Analyzing Retinal Microanatomy in ROP

Completed

• Conditions: Macular Edema; Retinopathy of Prematurity; Neurodevelopmental Disorders
• Interventions: Device: Swept Source OCT; Other: Magnetic Resonance Imaging; Other: Scavenged blood collection

• Registration Number: NCT02887157
• Lead Sponsor: Duke University

Brief Summary

Retinopathy of prematurity (ROP) is a disorder of development of the neural retina and its vasculature that may impact vision in vulnerable preterm neonates for a lifetime. This study utilizes new technology to determine visual and neurological development of very preterm infants in the intensive care nursery, during a period of rapid growth of the retina, optic nerve and brain. The long-term goal of this study is to help improve preterm infant health care via objective bedside imaging and analysis that characterizes early critical indicators of poor vision, neurological development and ROP, which will rapidly translate to better early intervention and improved future vision care.

Detailed Description

Retinopathy of prematurity (ROP) is a disorder of development of the neural retina and its vasculature that may impact vision in vulnerable preterm neonates for a lifetime. Clinical care of infants with ROP decreases the likelihood of blindness, but abnormal vision is common, especially in those with disease severe enough to require treatment. Because it has not been possible to distinguish whether disease and/or maldevelopment that affects specific retinal cells and/or the central nervous system (CNS) cause the vision loss, especially when it is less severe, there has been no strategy to prevent subnormal acuity in the majority of infants treated for ROP.

The interval that a preterm infant at risk for ROP spends in an intensive care nursery (ICN) is a time of rapid retinal development. Clinicians and researchers do not know how local, CNS and systemic development and disease processes are reflected in the retinal microanatomy. Abnormalities in the retina during infancy are likely early predictors of later vision problems and developmental delay. From study of preterm retinal substructures, brain anatomy, connectivity and functional networks and neuroinflammatory biomarkers this study will elucidate the pathway by which local retinal anatomic changes impact and may predict later subnormal vision and CNS function. The results of this research will enable the investigator to: distinguish ocular from non-ocular contributions to vision loss; guide future treatment directed to modify retinal anomalies such as edema; and determine which microanatomic retinal biomarkers are best to monitor effects of ROP, and effects of systemic therapies on the eye and brain. In contrast to indirect ophthalmoscopy or photography, novel non-contact ocular imaging at the bedside would enable direct telemedicine screening for ROP and for neural development in multiple nurseries.

The long-term goal is to help improve preterm infant health care via objective bedside imaging and analysis that characterizes early critical indicators of poor vision, neurological development and ROP. This will rapidly translate to early intervention and improved future vision care. Specific goals of this research are threefold: to implement technological innovations to improve optical coherence tomography (OCT) imaging in non-sedated infants in the ICN; to distinguish elements of retinal microanatomy which predict maldevelopment of visual pathway and poor neurodevelopment that may impact vision in preterm infants; and to delineate which elements and regions (posterior and peripheral) of preterm infant OCT-derived retinal microanatomy best inform us about severity of disease and visual outcomes in infants with ROP.

In addition to providing a breakthrough method for bedside analysis of the very preterm (VPT) infant posterior and peripheral retina, this study will provide the pediatric ophthalmologic and telemedicine community with methods to distinguish microanatomic markers that predict infants at risk for abnormal vision, visual pathway injury, poor functional development and progression of ROP (and combinations thereof). These biomarkers will be useful for determining ophthalmic and CNS therapeutic interventions and monitoring their impact on the visual pathway and will thus likely cross over with relevance to other infant eye and brain disease.

