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.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity (ROP)
• Intervention / Treatment: Drug: rhIGF-I/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.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Firenze, Italy
    • D.A.I. Materno Infantile, S.O.D. Neonatologia e Terapia Intensiva Neonatale - Azienda Ospedaliero-Universitaria Careggi
  • Genova, Italy
    • U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico
  • Padua, Italy, 35128
    • University of Padua
  • Rome, Italy
    • Dipartimento per la Tutella della Salute della Donna e della Vita Nascente, del Bambino e dell'Adolescente-U.O.C. Neonatologia-Poli. Gemelli
• Netherlands
  • Amsterdam, Netherlands, 1081 HZ
    • VU Medical Center
• Poland
  • Lódz, Poland, 93-338
    • Instytut Centrum Zdrowia Matki Polki
  • Poznan, Poland, 60-535
    • Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani
• Sweden
  • Lund, Sweden
    • Skånes University hospital Lund
  • Stockholm, Sweden
    • Karolinska Universtitetssjukhuset i Huddinge
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital
  • Chertsey, United Kingdom, KT16 OPZ
    • St Peter's Hospital; Ashford & S
  • Coventry, United Kingdom, CV2 2DX
    • University Hospital
  • Liverpool, United Kingdom
    • Alder Hey Children's NHS Foundation Trust
  • London, United Kingdom, WC1E 6AU
    • UCL EGA Institute for Women's Health
  • Manchester, United Kingdom, M13 9WL
    • St. Mary's Hospital
  • Norwich, United Kingdom, NR4 7UY
    • Norfolk and Norwich University
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604-3391
      • University of South Alabama Children's and Women's Hospital
  • California
    • Irvine, California, United States, 92697
      • Univ of California Irvine Med Center
  • Georgia
    • Augusta, Georgia, United States, 30904
      • Georgia Regents Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • Univ of Mississippi Medical Center
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Vidant Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • University of Wisconsin - Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: rhIGF-I/rhIGFBP-3; Continuous IV Infusion	Drug: rhIGF-I/rhIGFBP-3; Continuous intravenous infusion; Other Names: Mecasermin Rinfabate
NO_INTERVENTION: Control; The comparator group will receive no treatment with rhIGF-1/rhIGFBP-3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Discharge From Neonatal Intensive Care (TDNIC)		Day 0 to 40 Weeks Post Menstrual Age (EOS)
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
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)
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)
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)
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
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)
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
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)
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)
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)
Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3		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		Day 7 and Week 40 Post Menstrual Age

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 18, 2010
• Primary Completion (ACTUAL): March 30, 2016
• Study Completion (ACTUAL): March 30, 2016

Study Registration Dates

• First Submitted: March 9, 2010
• First Submitted That Met QC Criteria: March 30, 2010
• First Posted (ESTIMATE): March 31, 2010

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: ROP; retinopathy of prematurity; bronchopulmonary dysplasia; BPD; IGF-I; insulin-like growth factor
• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity; Physiological Effects of Drugs; Growth Substances; Mecasermin
• Other Study ID Numbers: ROPP-2008-01; 2007-007872-40 (EUDRACT_NUMBER)