Retinal Microanatomy in Retinopathy of Prematurity (BabySTEPS2)

Retinopathy of Prematurity Clinical Trial

— BabySTEPS2  

Official title:

Analyzing Retinal Microanatomy in Retinopathy of Prematurity to Improve Care 2 and School Age Follow on Study (BabySTEPS2)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04995341
• Other study ID #: Pro00107978
• Secondary ID: R01EY025009
• Status: Recruiting
• Phase: N/A
• Start date: August 16, 2021
• Est. completion date: March 31, 2026

Study information

• Verified date: May 2024
• Source: Duke University
• Contact: Cynthia A Toth, MD
• Phone: 919-684-5631
• Email: cynthia.toth[@]duke.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Retinopathy of prematurity (ROP) is a disorder of development of the neural retina and its vasculature that can impact vision in vulnerable preterm neonates for a lifetime. This study tests high-speed optical coherence tomography (OCT) technology compared to conventional color photographs at the bedside of very preterm infants in the intensive care nursery, to characterize previously unseen abnormalities that can predict a need for referral for ROP treatment, or poor visual or neurological development later in life, up to pre-school age. Our long-term goal is to help improve preterm infant health and vision via objective bedside imaging and analysis that characterizes early critical indicators of ROP, and poor visual function and neurological development, which will rapidly translate to better early intervention and improved future care.

Description:

As an increasing percentage of preterm infants survive worldwide, the number of infants at risk for retinopathy of prematurity (ROP) is increasing. These infants are also at high risk for future abnormal visual function and neurodevelopment. While current screening approaches address identifying eyes for treatment of severe ROP, there are no attempts to address the later subnormal vision of many preterm infants. In part, this is due to a lack of information about the retina beyond that of retinal vascular development. In addition, the most common method to screen for ROP remains indirect ophthalmoscopic examination by physicians with annotated drawings for documentation, a method proven to be poorly reproducible and stressful to the fragile infant. Bedside retinal photographs enable documentation and the possibility for telemedicine approaches, but lack information about retinal microanatomy, are poor quality in darkly pigmented eyes and also are stressful to the infant because of the required light exposure. We need an infant-friendly, more practical approach to evaluate ROP efficiently and additional information about ocular and neurovascular development that could lead to improved clinical care.

This research builds on our group's ability to reliably capture and process non-contact, infrared optical coherence tomography (OCT) and OCT-angiography of retinal microanatomy and microvasculature at high speed, across a wide field of view, and at the bedside in preterm infants. Our overall objectives are threefold: first, to evaluate infant microanatomy and microvascular flow findings relevant to vision and neurodevelopmental outcomes in children; second, to translate and test our imaging achievements for real-world use by nurses at the bedside and for better clinical insight and feedback; and third, to gather additional data in eyes that progress to treatment and dive deeper into the insight that they provide into pathways of disease in ROP. The investigational OCT imaging will be used in this research to gather information that is otherwise not accessible to the physician. This research will lay the groundwork for future use of infant OCT markers to guide care.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 236
• Est. completion date: March 31, 2026
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Children previously enrolled in BabySTEPS1 (Pro00069721) that have already consented to being contacted for this school age follow on study, Cohort 1 only

• Parent/Legal Guardian is able and willing to consent to study participation with follow up approximately between 4.5 and 5 years of age (consent available in Spanish* and English) (SA 1 only)

• Parent/Legal Guardian is able and willing to consent to study participation for the infant (SA 2 and 2c only)

• Infant/child undergoing clinically-indicated examination under anesthesia that may or may not have eye pathology (SA 2 only)

• Infant inborn or outborn at (SA 2 only):

• Duke Hospital (Years 1, 2 and 3) with birth weight =1000 grams, and/or 20 0/7 to 28/ 6/7 (<29 weeks) gestational age

• Duke Hospital (Years 1, 2 and 3) at high risk to require treatment for ROP irrespective of birth weight and gestational age (e.g. pre-plus, severe ROP in zone 1, APROP, etc.)

