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IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT01096784
First received: March 9, 2010
Last updated: May 4, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
Retinopathy of Prematurity (ROP) Drug: rhIGF-I/rhIGFBP-3 Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • 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).


Secondary Outcome Measures:
  • 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 ]

Enrollment: 121
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)
Arms Assigned Interventions
Active Comparator: rhIGF-I/rhIGFBP-3
Continuous IV Infusion
Drug: rhIGF-I/rhIGFBP-3
Continuous intravenous infusion
Other Name: Mecasermin Rinfabate
No Intervention: Control
The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3

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.

  Eligibility

Ages Eligible for Study:   up to 1 Day   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01096784

Locations
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
Italy
D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi
Firenze, Italy
U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico
Genova, Italy
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
Rome, Italy
Netherlands
VU medical Center
Amsterdam, Netherlands, 1081 HZ
Poland
Instytut Centrum Zdrowia Matki Polki
Lódz, Poland, 93-338
Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani
Poznan, Poland, 60-535
Sweden
Skånes University Hospital Lund
Lund, Sweden
Karolinska Universtitetssjukhuset i Huddinge
Stockholm, Sweden
United Kingdom
Addenbrookes Hospital
Cambridge, United Kingdom, CB2 0QQ
St Peter's Hospital; Ashford & S
Chertsey, United Kingdom, KT16 OPZ
University Hospital
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
Sponsors and Collaborators
Shire
Investigators
Study Director: Alexandra Mangili, MD, MPH Shire
Study Director: Adina Tocoian, MD, PhD Shire
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01096784     History of Changes
Other Study ID Numbers: ROPP-2008-01
2007-007872-40 ( EudraCT Number )
Study First Received: March 9, 2010
Results First Received: September 28, 2016
Last Updated: May 4, 2017

Keywords provided by Shire:
insulin-like growth factor
ROP
IGF-I
BPD
bronchopulmonary dysplasia
retinopathy of prematurity

Additional relevant MeSH terms:
Retinal Diseases
Premature Birth
Retinopathy of Prematurity
Eye Diseases
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Infant, Premature, Diseases
Infant, Newborn, Diseases

ClinicalTrials.gov processed this record on August 18, 2017