Study Timeline

• Study Start: 2016-07-22
• Study First Submitted: 2016-08-25
• Study First Submitted QC: 2016-08-29
• Study First Posted: 2016-09-02
• Primary Completion: 2020-12-31
• Study Completion: 2021-04-15
• Status Verified: 2023-01
• Last Update Submitted: 2023-02-08
• Last Update Posted: 2023-02-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 191

Inclusion Criteria

• Health care provider, knowledgeable of protocol, agrees that study personnel could contact the Parent/Legal Guardian
• Parent/Legal Guardian is able and willing to consent to study participation for the infant with likelihood of follow up at standard of care visits at approximately 1-month, 4-months, 9-months and 2 years corrected age
• Infant/child undergoing clinically indicated examination under anesthesia (for the testing of the custom widefield OCT lens) that may or may not have eye pathology. (Only for Aim 1)
• Infant meets the American Association of Pediatrics eligibility of ROP screening (Infants with a birth weight of ≤1500 g or gestational age of 30 weeks), and is age ≤ 34 6/7 weeks postmenstrual age at first visit
• Adults (over the age of 18 years) that may or may not have eye pathology (Only for Aim *Participants in Aim 3 will not have a brain MRI, collection of scavenged blood for neuroinflammatory markers, or the neurodevelopmental 2-year visit.

Exclusion Criteria

• Participant or Parent/Legal Guardian (of infant/child) unwilling or unable to provide consent
• Adult participant or infant/child has a health or eye condition that preclude eye examination or retinal imaging (e.g. corneal opacity such as with Peters anomaly or cataract)
• Infant has a health condition, other than prematurity, that has a profound impact on brain development (e.g. anencephaly). Note that infants with brain hemorrhages and sequelae would be eligible.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Specific Aim 2	Magnetic Resonance Imaging	Specific Aim 2 (distinguish elements of retinal microanatomy that predict maldevelopment of visual pathway and poor neurodevelopment that may impact vision in preterm infants) includes 68 very preterm infants undergoing the following during evaluation for ROP. 1. Swept Source OCT imaging of both eyes with the novel ultralight handpiece before or after ROP examination, timed with each examination. The axial length of the eye may be measured after the ROP exam. 2. Non-sedated research brain Magnetic Resonance Imaging will be obtained in 68 participants prior to discharge from the nursery whenever possible (as close to term age as possible). In the case of an early infant discharge to another hospital, every effort will be made to obtain brain MRI prior to transfer or an outpatient non-sedated brain MRI at near term age. 3. Scavenged blood collection: Residual samples of serum/plasma in the laboratory will be collected for neuroinflammatory marker testing.
Specific Aim 1B	Swept Source OCT	Specific Aim 1B (implement technical innovations to improve OCT imaging in non-sedated infants in the ICN: (1B) extend imaging to the vascular-avascular junction via a wide-field lens). Aim 1B only: 50 participants (25 healthy adult volunteers and 25 pediatric participants under going examination under anesthesia * Healthy adult volunteers will have SSOCT imaging of both eyes with the novel ultralight handpiece up to 10 times. * Pediatric participants undergoing examination under anesthesia will have SSOCT imaging of both eyes with the novel ultralight handpiece once during their EUA in the Duke Eye Center Operating Rooms (OR). These participants will be enrolled into the study at DUHS including the Duke Eye Center clinics and OR for testing the custom widefield lens.
Specific Aim 2	Swept Source OCT	Specific Aim 2 (distinguish elements of retinal microanatomy that predict maldevelopment of visual pathway and poor neurodevelopment that may impact vision in preterm infants) includes 68 very preterm infants undergoing the following during evaluation for ROP. 1. Swept Source OCT imaging of both eyes with the novel ultralight handpiece before or after ROP examination, timed with each examination. The axial length of the eye may be measured after the ROP exam. 2. Non-sedated research brain Magnetic Resonance Imaging will be obtained in 68 participants prior to discharge from the nursery whenever possible (as close to term age as possible). In the case of an early infant discharge to another hospital, every effort will be made to obtain brain MRI prior to transfer or an outpatient non-sedated brain MRI at near term age. 3. Scavenged blood collection: Residual samples of serum/plasma in the laboratory will be collected for neuroinflammatory marker testing.
Specific Aim 3	Swept Source OCT	Specific Aim 3 (delineate which elements and regions (posterior) or (peripheral) of preterm infant OCT-derived retinal microanatomy best inform us about severity of disease and visual outcomes in infants with ROP will include the same 68 participants plus an additional 42 very preterm infants undergoing evaluation for ROP and visual function but who will not be in the neurodevelopmental study and thus will not have brain MRI, 2-year Bayley Scales testing or neuroinflammatory marker testing on scavenged blood. The Specific Aim 3 subjects will undergo the following: 1. Swept Source OCT imaging of both eyes with the novel ultralight handpiece as described in Aim 2. The axial length of the eye may be measured after the ROP exam. 2. After imaging with the original lens (ultralight handpiece) both eyes will be imaged with the widefield OCT lens. before or after the ROP exam. 3. Ocular and systemic health data will be extracted from the study participant's medical record.
Specific Aim 2	Scavenged blood collection	Specific Aim 2 (distinguish elements of retinal microanatomy that predict maldevelopment of visual pathway and poor neurodevelopment that may impact vision in preterm infants) includes 68 very preterm infants undergoing the following during evaluation for ROP. 1. Swept Source OCT imaging of both eyes with the novel ultralight handpiece before or after ROP examination, timed with each examination. The axial length of the eye may be measured after the ROP exam. 2. Non-sedated research brain Magnetic Resonance Imaging will be obtained in 68 participants prior to discharge from the nursery whenever possible (as close to term age as possible). In the case of an early infant discharge to another hospital, every effort will be made to obtain brain MRI prior to transfer or an outpatient non-sedated brain MRI at near term age. 3. Scavenged blood collection: Residual samples of serum/plasma in the laboratory will be collected for neuroinflammatory marker testing.

