Randomised Phase 2b trial of rhIGF-1/rhIGFBP-3 (OHB-607) for bronchopulmonary dysplasia prevention in preterm neonates: study protocol

Abstract

Introduction

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity, characterised by impaired alveolarisation and pulmonary vascular development. BPD has been associated with an increased risk of respiratory morbidity, neurodevelopmental impairment and death, intensifying a lifelong health and economic burden. The current standard of neonatal care is primarily supportive, with no approved therapies to restore lung development, promote maturation and lung growth or prevent long-term sequelae. Therefore, there is a critical unmet need for novel interventions, particularly in high-risk, extremely premature (EP) infants. In EP infants, serum insulin-like growth factor-1 (IGF-1) levels decrease rapidly and remain low for the first weeks after birth relative to the corresponding foetal levels in utero.

Methods and analysis

OHB-607, a recombinant human IGF-1 combined with its binding protein-3, may replenish IGF-1 during this period of deficiency and support lung and vascular maturation. OHB-607 is being investigated as a first-line therapy to prevent severe BPD in EP infants in a Phase 2b, multicentre, open-label, randomised trial. Here, we present the Phase 2b study protocol. Target enrolment is 338 EP infants. To mimic physiological IGF-1 levels in utero, OHB-607 will be administered starting within 24 hours of birth until 29⁺⁶ weeks postmenstrual age (PMA) via continuous intravenous infusion. The primary endpoint is the incidence of severe BPD, based on the modified National Institute of Child Health and Human Development criteria, or death by 36 weeks PMA. Key secondary endpoints include weaning from respiratory support at 12 months corrected age and BPD severity (Grade 2/3) by the 2019 Neonatal Research Network definition. Other secondary endpoints include other complications of prematurity, neurodevelopmental outcomes and family and infant well-being and social functioning through 24 months’ corrected age, and pharmacokinetic and dynamic impact of OHB-607 on the multisystem consequences of prematurity, and overall safety in modifying the natural history of BPD and its consequences.

Ethics and dissemination

Findings will be disseminated via local and international congresses and publications.

Trial registration number

ClinicalTrials.gov (NCT03253263), Clinicaltrialsregister.eu (EudraCT: 2018-001393-16), Euclinicaltrials.eu (EUCT: 2024-515914-41-00) and Pmda.go.jp (PMDA: jRCT2031240339).

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, with no approved therapies that effectively prevent BPD or its long-term respiratory and neurodevelopmental effects.

WHAT THIS STUDY HOPES TO ADD

• To evaluate OHB-607 as replacement therapy for transient postnatal insulin-like growth factor-1 (IGF-1) deficiency in extremely premature infants to prevent severe BPD and improve long-term outcomes.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• OHB-607 might transform clinical practice in neonatology by becoming the first therapy indicated for the prevention of BPD and other complications of prematurity.

Introduction

Bronchopulmonary dysplasia (BPD) and its long-term sequelae exist along a continuum that includes chronic lung disease (CLD) of prematurity, with substantial lifelong pulmonary, social and economic consequences.¹ It was first described by Northway et al² as severe lung injury characterised by airway injury, inflammation, fibrosis and emphysematous changes resulting from mechanical ventilation and oxygen exposure, which is now termed ‘classic’ or ‘old’ BPD.^2–4 With the increasing survival of infants born <32 weeks’ gestational age (GA), the disease phenotype has shifted toward a histopathologically distinct ‘new’ BPD characterised by disruption in alveolar and vascular development, resulting in impaired lung growth with far more devastating consequences on infant survival and function over the long term.^5–7 While improved obstetrical and neonatal care dramatically increased the survival rates of extremely premature (EP) infants, this has led to a rising incidence of BPD and escalating challenge for neonatology.

The definition of BPD has been evolving to reflect the impact of disrupted lung development.^{3 8–11} BPD and its more severe forms, in particular, have been associated with higher morbidity and mortality than in premature infants without BPD and an increased risk of cognitive and motor impairments that persist into adulthood.^{5 9 12–15} Lung abnormalities associated with BPD may also continue throughout the life span and can be considered the earliest and most prolonged obstructive lung disease in humans, exerting a substantial long-term health and economic burden to the individual and the healthcare system.^16–20 Additionally, the chronic nature of BPD exerts significant psychosocial and financial stress on infants and their families, including long-term caregiving responsibilities and loss of income.¹⁷ However, it has been reported that there is limited awareness of the long-term impact of prematurity and respiratory challenges for BPD survivors, particularly among adult pulmonologists.^{21 22}

