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IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01096784
First Posted: March 31, 2010
Last Update Posted: June 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Shire
March 9, 2010
March 31, 2010
September 28, 2016
June 7, 2017
June 7, 2017
June 1, 2010
March 1, 2016   (Final data collection date for primary outcome measure)
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).
Severity of retinopathy of prematurity [ Time Frame: At term age (post menstrual week 40) ]
Complete list of historical versions of study NCT01096784 on ClinicalTrials.gov Archive Site
  • 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 ]
  • Incidence of mild and severe bronchopulmonary dysplasia [ Time Frame: At term age (post menstrual week 40) ]
  • Body weight [ Time Frame: At birth, day 1, 2 and 3 and thereafter twice weekly up post menstrual age week 40 (appr.) ]
    Development of body weight in treated infants will be compared with untreated controls
  • Length [ Time Frame: Once weekly up to End of Study (at term age (post menstrual week 40)) ]
    Development of length in treated infants will be compared with untreated controls
  • Brain volume and head circumference [ Time Frame: Study days 1, 3, 7, 14, 21 and at PMA 6 weeks and at term age (post menstrual week 40) ]
    Development of brain volume and head circumference in treated infants will be compared with untreated controls
  • Number of days in neonatal intensive care [ Time Frame: At home discharge ]
    Total number of days in neonatal intensive care prior to home discharge for treated infants will be compared with untreated controls
  • Adverse events [ Time Frame: Throughout the study ]
    Hematology, clinical chemistry, physical examinations and vital signs including heart rate, blood pressure, oxygen saturation and breath frequency will be monitored from birth throughout the study.
  • IGF-I levels [ Time Frame: From day of birth up to end of study ]
    IGF-I levels and associated pharmacokinetic parameters during and after continuous infusion of rhIGF-I/rhIGFBP-3 will be monitored from day of birth up to stusy end (postmenstrual week 40)
  • Blood glucose levels [ Time Frame: Throughout the treatment period ]
  • Long term follow up [ Time Frame: At 2.5 and 5.5 years of age ]
    All infants will be screened at 2.5 and 5.5 years of age with regard to visual development. Ocular fundus photographs for digital image analysis of the retinal vascular morphology will be taken at 2.5 and 5.5 years and at 5.5 years of age the children will have a clinical physical examination, including ultrasound of heart, kidney and spleen size, as well as a test of neuropsycologic functions (e.g. WISC) and test of pulmonary function. The pubertal development will be investigated by a pediatric endocrinologist at 10.5 years for the girls and at 12 years for the boys.
Not Provided
Not Provided
 
IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity
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
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Retinopathy of Prematurity (ROP)
Drug: rhIGF-I/rhIGFBP-3
Continuous intravenous infusion
Other Name: Mecasermin Rinfabate
  • Active Comparator: rhIGF-I/rhIGFBP-3
    Continuous IV Infusion
    Intervention: Drug: rhIGF-I/rhIGFBP-3
  • No Intervention: Control
    The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
121
March 1, 2016
March 1, 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
up to 1 Day   (Child)
No
Contact information is only displayed when the study is recruiting subjects
Italy,   Netherlands,   Poland,   Sweden,   United Kingdom,   United States
 
 
NCT01096784
ROPP-2008-01
2007-007872-40 ( EudraCT Number )
Yes
Not Provided
Not Provided
Shire
Shire
Not Provided
Study Director: Alexandra Mangili, MD, MPH Shire
Study Director: Adina Tocoian, MD, PhD Shire
Shire
May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP