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Retinopathy of Prematurity (ROP)Phase 2NCT01096784

IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

A Phase 2 study testing rhIGF-I/rhIGFBP-3 in people with Retinopathy of Prematurity (ROP), run by Shire at 24 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages Up to 1 day
Conditions the study is for
Retinopathy of Prematurity (ROP)
What is being tested?
rhIGF-I/rhIGFBP-3
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
121 participants
Where
24 sitesin 6 countries
Study dates
18 Jun 2010to 30 Mar 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 1 day
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 10Show fewer
  • 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

Trial locations and contacts

24 sites in 6 countries.

24 sites in 6 countries

United States8 sites

  • Georgia Regents Medical Center

    Augusta, Georgia, 30904

  • Vidant Medical Center

    Greenville, North Carolina, 27834

  • Univ of California Irvine Med Center

    Irvine, California, 92697

  • Univ of Mississippi Medical Center

    Jackson, Mississippi, 39216-4505

  • University of Wisconsin - Madison

    Madison, Wisconsin, 53715

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

    Mobile, Alabama, 36604-3391

  • West Virginia University Hospital

    Morgantown, West Virginia, 26506

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

Other trials in United States

United Kingdom7 sites

  • Addenbrookes Hospital

    Cambridge, CB2 0QQ

  • St Peter's Hospital; Ashford & S

    Chertsey, KT16 OPZ

  • University Hospital

    Coventry, CV2 2DX

  • Alder Hey Children's NHS Foundation Trust

    Liverpool

  • UCL EGA Institute for Women's Health

    London, WC1E 6AU

  • St. Mary's Hospital

    Manchester, M13 9WL

  • Norfolk and Norwich University

    Norwich, NR4 7UY

Other trials in United Kingdom

Italy4 sites

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

    Florence

  • U.O.C Patologia e Terapia Intensiva Neonatale, Istituto Giannina Gaslini-Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico

    Genova

  • University of Padua

    Padua, 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

Other trials in Italy

Poland2 sites

  • Instytut Centrum Zdrowia Matki Polki

    Lódz, 93-338

  • Ginekologiczno-Położniczy Szpital Kliniczny Uniwersytetu Medycznego w Poznani

    Poznan, 60-535

Other trials in Poland

Sweden2 sites

  • Skånes University Hospital Lund

    Lund

  • Karolinska Universtitetssjukhuset i Huddinge

    Stockholm

Other trials in Sweden

Netherlands1 site

  • VU medical Center

    Amsterdam, 1081 HZ

Other trials in Netherlands

About this study

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

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.

Read the 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.

Being tested
rhIGF-I/rhIGFBP-3
Keywords
insulin-like growth factor, ROP, IGF-I, BPD, bronchopulmonary dysplasia, retinopathy of prematurity
Medical subject headings
Retinopathy of Prematurity, Bronchopulmonary Dysplasia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rhIGF-I/rhIGFBP-3Drug

    Also called Mecasermin Rinfabate

    Continuous intravenous infusion

Study groups in NCT01096784
Study groupRoleWhat they receive
rhIGF-I/rhIGFBP-3Active comparatorContinuous IV Infusion
Receives: Drug: rhIGF-I/rhIGFBP-3
ControlNo interventionThe comparator group will receive no treatment with rhIGF-1/rhIGFBP-3

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: End of study

Secondary outcomes (13)

  1. Time to Discharge From Neonatal Intensive Care (TDNIC)

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  2. 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.

    Measured: At 36 Weeks Post Menstrual Age

  3. Rate of Change in Body Weight

    The rate of change is the rate of specific body weight change per day in kilogram (kg).

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  4. Rate of Change in Length

    The rate of change is the length change per day in centimeter (cm).

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  5. Rate of Change in Head Circumference

    The rate of change is the head circumference change per day in centimetre (cm).

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  6. 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

    Measured: 40 Weeks PMA/ (EOS) +/- 4 days

  7. 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).

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  8. 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.

    Measured: Every 1-2 weeks starting at 31 weeks PMA/ EOS +/- 4 days

  9. 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.

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  10. 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.

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  11. 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.

    Measured: Day 0 to 40 Weeks Post Menstrual Age (EOS)

  12. Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3

    Measured: Day 0 and Week 40 Post Menstrual Age

  13. Serum Concentrations of Acid Labile Sub-unit (ALS) After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3

    Measured: Day 7 and Week 40 Post Menstrual Age

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Mar 2010 (estimated)
  2. Study start18 Jun 2010
  3. Primary completion30 Mar 2016
  4. Study completion30 Mar 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
121 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01096784
Sponsor's protocol ID
ROPP-2008-01
Other IDs
2007-007872-40
Status last verified
May 2021
First submitted
9 Mar 2010
Last updated
14 Jun 2021
Data monitoring committee
Yes

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.

    PubMed 19190540

  • 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.

    PubMed 23095978

  • 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.

    PubMed 31756675

  • 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.

    PubMed 30471715

  • 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.

    PubMed 28934640

  • 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.

    PubMed 27870826

  • 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.

    PubMed 24069180

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing rhIGF-I/rhIGFBP-3 in people with Retinopathy of Prematurity (ROP), run by Shire at 24 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, United Kingdom, Italy, Poland, Sweden and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population (time frame: End of study). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01096784, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2021.

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