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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01096784
Other study ID # ROPP-2008-01
Secondary ID 2007-007872-40
Status Completed
Phase Phase 2
First received
Last updated
Start date June 18, 2010
Est. completion date March 30, 2016

Study information

Verified date May 2021
Source Takeda
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 information / eligibility

Status Completed
Enrollment 121
Est. completion date March 30, 2016
Est. primary completion date March 30, 2016
Accepts healthy volunteers No
Gender All
Age group N/A to 1 Day
Eligibility 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


Intervention

Drug:
rhIGF-I/rhIGFBP-3
Continuous intravenous infusion

Locations

Country Name City State
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 Dipartimento per la Tutella della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente-U.O.C. Neonatologia-Poli. Gemelli Rome
Netherlands VU medical Center Amsterdam
Poland Instytut Centrum Zdrowia Matki Polki Lódz
Poland Ginekologiczno-Polozniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani Poznan
Sweden Skånes University Hospital Lund Lund
Sweden Karolinska Universtitetssjukhuset i Huddinge Stockholm
United Kingdom Addenbrookes Hospital Cambridge
United Kingdom St Peter's Hospital; Ashford & S Chertsey
United Kingdom University Hospital Coventry
United Kingdom Alder Hey Children's NHS Foundation Trust Liverpool
United Kingdom UCL EGA Institute for Women's Health London
United Kingdom St. Mary's Hospital Manchester
United Kingdom Norfolk and Norwich University Norwich
United States Georgia Regents Medical Center Augusta Georgia
United States Vidant Medical Center Greenville North Carolina
United States Univ of California Irvine Med Center Irvine California
United States Univ of Mississippi Medical Center Jackson Mississippi
United States University of Wisconsin - Madison Madison Wisconsin
United States University of South Alabama Children's and Women's Hospital Mobile Alabama
United States West Virginia University Hospital Morgantown West Virginia
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma

Sponsors (1)

Lead Sponsor Collaborator
Shire

Countries where clinical trial is conducted

United States,  Italy,  Netherlands,  Poland,  Sweden,  United Kingdom, 

References & Publications (2)

Ley D, Hansen-Pupp I, Niklasson A, Domellöf M, Friberg LE, Borg J, Löfqvist C, Hellgren G, Smith LE, Hård AL, Hellström A. Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokineti — View Citation

Löfqvist C, Niklasson A, Engström E, Friberg LE, Camacho-Hübner C, Ley D, Borg J, Smith LE, Hellström A. A pharmacokinetic and dosing study of intravenous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants. Pediatr Res. 2009 May;65(5):574-9. doi: 10.1203/PDR.0b013e31819d9e8c. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Time to Discharge From Neonatal Intensive Care (TDNIC) Day 0 to 40 Weeks Post Menstrual Age (EOS)
Secondary 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
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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
Secondary 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)
Secondary 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
Secondary 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)
Secondary 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)
Secondary 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)
Secondary Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3 Day 0 and Week 40 Post Menstrual Age
Secondary 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
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