | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Number of Participants With Bronchopulmonary Dysplasia (BPD) | 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. | At 36 Weeks Post Menstrual Age | 
| Rate of Change in Body Weight | The rate of change is the rate of specific body weight change per day in kilogram (kg). | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Rate of Change in Length | The rate of change is the length change per day in centimeter (cm). | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Rate of Change in Head Circumference | The rate of change is the head circumference change per day in centimetre (cm). | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Brain Development Assessed by Brain Volume at 40 Weeks PMA/EOS | 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 | 40 Weeks PMA/ (EOS) +/- 4 days | 
| Percentage of Participants With Intraventricular Hemorrhage (IVH) | Development of intraventricular hemorrhage was assessed by cerebral ultrasound and coded as a binary endpoint (presence or absence of IVH). | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP) | 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. | Every 1-2 weeks starting at 31 weeks PMA/ EOS +/- 4 days | 
| Percentage of Participants With Maximum Severity of ROP Stage Greater Than or Equal to 3 at Any Time During the 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. | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Number of Participants With Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) | 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. | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Percentage of Serum IGF-1 Concentrations Falling Within Target Range After Infusion of rhIGF-1/rhIGFBP-3 | 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. | Day 0 to 40 Weeks Post Menstrual Age (EOS) | 
| Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3 |  | Day 0 and Week 40 Post Menstrual Age | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
insulin-like growth factor, ROP, IGF-I, BPD, bronchopulmonary dysplasia, retinopathy of prematurity