IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
|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|
- Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population [ Time Frame: 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).
- Time to Discharge From Neonatal Intensive Care (TDNIC) [ Time Frame: Day 0 to 40 Weeks Post Menstrual Age (EOS) ]
- Number of Participants With Bronchopulmonary Dysplasia (BPD) [ Time Frame: 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 Body Weight [ Time Frame: 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).
- Rate of Change in Length [ Time Frame: Day 0 to 40 Weeks Post Menstrual Age (EOS) ]The rate of change is the length change per day in centimeter (cm).
- Rate of Change in Head Circumference [ Time Frame: Day 0 to 40 Weeks Post Menstrual Age (EOS) ]The rate of change is the head circumference change per day in centimetre (cm).
- Brain Development Assessed by Brain Volume at 40 Weeks PMA/EOS [ Time Frame: 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 Intraventricular Hemorrhage (IVH) [ Time Frame: 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).
- Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP) [ Time Frame: 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 Maximum Severity of ROP Stage Greater Than or Equal to 3 at Any Time During the Study [ Time Frame: 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.
- Number of Participants With Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) [ Time Frame: 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.
- Percentage of Serum IGF-1 Concentrations Falling Within Target Range After Infusion of rhIGF-1/rhIGFBP-3 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 7 and Week 40 Post Menstrual Age ]
|Study Start Date:||June 1, 2010|
|Study Completion Date:||March 1, 2016|
|Primary Completion Date:||March 1, 2016 (Final data collection date for primary outcome measure)|
Active Comparator: rhIGF-I/rhIGFBP-3
Continuous IV Infusion
Continuous intravenous infusion
Other Name: Mecasermin Rinfabate
No Intervention: Control
The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01096784
|United States, Alabama|
|University of South Alabama Children's and Women's Hospital|
|Mobile, Alabama, United States, 36604-3391|
|United States, California|
|Univ of California Irvine Med Center|
|Irvine, California, United States, 92697|
|United States, Georgia|
|Georgia Regents Medical Center|
|Augusta, Georgia, United States, 30904|
|United States, Mississippi|
|Univ of Mississippi Medical Center|
|Jackson, Mississippi, United States, 39216-4505|
|United States, North Carolina|
|Vidant Medical Center|
|Greenville, North Carolina, United States, 27834|
|United States, Oklahoma|
|University of Oklahoma Health Sciences Center|
|Oklahoma City, Oklahoma, United States, 73104|
|United States, West Virginia|
|West Virginia University Hospital|
|Morgantown, West Virginia, United States, 26506|
|United States, Wisconsin|
|University of Wisconsin - Madison|
|Madison, Wisconsin, United States, 53715|
|D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi|
|U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico|
|University of Padua|
|Padua, Italy, 35128|
|Dipartimento per la Tutella della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente-U.O.C. Neonatologia-Poli. Gemelli|
|VU medical Center|
|Amsterdam, Netherlands, 1081 HZ|
|Instytut Centrum Zdrowia Matki Polki|
|Lódz, Poland, 93-338|
|Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani|
|Poznan, Poland, 60-535|
|Skånes University Hospital Lund|
|Karolinska Universtitetssjukhuset i Huddinge|
|Cambridge, United Kingdom, CB2 0QQ|
|St Peter's Hospital; Ashford & S|
|Chertsey, United Kingdom, KT16 OPZ|
|Coventry, United Kingdom, CV2 2DX|
|Alder Hey Children's NHS Foundation Trust|
|Liverpool, United Kingdom|
|UCL EGA Institute for Women's Health|
|London, United Kingdom, WC1E 6AU|
|St. Mary's Hospital|
|Manchester, United Kingdom, M13 9WL|
|Norfolk and Norwich University|
|Norfolk, United Kingdom, NR4 7UY|
|Study Director:||Alexandra Mangili, MD, MPH||Shire|
|Study Director:||Adina Tocoian, MD, PhD||Shire|