• Duke Regional Hospital (Years 4 and 5) that meets the American Association of Pediatrics eligibility of ROP screening (Infants with a birth weight of =1500 g or gestational age of 30 weeks)

• Adults (over the age of 18 years) that may or may not have eye pathology (SA 2 only)

Exclusion Criteria:

• Participant or Parent/Legal Guardian 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 Peter's anomaly or cataract) (SA2 only)

• Infant has a health condition, other than prematurity, that has a profound impact on brain development (e.g. anencephaly) (SA2 only)

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

Device:
• Investigational ultracompact OCT and OCTA system
Handheld bedside retinal OCT and OCT angiography imaging with an investigational portable system with ultracompact handpiece
• retinal photographs
retinal photographs with a commercial portable bedside widefield fundus camera system

Locations

Country	Name	City	State
United States	Duke University Eye Center	Durham	North Carolina
United States	University of Pennsylvania, Center for Preventive Ophthalmology and Biostatistics	Philadelphia	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Duke University	National Eye Institute (NEI), University of Pennsylvania

Country where clinical trial is conducted

United States, 

References & Publications (24)

Campbell JP, Kalpathy-Cramer J, Erdogmus D, Tian P, Kedarisetti D, Moleta C, Reynolds JD, Hutcheson K, Shapiro MJ, Repka MX, Ferrone P, Drenser K, Horowitz J, Sonmez K, Swan R, Ostmo S, Jonas KE, Chan RV, Chiang MF; Imaging and Informatics in Retinopathy of Prematurity Research Consortium. Plus Disease in Retinopathy of Prematurity: A Continuous Spectrum of Vascular Abnormality as a Basis of Diagnostic Variability. Ophthalmology. 2016 Nov;123(11):2338-2344. doi: 10.1016/j.ophtha.2016.07.026. Epub 2016 Aug 31. — View Citation

Chen X, Imperio R, Seely KR, Viehland C, Izatt JA, Prakalapakorn SG, Freedman SF, Toth CA. Slow progressive perifoveal vascular formation in an infant with aggressive posterior retinopathy of prematurity. J AAPOS. 2020 Oct;24(5):323-326. doi: 10.1016/j.jaapos.2020.07.007. Epub 2020 Oct 9. — View Citation

Chen X, Mangalesh S, Dandridge A, Tran-Viet D, Wallace DK, Freedman SF, Toth CA. Spectral-Domain OCT Findings of Retinal Vascular-Avascular Junction in Infants with Retinopathy of Prematurity. Ophthalmol Retina. 2018 Sep;2(9):963-971. doi: 10.1016/j.oret.2018.02.001. Epub 2018 Mar 21. — View Citation

Chen X, Mangalesh S, Tran-Viet D, Freedman SF, Vajzovic L, Toth CA. Fluorescein Angiographic Characteristics of Macular Edema During Infancy. JAMA Ophthalmol. 2018 May 1;136(5):538-542. doi: 10.1001/jamaophthalmol.2018.0467. — View Citation

Chen X, Tai V, McGeehan B, Ying GS, Viehland C, Imperio R, Winter KP, Raynor W, Tran-Viet D, Mangalesh S, Maguire MG, Toth CA; BabySTEPS Group. Repeatability and Reproducibility of Axial and Lateral Measurements on Handheld Optical Coherence Tomography Systems Compared with Tabletop System. Transl Vis Sci Technol. 2020 Oct 21;9(11):25. doi: 10.1167/tvst.9.11.25. eCollection 2020 Oct. — View Citation

Chen X, Viehland C, Tran-Viet D, Prakalapakorn SG, Freedman SF, Izatt JA, Toth CA. Capturing Macular Vascular Development in an Infant With Retinopathy of Prematurity. JAMA Ophthalmol. 2019 Sep 1;137(9):1083-1086. doi: 10.1001/jamaophthalmol.2019.2165. No abstract available. — View Citation

Hsu ST, Chen X, House RJ, Kelly MP, Toth CA, Vajzovic L. Visualizing Macular Microvasculature Anomalies in 2 Infants With Treated Retinopathy of Prematurity. JAMA Ophthalmol. 2018 Dec 1;136(12):1422-1424. doi: 10.1001/jamaophthalmol.2018.3926. No abstract available. — View Citation

Hsu ST, Chen X, Ngo HT, House RJ, Kelly MP, Enyedi LB, Materin MA, El-Dairi MA, Freedman SF, Toth CA, Vajzovic L. Imaging Infant Retinal Vasculature with OCT Angiography. Ophthalmol Retina. 2019 Jan;3(1):95-96. doi: 10.1016/j.oret.2018.06.017. Epub 2018 Jul 26. No abstract available. — View Citation

Hsu ST, Ngo HT, Stinnett SS, Cheung NL, House RJ, Kelly MP, Chen X, Enyedi LB, Prakalapakorn SG, Materin MA, El-Dairi MA, Jaffe GJ, Freedman SF, Toth CA, Vajzovic L. Assessment of Macular Microvasculature in Healthy Eyes of Infants and Children Using OCT Angiography. Ophthalmology. 2019 Dec;126(12):1703-1711. doi: 10.1016/j.ophtha.2019.06.028. Epub 2019 Jul 15. — View Citation