Despite widespread clinical use, steroids and surfactants have shown limited efficacy in restoring normal lung architecture or preventing long-term complications of BPD.^{3 13} Concerns have also been raised about the risk of adverse neurodevelopmental outcomes with postnatal steroids.^{3 13} Therefore, there is an urgent unmet need for new therapies that go beyond treating symptoms of disease (oedema, inflammation and infection) but that target ongoing alveolarisation and vascularisation, key elements deficient in infants with BPD.³ Accelerating efforts toward the discovery of new therapies to address the needs of an increasing population of EP infant survivors who live with BPD and its systemic sequelae.^{3 15 23}

Insulin-like growth factor-1 (IGF-1) is a promising candidate for the prevention of BPD, as EP infants at greatest risk of BPD are uniformly deficient in IGF-1.²⁴ IGF-1 plays a crucial role in lung development, maturation and growth by regulating cellular proliferation, differentiation and survival within the developing lung tissue.²⁵ During lung development, IGF-1 promotes alveolarisation, airway branching and vascularisation, facilitating proper lung structure and function (figure 1). It also influences the maturation of lung tissues, aiding in the transition from immature to fully functional lungs, which is essential for effective respiration following birth. Additionally, IGF-1 supports postnatal lung growth and repair by stimulating cellular proliferation and reducing apoptosis, thereby contributing to lung regeneration and adaptation after injury or under pathological conditions.²⁵ IGF-1 replacement therapy was proposed as a strategy to promote lung development in EP infants, thereby mitigating impaired lung growth characteristic of BPD and reducing long-term pulmonary morbidity.²⁵

Figure 1. Illustration of the potential central role of IGF-1 in premature lung development. Reproduced from Cui X, Fu J. Reinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia. Respir Res. 2024;25(1):384. doi: 10.1186/s12931-024-02996-8, under the Creative Commons Attribution licence (CC BY 4.0 6143671483388).

Central role of growth factors in regulating pulmonary morphogenesis, angiogenesis and alveolar regeneration. IGF-1 stimulates the transcription of VEGF through MAPK and AKT pathways, which in turn induce angiogenesis, a crucial factor in the development of the lung. Interaction between IGF-1 and its receptor, IGF-1R, promotes normal alveolar and microvascular development. IGF-1 lessens the severity of pulmonary fibrosis that results from neonatal damage by attenuating transforming TGF-β. Mesenchymal release of FGF10 is associated with increased VEGF expression in the epithelium. Alveolar lipofibroblast-derived FGF10 stimulates the local proliferation of AT2 cells by FGF10-FGFR2 activation, which leads to differentiation into AT1 cells. Adventitial fibroblast-derived FGF10 promotes FGFR2 and FGFR1 signalling in the vascular smooth muscle and endothelial compartments, stimulating pulmonary vasculature remodelling.

AT1/2, alveolar type 1/2; FGF10, fibroblast growth factor 10; FGFR1/2, fibroblast growth factor receptor 1/2; IGF-1/R, insulin-like growth factor-1/receptor; MAPK, mitogen-activated protein kinase; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

OHB-607 (rhIGF-1/rhIGF-BP3), a recombinant human (rh) form of IGF-1 combined with its binding protein-3 (IGFBP-3), may replenish IGF-1 in EP infants and thereby help promote continued development and maturation of the lung and other vital organs and the vasculature that supports them. The complex is delivered by continuous central line intravenous infusion in EP infants until endogenous IGF-1 production begins around 30 weeks postmenstrual age (PMA).^26–28 OHB-607 was initially evaluated in a proof-of-concept Phase 2a study based on the hypothesis that restoring postnatal IGF-1 to physiological fetal levels could reduce retinopathy of prematurity (ROP), consistent with early preclinical and observational data.²⁶ As emerging clinical data increasingly demonstrated that IGF-1 deficiency in EP infants was associated with multiple complications of prematurity, the Phase 2a study prospectively included several clinically relevant endpoints, including BPD, intraventricular haemorrhage (IVH) and somatic growth outcomes, reflecting this broader biological hypothesis. While IGF-1 supplementation did not reduce the incidence of ROP, it was associated with a marked reduction in severe BPD (53% in the full analysis set and 89% in the evaluable set), with a non-significant trend toward the reduction in severe IVH. The evaluable set was predefined to assess outcomes among infants who met the target physiological IGF-1 exposure, defined as ≥70% of serum IGF-1 concentrations within the prespecified foetal range (28–109 µg/L) and receipt of ≥70% of the intended infusion duration. In this subgroup, the effect of OHB-607 was most pronounced for BPD severity, exceeding effects observed for other complications.²⁶ Collectively, these findings informed the evolution of the clinical development strategy, leading to the selection of BPD prevention as the primary endpoint in subsequent studies, while continuing to evaluate ROP, IVH and other morbidities as important secondary outcomes. In 2022, OHB-607 was acquired from Takeda by Oak Hill Bio and is currently being developed, in partnership with Chiesi Farmaceutici S.p.A., as a potential first-line treatment to prevent BPD and its evolution in EP infants.^{29 30}