Primary Outcome Measures

Name	Time	Method
Brain MRI grading	3 years	Grading and analysis of brain MRI scans collected at approximately term-equivalent age
Maximum ROP stage as determined during clinical evaluation	4 years	Analysis of maximum ROP stage per eye as determined during clinical evaluation
Number of infants with reproducible imaging of the peripheral vascular-avascular junction (Aim 1B)	4 years	Analysis of reproducibility of imaging of the peripheral vascular-avascular junction in infants
Initiate ICN research imaging with the novel ultralight hand piece and high speed SSOCT (Aim 1A)	4 years	Start-up of research imaging in the intensive care nursery using the new ultralight hand piece and swept source OCT
Number of microns of retinal thickness and distance from foveal to ellipsoid zone band as seen on retinal vascular imaging using infant specific automated image processing	3 months	Develop infant-specific automated image processing/analyses for retinal vascular imaging
Retinal microanatomy grading from Swept Source Optical Coherence Tomography (SSOCT)	4 years	Grading and measurement of retinal microanatomy from SSOCT images
Peripheral retinal microanatomy grading	4 years	Analyses of peripheral retinal microanatomy at the vascular-avascular junction as recorded via SSOCT
Number of microns of retinal thickness and distance from foveal to ellipsoid zone band as seen from multi-layer segmentation using infant specific automated image processing (1C)	3 months	Develop infant-specific automated image processing/analyses or multi-layer segmentation
Neurodevelopmental scores	3 years	Analysis of Bayley Scales-III Neurodevelopmental testing at age 2 years
Visual acuity scores	3 years	Analyses of data from Teller Visual acuity testing at 9 months
ROP severity grade of retinal microanatomy by OCT	4 years	Severity of ROP as determined by analysis of posterior and peripheral retinal microanatomy

Secondary Outcome Measures

Name	Time	Method
ROP specifics from OCT imaging	4 years	ROP specifics including zone, plus or preplus disease, stage per clock hour, vitreous hemorrhage from OCT imaging
Clinician's decision to treat	4 years	Analysis of the clinician's decision to treat
Neuroinflammatory marker scores	2 years	Analysis of left over blood samples to determine presence and severity of neuroinflammation
Presence of non-ROP ocular conditions	4 years	Analysis of clinical data for strabismus,, amblyopia, refractive error, nystagmus
ROP specifics from clinical examination	4 years	ROP specifics including zone, plus or preplus disease, stage per clock hour, vitreous hemorrhage from clinical examination

Trial Locations

Locations (4)

University of Florida; 🇺🇸 Gainesville, Florida, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Duke University Eye Center; 🇺🇸 Durham, North Carolina, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States