Clinical trial NCT01096784: IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Retinopathy of Prematurity (ROP)
Keywords: insulin-like growth factor
ROP
IGF-I
BPD
bronchopulmonary dysplasia
retinopathy of prematurity
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-03-31
Enrollment: 121
Sex: ALL
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population
timeFrame: End of study
Secondary outcomes:
measure: Time to Discharge From Neonatal Intensive Care (TDNIC)
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Number of Participants With Bronchopulmonary Dysplasia (BPD)
timeFrame: At 36 Weeks Post Menstrual Age
measure: Rate of Change in Body Weight
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Rate of Change in Length
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Rate of Change in Head Circumference
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Brain Development Assessed by Brain Volume at 40 Weeks PMA/EOS
timeFrame: 40 Weeks PMA/ (EOS) +/- 4 days
measure: Percentage of Participants With Intraventricular Hemorrhage (IVH)
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP)
timeFrame: Every 1-2 weeks starting at 31 weeks PMA/ EOS +/- 4 days
measure: Percentage of Participants With Maximum Severity of ROP Stage Greater Than or Equal to 3 at Any Time During the Study
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Number of Participants With Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE)
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Percentage of Serum IGF-1 Concentrations Falling Within Target Range After Infusion of rhIGF-1/rhIGFBP-3
timeFrame: Day 0 to 40 Weeks Post Menstrual Age (EOS)
measure: Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3
timeFrame: Day 0 and Week 40 Post Menstrual Age
measure: Serum Concentrations of Acid Labile Sub-unit (ALS) After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3
timeFrame: Day 7 and Week 40 Post Menstrual Age
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama Children's and Women's Hospital
state: Alabama
city: Irvine
country: United States
facility: Univ of California Irvine Med Center
state: California
city: Augusta
country: United States
facility: Georgia Regents Medical Center
state: Georgia
city: Jackson
country: United States
facility: Univ of Mississippi Medical Center
state: Mississippi
city: Greenville
country: United States
facility: Vidant Medical Center
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Firenze
country: Italy
facility: D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi
city: Genova
country: Italy
facility: U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico
city: Padua
country: Italy
facility: University of Padua
city: Rome
country: Italy
facility: Dipartimento per la Tutella della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente-U.O.C. Neonatologia-Poli. Gemelli
city: Amsterdam
country: Netherlands
facility: VU medical Center
city: Lódz
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
city: Poznan
country: Poland
facility: Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani
city: Lund
country: Sweden
facility: Skånes University Hospital Lund
city: Stockholm
country: Sweden
facility: Karolinska Universtitetssjukhuset i Huddinge
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Chertsey
country: United Kingdom
facility: St Peter's Hospital; Ashford & S
city: Coventry
country: United Kingdom
facility: University Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: UCL EGA Institute for Women's Health
city: Manchester
country: United Kingdom
facility: St. Mary's Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Lofqvist C, Niklasson A, Engstrom E, Friberg LE, Camacho-Hubner C, Ley D, Borg J, Smith LE, Hellstrom 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.
citation: Ley D, Hansen-Pupp I, Niklasson A, Domellof M, Friberg LE, Borg J, Lofqvist C, Hellgren G, Smith LE, Hard AL, Hellstrom A. Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety. Pediatr Res. 2013 Jan;73(1):68-74. doi: 10.1038/pr.2012.146. Epub 2012 Oct 24.
citation: Klevebro S, Hellgren G, Hansen-Pupp I, Wackernagel D, Hallberg B, Borg J, Pivodic A, Smith L, Ley D, Hellstrom A. Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants. Growth Horm IGF Res. 2020 Feb;50:1-8. doi: 10.1016/j.ghir.2019.11.001. Epub 2019 Nov 9.
citation: Ley D, Hallberg B, Hansen-Pupp I, Dani C, Ramenghi LA, Marlow N, Beardsall K, Bhatti F, Dunger D, Higginson JD, Mahaveer A, Mezu-Ndubuisi OJ, Reynolds P, Giannantonio C, van Weissenbruch M, Barton N, Tocoian A, Hamdani M, Jochim E, Mangili A, Chung JK, Turner MA, Smith LEH, Hellstrom A; study team. rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial. J Pediatr. 2019 Mar;206:56-65.e8. doi: 10.1016/j.jpeds.2018.10.033. Epub 2018 Nov 22.
citation: Hansen-Pupp I, Hellstrom A, Hamdani M, Tocoian A, Kreher NC, Ley D, Hallberg B. Continuous longitudinal infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants: Evaluation of feasibility in a phase II study. Growth Horm IGF Res. 2017 Oct;36:44-51. doi: 10.1016/j.ghir.2017.08.004. Epub 2017 Aug 31.
citation: Chung JK, Hallberg B, Hansen-Pupp I, Graham MA, Fetterly G, Sharma J, Tocoian A, Kreher NC, Barton N, Hellstrom A, Ley D. Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in preterm infants. Pediatr Res. 2017 Mar;81(3):504-510. doi: 10.1038/pr.2016.255. Epub 2016 Nov 21.
citation: Lundgren P, Stoltz Sjostrom E, Domellof M, Kallen K, Holmstrom G, Hard AL, Smith LE, Lofqvist C, Hellstrom A. WINROP identifies severe retinopathy of prematurity at an early stage in a nation-based cohort of extremely preterm infants. PLoS One. 2013 Sep 12;8(9):e73256. doi: 10.1371/journal.pone.0073256. eCollection 2013.