We present the study design of a Phase 2b multicentre, randomised, open-label two-arm clinical trial evaluating the efficacy and safety of OHB-607 in preventing severe BPD and measures of CLD, and neurodevelopmental outcomes through 24 months of chronological age compared with standard neonatal care (SNC) in EP infants (Clinical Trials Identifier: NCT03253263).

Methods and analysis

This manuscript is based on the study protocol V.1.1 Amend V.4.0 (dated 17 January 2025) and SAP V.2.0 (dated 10 October 2025).

Study objectives

The primary objective is to assess the effect of OHB-607 on CLD, as indicated by the reduction of severe BPD defined by a modified National Institute of Child Health and Human Development (NICHD) severity grading at 36 weeks (±3 days) PMA, or death at or before 36 weeks PMA, whichever comes first, as compared with the SNC group.^{10 11} Two key secondary objectives are to assess the effect of OHB-607 on time to final weaning off respiratory technology support (RTS) through 12 months corrected age (CA), and the incidence of Grade 2 and Grade 3 (severe) BPD at 36 weeks (±3 days) PMA (Neonatal Research Network (NRN) definition), or death at or before 36 weeks PMA, whichever comes first, as compared with the SNC group.⁸

Study design

This Phase 2b trial is a randomised, open-label, two-arm study conducted in two parts (A and B), following a single consent process (figure 2). Part A will be completed when all subjects reach 40 weeks PMA, or are discharged from, or transferred from, the newborn, neonatal or equivalent hospital medical or intensive care unit, or to a non-affiliated medical care unit or facility, withdraw from the study or die, whichever comes first. Following the completion of Part A, participants will proceed to Part B, an observational, non-interventional arm. Clinical site visits will occur at 6, 12 and 24 months CA (all ±4 weeks). Follow-up telephone calls will be performed monthly for the first 3 months (each ±1 week) and at 9, 15, 18 and 21 months (all ±4 weeks) CA, or in person if coincident with routine hospital care. Part B will be completed at 24 months CA, withdrawal, death or loss to follow-up, whichever comes first.

Figure 2. Study design.

¹Enrolment includes n=29 subjects receiving 400 µg/kg/day and n=28 subjects with SNC of GA 26 to 27^+6/7 weeks enrolled in the initial Phase 2b.

²BPD severity as defined by the protocol’s modified NICHD BPD definition.^{10 11}

³BPD severity as defined by the modified NRN criteria Jensen et al.⁸

BPD, bronchopulmonary dysplasia; CA, corrected age (age (in months) after expected date of full-term delivery); GA, gestational age; IV, intravenous; NICHD, National Institute of Child Health and Human Development; NICU, neonatal intensive care unit; NRN, Neonatal Research Network; PMA, postmenstrual age; RTS, respiratory technology support; SNC, standard neonatal care.

Patient involvement

Patients, parents and advocacy representatives were involved in the development of this study. During the early design phase of the Phase 2b clinical trial, Takeda conducted a survey of parents and outreach to parent groups and advocacy organisations. Their input informed the choice of outcomes considered meaningful to families and helped define acceptable levels of participant burden and safety oversight. Following the programme transition to Oak Hill Bio, informal feedback from parents and advocacy partners was sought and used to guide operational planning and feasibility considerations. To reduce participant and site burden, practical modifications in the study design were implemented, such as replacing home-completed questionnaires with telephone-assisted completion supported by study staff. Patients and advocacy representatives were not involved in drafting this manuscript, but their early contributions were integral to shaping the protocol’s design with a family-centred focus.

Participating centres

The study will be conducted in up to 60 sites, including, but not limited to, countries in North America, Europe and the Asia Pacific.

