IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

NCT ID: NCT01096784

Last Updated: 2021-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-18
• Study Completion Date: 2016-03-30

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.

Conditions

Retinopathy of Prematurity (ROP)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

rhIGF-I/rhIGFBP-3

Continuous IV Infusion

Group Type: ACTIVE_COMPARATOR

rhIGF-I/rhIGFBP-3

Intervention Type: DRUG

Continuous intravenous infusion

Control

The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

rhIGF-I/rhIGFBP-3

Continuous intravenous infusion

Intervention Type: DRUG

Other Intervention Names

Mecasermin Rinfabate

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

• Maximum Eligible Age: 1 Day
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shire

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Takeda

Locations

University of South Alabama Children's and Women's Hospital

Mobile, Alabama, United States

Univ of California Irvine Med Center

Irvine, California, United States

Georgia Regents Medical Center

Augusta, Georgia, United States

Univ of Mississippi Medical Center

Jackson, Mississippi, United States

Vidant Medical Center

Greenville, North Carolina, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

West Virginia University Hospital

Morgantown, West Virginia, United States

University of Wisconsin - Madison

Madison, Wisconsin, United States

D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi

Florence, , 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, , Italy

VU medical Center

Amsterdam, , Netherlands

Instytut Centrum Zdrowia Matki Polki

Lódz, , Poland

Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani

Poznan, , Poland

Skånes University Hospital Lund

Lund, , Sweden

Karolinska Universtitetssjukhuset i Huddinge

Stockholm, , Sweden

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 Kingdom

Countries

United States; Italy; Netherlands; Poland; Sweden; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 19190540 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23095978 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31756675 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30471715 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28934640 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27870826 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24069180 (View on PubMed)

Other Identifiers

2007-007872-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ROPP-2008-01

Identifier Type: -

Identifier Source: org_study_id