Design of a Phase 2 Randomized Controlled Trial and Long-Term Extension Study of Recombinant Human IGF-1/IGFBP-3 for Prevention of Comorbidities of Extreme Prematurity

Presenter: N. Marlow (e-mail: [e-mail])

Introduction: Insulin-like growth factor 1 (IGF-1) is involved in fetal development of multiple organ systems, including the eye, lung, and brain. Levels of serum IGF-1 fall after preterm birth and are notably lower in preterm infants than in fetuses of corresponding gestational age (GA). Supplementation to fetal IGF-1 levels with recombinant human (rh) IGF-1/rhIGFBP-3 is being investigated for prevention of retinopathy of prematurity (ROP) and other comorbidities of prematurity. A phase 2 study was initiated to assess dosing, efficacy and safety of rhIGF-1/rhIGFBP-3 administered as a continuous intravenous (IV) infusion in extremely preterm infants. The early sections (A–C) of this study demonstrated safety of rhIGF-1/rhIGFBP-3 administration in infants <28 weeks GA. We report the design of the final section (D) of this study and the associated long-term extension study (PEDAL).

Materials and Methods: Section D is a phase 2 multicenter, randomized, assessor-masked study in extremely preterm infants born at GA 23 weeks + 0 days to 27 weeks + 6 days, randomized 1:1 to rhIGF-1/rhIGFBP-3 or standard neonatal care (control). rhIGF-1/rhIGFBP-3 was administered at 250 μg/kg/24 hour as a continuous IV infusion from day of birth up to a postmenstrual age of 29 weeks + 6 days. Primary endpoint is maximum severity of ROP stage. Secondary endpoints include time to discharge from neonatal care (an indicator of overall health), severity of bronchopulmonary dysplasia, prevalence of intraventricular hemorrhage, body weight, length, head circumference, and brain volume using magnetic resonance imaging. PEDAL is designed to evaluate long-term safety and efficacy outcomes following short-term exposure to rhIGF-1/rhIGFBP-3 versus standard neonatal care. The study is enrolling infants after term equivalent age, by invitation from both the treated and control groups of Section D; no investigational product is administered in this study. Enrolled infants will be followed through 5 years corrected age, with a 2-year interim evaluation. Primary efficacy endpoint is ROP-associated visual outcomes. Secondary efficacy assessments include growth parameters, cognitive/physical development, child behavior, pulmonary morbidity and survival. Long-term safety and health-related quality of life will also be assessed. Figure 1 illustrates the overall design of both studies. Section D enrolment was completed in December 2015; 121 infants were enrolled across 7 countries and 21 clinical sites, and the study was completed in March 2016. Enrolment in PEDAL is ongoing, with 73 infants enrolled to date (as of May 9). A 2-year interim analysis is planned for December 2018, and completion is estimated by August 2021. (ClinicalTrials.gov identifiers: Section D, NCT01096784; PEDAL, NCT02386839.)

Conclusion: These trials test the hypothesis that a novel therapeutic intervention (rhIGF-1/rhIGFBP-3) may reduce the extent of morbidity and shift the distribution of disease severity in a population of extremely preterm infants, in both a short- and long-term perspective. The studies also have the potential to stimulate further avenues of research into the prevention of ROP and other comorbidities of prematurity. They may set a new benchmark for neonatal drug development in which multiple complications of prematurity are targeted as the primary efficacy outcome.

Keywords: long-term outcomes, preterm, randomized controlled trial, retinopathy of prematurity, IGF-1, rhIGF-1/rhIGFBP-3, ROP, BPD, neurodevelopment, growth

Fig. 1 Overall Study Design for Section D and PEDAL.