Study population

This ongoing study aims to enrol 338 EP neonates born between 23⁺⁰ weeks and 27⁺⁶ weeks GA, whose parents provided informed consent. A 60:40 enrolment ratio of low GA (23⁺⁰ weeks to 25⁺⁶ weeks) to high GA (26 weeks to 27⁺⁶ weeks) is used to leverage the higher incidence of severe BPD among the lower GA infants, reducing the sample size needed to demonstrate a 20% absolute reduction in severe BPD with OHB-607 versus SNC. Infants with major congenital malformations, persistent glucose metabolism abnormalities, significant neurological disease or any condition or therapy that, in the investigator’s opinion, may pose a risk to the neonate are excluded from the study. Full details of the study eligibility criteria can be found in box 1.

Box 1. Eligibility criteria.

Inclusion criteria:

• Written informed consents and/or assents must be signed and dated by the participant’s parent(s) prior to any study related procedures. The informed consent and any assents for underage parents must be approved by the IRB/IEC (in accordance with local regulations).

• Written informed consents and/or assents must be signed and dated by the participant’s birth mother prior to providing study-related information related to birth mother medical history, pregnancy and the birth of the participant. The informed consent and any assents for underage birth mothers must be approved by the IRB/IEC (in accordance with local regulations).

• Subjects must be between 23⁺⁰ weeks and 27⁺⁶ weeks GA, inclusive.

Exclusion criteria:

• Detectable major (or severe) congenital malformation identified before randomisation.

• Known or suspected chromosomal abnormality, genetic disorder or syndrome, identified before randomisation, according to the investigator’s opinion.

• Hypoglycaemia at baseline (blood glucose 45 mg/dL or 2.5 mmol/L) which persists in spite of glucose supplementation, to exclude severe congenital abnormalities of glucose metabolism.

• Clinically significant neurological disease identified before randomisation according to cranial ultrasound (haemorrhages confined to the germinal matrix are allowed) and investigator’s opinion.

• Any other condition or therapy that, in the investigator’s opinion, may pose a risk to the participant or interfere with the participant’s potential compliance with this protocol or interfere with the interpretation of results.

• Current or planned participation in a clinical study of another investigational study treatment, device or procedure (participation in non-interventional studies is permitted on a case-by-case basis).

• The participant or participant’s parent(s) is/are unable to comply with the protocol or is unlikely to be available for long-term follow-up as determined by the investigator.

• Birth mother with active COVID-19 infection at birth or a history of severe COVID-19 infection (requiring intensive care hospitalisation) during pregnancy.

• Birth mother with known HIV or hepatitis (B, C or E) infection.

Initially, enrolment was restricted to high GA infants who received either OHB-607 at 250 µg/kg/24 hours, OHB-607 at 400 µg/kg/24 hours or SNC. After approximately 75 high GA infants, that is, ≥26 weeks’ GA (approximately 25 participants in each treatment group) had completed the 40-week PMA visit, a scheduled review by the Data Safety Monitoring Board (DSMB) was performed to assess the safety of the higher dose in the higher GA subgroup, who concluded that the 400 µg/kg/24 hours dose was sufficiently safe. In addition, infants receiving the 400 µg/kg/24 hours dose reached the physiological serum range for IGF-1 (28 to 109 µg/L) more rapidly and completely than infants receiving the 250 µg/kg/24 hours dose.²⁸ Following the DSMB review, OHB-607 was out-licensed, and a protocol amendment was made such that the entire EP subgroup in a ratio of 60:40 low to high GA infants would be randomised to either OHB-607 at a dose of 400 µg/kg/24 hours or SNC.

Therapy

Eligible infants will be assigned 1:1 to receive either OHB-607 or SNC until reaching 30 weeks PMA, when endogenous production of IGF-1 is expected to be sufficient to maintain physiological serum IGF-1 levels for the corresponding GA. Treatment may be discontinued if intravenous access is not possible or for other medical reasons based on the investigator’s or responsible physician’s clinical judgement. In cases where the central line is removed, peripheral intravenous administration of OHB-607 may be continued at the discretion of the responsible physician.

Outcomes

The primary endpoint is the incidence of severe BPD, defined by a modified NICHD severity grading or death for all subjects at 36 weeks (±3 days) PMA. BPD was classified as follows: no BPD, oxygen for <28 days after birth or none; mild BPD, a need for oxygen for at least the first 28 days after birth but in room air at 36 weeks PMA; moderate BPD, oxygen for at least the first 28 days after birth plus treatment with <30% oxygen at 36 weeks PMA; severe BPD, oxygen for at least the first 28 days after birth plus ≥30% oxygen and/or any invasive or non-invasive positive pressure ventilation including high flow nasal cannula (HFNC) ≥2 L/min at 36 weeks PMA. This modified definition differs from the published 2001 NICHD severity grading as it does not include a physiological test to confirm oxygen requirement at 36 weeks PMA and explicitly includes HFNC ≥2 L/min as equivalent to positive pressure support.^{10 11} These modifications were made to reflect current neonatal intensive care unit practice and to improve classification consistency.

Secondary endpoints include: a reduction in the burden of CLD through 12 months CA, as assessed by time to weaning off RTS and a reduction in the incidence of severe BPD at 36 weeks (±3 days) PMA as defined by NRN (‘Jensen’ classification) grade 2 and grade 3 BPD or death at or before 36 weeks PMA, whichever comes first. Other important secondary endpoints include the occurrence of severe (Grade 3 and 4) IVH and Stage 3 and above ROP up to 40 weeks PMA, as compared with the SNC group.⁸ Incidence of severe IVH will be derived from the IVH grading as assessed by central blinded reviewers.³¹ Incidence and severity of ROP through 40 weeks PMA will be evaluated according to the International Classification definition and assessed by a blinded reviewer.³² Further secondary endpoints include neurodevelopmental impairment as determined by the Bayley Scales of Infant and Toddler Development (BSID) scales at 24 months CA. The effect of OHB-607 on the occurrence of any of the following events will be assessed as a composite exploratory endpoint: (1) incidence of severe BPD at 36 weeks (±3 days) PMA; (2) severe (Grade 3 and 4) IVH up to 40 weeks PMA as assessed by cranial ultrasounds (CUSs); (3) severe ROP (Stage 3 and above) before 40 weeks PMA; (4) death before or at 40 weeks PMA. The complete list of endpoints for the Phase 2b trial is given in box 2.

Box 2. Clinical outcomes.

Primary endpoints

• Reduction in the incidence of severe BPD at 36 weeks (±3 days) PMA, or death at or before 36 weeks PMA, whichever comes first.¹

Secondary endpoints

• Reduction in the burden of CLD, as indicated by a reduction in time to final weaning off of RTS through 12 months CA.²

• Reduction in the incidence of severe BPD at 36 weeks (±3 days) PMA, or death at or before 36 weeks PMA, whichever comes first.³

• Occurrence of severe (Grade 3 and 4) IVH before 40 weeks PMA, as assessed by cranial ultrasound.⁴

• Occurrence of severe ROP (Stage 3 and above) up to 40 weeks PMA.

• Respiratory severity measured by CLDPSS at 12 months CA.

• Neurodevelopmental impairment by BSID at 24 months CA.

• Chronic respiratory morbidity outcomes at 24 months CA.

• Incidence and severity of BPD for preterm infants born at <32 weeks GA.¹

• Incidence of all severity grades of BPD as assessed by Jensen et al.⁸

• Incidence of all grades of IVH as assessed by centrally read cranial ultrasound and classified according to the Volpe criteria.³¹

• Physical and cognitive development as measured by ASQ−3 administered at 12 and 24 months CA.

• Incidence of all stages of ROP (Stages 0–5) through 40 weeks PMA according to International classification by a local blinded reviewer.³²

• Mortality rates from randomisation to initial hospital discharge and from initial discharge through 24 months CA.

• Relationships between IGF-1 exposure and respiratory, neurological, BPD, IVH, NEC and ROP endpoints.

Exploratory endpoints

• Incidence of severe BPD at 36 weeks (±3 days) PMA, severe (Grade 3 and 4) IVH up to 40 weeks PMA as assessed by cranial ultrasound, severe ROP (Stage 3 and above) up to 40 weeks PMA, death before or at 40 weeks PMA.

• Relationship between early neonatal morbidities (severe IVH, ROP and BPD) in those who survive to 40 weeks PMA and long-term poor outcome (death, BSID, blindness, deafness) at 24 months CA.

• Cranial intraventricular diameter measured at the cranial ultrasound scan at 36 weeks PMA (or discharge from/transfer from the NICU, whichever comes first) to assess PHVD and verified through central review.

• Other clinical outcomes: morbidity count of (BPD (yes/no), IVH (yes/no), ROP (ROP ≥3 vs ROP <3) and NEC (yes/no)), body growth z-scores (weight, length and head circumference), incidence of hyperglycaemia defined as ≥180 mg/dL blood glucose (≥10 mmol/L), incidence of pulmonary arterial hypertension diagnosed as part of routine care, analysed according to BPD grade, surfactant use for respiratory distress syndrome, NEC ≥Stage II by Bell’s classification, culture proven late-onset sepsis.

• HRQoL: PedsQL Infant Scales through 24 months CA, parent(s)/caregiver(s) EQ-5D-5L through 24 months CA and healthcare resource use.

• PK profile: Serum concentrations of IGF-1 and IGFBP-3 and associated PK parameters (C0, Cmax, Cmin, Cavg, tmax and AUC, as appropriate).

Data collection and monitoring

Safety and efficacy analyses will be conducted from randomisation to study end and displayed in three clinical study reports at the end of Part A, the midpoint of Part B and at the end of Part B. BPD incidence and severity will be assessed at 36 weeks PMA. Assessments include IVH via CUSs, RTS usage, measurement of growth parameters (including body weight, body length (or height) and head circumference), ROP examinations and general health measures.

Respiratory severity scores will be used to assess longer-term respiratory outcomes and will be determined using information captured during follow-up telephone calls and clinical site visits at intervals specified until 12 months CA using the Chronic Lung Disease Prematurity Severity Scale (CLDPSS).⁴ Morbidity will be evaluated by a questionnaire; neurodevelopment by Ages and Stages Questionnaires Third Edition and BSID; health-related quality of life by age-appropriate Pediatric Quality of Life Inventory; caregiver health by EuroQol 5-dimensional 5-level Descriptive System; and healthcare resource use by tracking inpatient, outpatient, emergency room and specialist visits.^33–35

Safety will be evaluated via adverse event reporting using the Neonatal Adverse Event Severity Scoring terminology and grading laboratory tests and vital signs.³⁶ Physical and neurological development, including cerebral palsy, vision and physical development, will be assessed using standard, age-appropriate tools. Vision and hearing assessments, brain stem auditory evoked responses or alternative auditory assessments at discharge and through the end of Part B will be included if collected as part of SNC. IGF-1/IGFBP-3 concentrations and associated pharmacokinetic parameters will be collected across Part A. Feeding regimen and any changes to it or the use of feeding devices during hospitalisation will also be recorded.

Statistical analysis

The sample size of 338 was calculated to have 85% power with a predetermined two-tailed alpha level of 0.05 significance to demonstrate an absolute reduction in severe BPD from approximately 46.92% (determined from a 60:40 blend of 23–25 wGA and 26–27 wGA results from a previous Phase 2 study) to approximately 26.72% (which represents 80% of the effect size in terms of risk difference from the former Phase 2 study).²⁶ The sample size accounts for a dropout rate of 4% and an overall death rate of 15.9%, where the primary endpoint of severe BPD or death will be analysed. A blinded sample size re-estimation is planned once 75% of the participants reach the 36-week PMA follow-up time point, based on the overall event rate of severe BPD by NICHD or death.³⁷

The intent-to-treat population will be used for efficacy analyses, with missing data imputed. An interim futility analysis will be conducted when 50% of enrolled participants reach 36 weeks PMA. The futility analysis will calculate the conditional power of the study to achieve a statistically significant result (<10% conditional power boundary) given the results at the time the analysis is conducted. The interim analysis will be assessed by a team of independent, unblinded physicians and an unblinded statistician. The primary and key secondary endpoints will be assessed sequentially using a gatekeeping strategy at the full alpha level of 0.05. If the comparison of the primary endpoint is not successful, then assessments of efficacy will not proceed for secondary endpoints. If all assessments are successful for the primary and key secondary efficacy endpoints, then significance assessment will proceed using a fallback procedure for multiple testing applied to selected, important secondary endpoints. Imputed datasets will be used for the primary endpoint and key secondary endpoints for BPD only if there are withdrawals from the study or loss to follow-up before 36 weeks PMA, which prevents the assessment of BPD at 36 weeks PMA. Summary statistics by country will be presented to evaluate the consistency of results geographically. A subgroup analysis by GA strata and by sex will also be presented. The analysis method used for the primary endpoint, as well as for severe IVH and ROP, will be a generalised linear mixed model with a log-link function and the incidence of severe BPD or death at 36 weeks (±3 days) as the outcome. Predictors in the model will include treatment group, GA at birth, birth weight, maternal smoking during pregnancy and Apgar (appearance, pulse, grimace, activity and respiration) score. Random effects will be included for country. The relationship between early neonatal morbidities (severe IVH, ROP and BPD) in those who survive to 40 weeks PMA and long-term poor outcome (death, BSID, blindness, deafness) at 24 months CA will be modelled by means of logistic regression in a prespecified exploratory analysis.

Discussion

IGF-1 is the most important foetal growth factor, influencing the growth and development of vital organs such as the lungs, brain and eyes during the last trimester by supporting organ vascularisation. Lower IGF-1 levels at birth in EP infants have been associated with an increased risk of BPD, ROP, IVH, as well as neurodevelopmental and growth impairments, supporting the investigation of OHB-607 for preventing BPD and other complications of prematurity.^38–42 The onset of significant endogenous IGF-1 production in EP infants is estimated to be approximately 30 weeks PMA.^{27 43–45} This broadly corresponds with the estimated duration of rhIGF-1/rhIGFBP-3 treatment to attain clinical benefits, suggesting administration over this time period would maintain IGF-1 throughout the period of endogenous IGF-1 production deficit.⁴⁵ Furthermore, this time window overlaps with the estimated time to attain full enteral feeds in EP infants, suggesting the addition of rhIGF-1/rhIGFBP-3 treatment to SNC may suffice to achieve the desired IGF-1 exposure and not necessitate prolonged intravenous or central line access.⁴⁶

BPD is often defined by the modified NICHD criteria, based on the use and duration of oxygen need in the first 28 days after birth and the subsequent level of oxygen and respiratory support required at 36 weeks PMA.¹⁰ More recently, the NRN (‘Jensen’ scoring) has considered contemporary modes of flow and pressure-based respiratory support independently of the level of oxygen supplementation.^{8 47} The most clinically severe forms of BPD are encompassed in the NICHD classification system as ‘severe’, whereas these are considered to overlap with ‘Grade 2 and Grade 3’ by NRN.^{10 48} We will assess the efficacy of OHB-607 in reducing CLD at 36 weeks PMA using both BPD severity scores, the modified NICHD severity grading (primary endpoint) and the NRN criteria (key secondary endpoint). Longer-term measures of respiratory severity at 12 m CA time to weaning off RTS and assessments of respiratory morbidity using CLDPSS will also be assessed.⁴ Our study design is supported by a systematic review of 40 meta-analyses in neonates receiving respiratory support, which found that 77% of the included studies had their evidence certainty downgraded due to risk of bias and lack of blinding. However, the authors assert improper downgrading of evidence in the context of neonatal ventilation clinical trials, where knowledge of the received treatment does not influence the efficacy outcome assessment in BPD prevention.⁴⁹ The incidence of severe IVH and ROP will also be evaluated as prespecified secondary outcomes and by blinded efficacy reviewers.

Previous Phase 2a trial results showed a substantial reduction in severe BPD with OHB-607 treatment administered at a dose of 250 µg/kg/day via a central line compared with standard of care (21.3% vs 44.9%), with a similar incidence of pathogen-confirmed sepsis (65.9% vs 67.4%), including coagulase-negative staphylococcal sepsis (36.4% vs 37.2%) between the two arms.²⁶ While central line dwell time has been associated with an increased risk of central line-associated bloodstream infections, current neonatal care practices can minimise their occurrence as central line bundles have become standard of care.^50–52 It is recommended, therefore, that OHB-607 be administered with stringent infection control measures, including central line care bundles, since treatment is required over several weeks, mimicking steady intrauterine IGF-1 levels, until the infant’s IGF-1 production begins.⁵³

A growing body of evidence suggests that prematurity itself is associated with lung abnormalities that can persist into adolescence and adulthood, irrespective of BPD status.^{15 54 55} BPD is also not solely a pulmonary condition but a multifaceted disease associated with neurodevelopmental impairment, pulmonary hypertension, feeding difficulties, growth restriction and increased risk of hospital readmission.¹³ Adverse neurodevelopment outcomes have been positively correlated with increasing BPD severity.^{12 56} Other complications associated with severe BPD include an increased risk for cerebral palsy and developmental delays, lower IQ scores, impaired executive functioning, behavioural challenges, delays in expressive and receptive language development, and an increased risk of growth failure.¹⁸ Consequently, BPD management requires a multidisciplinary team due to the disease’s complex, multisystem impact on EP infants.¹³ Although the NICHD and NRN respiratory severity scores reflect pulmonary morbidity at 36 weeks PMA, they may not fully reflect the continuum of respiratory morbidity and mortality beyond the early neonatal period, encompassing manifestations of CLD of prematurity.^{10 48} To address this gap, the concept of chronic pulmonary insufficiency of prematurity (CPIP) has been introduced, to include the persistent respiratory dysfunction observed in preterm born infants as they grow. Thus, BPD represents one stage of the longitudinal continuum of CPIP, which will likely encompass manifestations of CLD identified in this trial.⁵⁷

Critically, BPD prevention with OHB-607 could have cascading clinical benefits beyond pulmonary health. A unifying characteristic of EP infants is the development of postnatal IGF-1 deficiency after birth, before the liver normally begins producing IGF-1 around 30 weeks GA.^{3 15 24 58} Emerging data suggest that impaired IGF-1 exposure during the critical postnatal transition may disrupt angiogenesis and metabolic signalling, including pathways at the pyruvate–acetyl-CoA interface, with downstream effects on epigenetic regulation and microvascular development across multiple progenitor cell compartments in tissues and organs. Given the close coupling of pulmonary and cerebral vascular development in early life, these shared mechanisms may help explain the increasingly well-described association between severe BPD and adverse neurodevelopmental outcomes in EP infants, including those involving central nervous system (CNS) injury and impaired brain maturation, as recently highlighted in the literature.⁵⁹ Therefore, IGF-1 replacement with OHB-607 could impact the impaired growth and development seen after EP birth across multiple tissues and organ systems, including the eye, lung and CNS.

While recognising that IGF-1 replacement is inherently systemic, the lung was selected as the primary efficacy readout because severe BPD is a frequent, early and clinically adjudicated morbidity with established diagnostic criteria, sets a regulatory precedent and has strong prognostic relevance in this area of high unmet medical need. Neurodevelopmental outcomes evolve over longer time horizons and are influenced by multiple downstream and intercurrent factors; accordingly, these outcomes are incorporated as important secondary and longer-term endpoints rather than as the primary endpoint. This strategy enables evaluation of a biologically plausible systemic therapy while anchoring primary efficacy to a robust and clinically meaningful early outcome, consistent with contemporary neonatal trial design principles and emerging evidence linking pulmonary and neurodevelopmental outcomes.

Thus, early intervention with OHB-607, which has the potential to alter CLD progression by reprogramming lung development and promoting lung growth, may simultaneously decrease the burden of other conditions of prematurity and improve neurodevelopmental outcomes in a broad EP population. Several in vitro and in vivo studies have also provided evidence of improved brain growth and the number of neurons, as well as distinct developmental patterns in different regions of the prenatal vertebrate and human brain, with varying IGF-1 expression levels. These studies have also explored the role of IGF-1 signalling in neurogenesis, maturation and myelination, supporting its role in brain development.^60–62 Furthermore, preclinical studies support the essential role of IGF-1 in normal retinal vascular development and suggest that IGF-1 supplementation could be a potential treatment for preventing ROP.^{63 64} This Phase 2b study will provide critical new evidence on the efficacy and safety of OHB-607 in this regard and, we hope, herald a new era of research and treatment development in the neonatal population, which has been historically underserved in terms of clinical trials and new therapy registrations.

Ethics

Informed consent and materials involving underage parents must be approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) per local regulations. A full list of the approving IRBs/IECs is provided in online supplemental file 1. Outside the EU, investigators or their delegates must submit the protocol, approved consent forms and recruitment materials to the IRB/IEC for approval before site initiation. They are also responsible for providing study updates and protocol amendments at least once a year. The study is registered at ClinicalTrials.gov (NCT03253263), Clinicaltrialsregister.eu (EudraCT: 2018-001393-16), Euclinicaltrials.eu (EUCT: 2024-515914-41-00) and Pmda.go.jp (PMDA: jRCT2031240339).

Dissemination plan

The Phase 2b OHB-607 trial is enrolling. We aim to promote awareness and engagement through transparent communication of the study design, rationale and objectives. This manuscript outlines key details and will serve as a reference for clinicians, researchers and regulators. Supplementary outreach includes presentations at international conferences to support enrolment and collaboration.

Data availability statement

No data are available.