Lee J, El-Dairi MA, Tran-Viet D, Mangalesh S, Dandridge A, Jiramongkolchai K, Viehland C, Toth CA. LONGITUDINAL CHANGES IN THE OPTIC NERVE HEAD AND RETINA OVER TIME IN VERY YOUNG CHILDREN WITH FAMILIAL EXUDATIVE VITREORETINOPATHY. Retina. 2019 Jan;39(1):98-110. doi: 10.1097/IAE.0000000000001930. — View Citation

Maldonado RS, Toth CA. Optical coherence tomography in retinopathy of prematurity: looking beyond the vessels. Clin Perinatol. 2013 Jun;40(2):271-96. doi: 10.1016/j.clp.2013.02.007. — View Citation

Mangalesh S, Bleicher ID, Chen X, Viehland C, LaRocca F, Izatt JA, Freedman SF, Hartnett ME, Toth CA. Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2019 Apr;257(4):677-688. doi: 10.1007/s00417-019-04274-6. Epub 2019 Feb 21. — View Citation

Mangalesh S, Chen X, Tran-Viet D, Viehland C, Freedman SF, Toth CA. ASSESSMENT OF THE RETINAL STRUCTURE IN CHILDREN WITH INCONTINENTIA PIGMENTI. Retina. 2017 Aug;37(8):1568-1574. doi: 10.1097/IAE.0000000000001395. — View Citation

Mangalesh S, McGeehan B, Tai V, Chen X, Tran-Viet D, Vajzovic L, Viehland C, Izatt JA, Cotten CM, Freedman SF, Maguire MG, Toth CA; Study of Eye Imaging in Preterm Infants Group. Macular OCT Characteristics at 36 Weeks' Postmenstrual Age in Infants Examined for Retinopathy of Prematurity. Ophthalmol Retina. 2021 Jun;5(6):580-592. doi: 10.1016/j.oret.2020.09.004. Epub 2020 Sep 11. — View Citation

Mangalesh S, Sarin N, McGeehan B, Prakalapakorn SG, Tran-Viet D, Cotten CM, Freedman SF, Maguire MG, Toth CA; BabySTEPS Group. Preterm Infant Stress During Handheld Optical Coherence Tomography vs Binocular Indirect Ophthalmoscopy Examination for Retinopathy of Prematurity. JAMA Ophthalmol. 2021 May 1;139(5):567-574. doi: 10.1001/jamaophthalmol.2021.0377. — View Citation

Mangalesh S, Tran-Viet D, Pizoli C, Tai V, El-Dairi MA, Chen X, Viehland C, Edwards L, Finkle J, Freedman SF, Toth CA. Subclinical Retinal versus Brain Findings in Infants with Hypoxic Ischemic Encephalopathy. Graefes Arch Clin Exp Ophthalmol. 2020 Sep;258(9):2039-2049. doi: 10.1007/s00417-020-04738-0. Epub 2020 May 29. — View Citation

Mangalesh S, Wong BM, Chen X, Tran-Viet D, Stinnett SS, Sarin N, Winter KP, Vajzovic L, Freedman SF, Toth CA. Morphological characteristics of early- versus late-onset macular edema in preterm infants. J AAPOS. 2020 Oct;24(5):303-306. doi: 10.1016/j.jaapos.2020.06.006. Epub 2020 Sep 15. — View Citation

O'Sullivan ML, Ying GS, Mangalesh S, Tai V, Divecha HR, Winter KP, Toth CA, Chen X; BabySTEPS Group. Foveal Differentiation and Inner Retinal Displacement Are Arrested in Extremely Premature Infants. Invest Ophthalmol Vis Sci. 2021 Feb 1;62(2):25. doi: 10.1167/iovs.62.2.25. — View Citation

Seely KR, Wang KL, Tai V, Prakalapakorn SG, Chiu SJ, Viehland C, Grace S, Izatt JA, Freedman SF, Toth CA. Auto-Processed Retinal Vessel Shadow View Images From Bedside Optical Coherence Tomography to Evaluate Plus Disease in Retinopathy of Prematurity. Transl Vis Sci Technol. 2020 Aug 7;9(9):16. doi: 10.1167/tvst.9.9.16. eCollection 2020 Aug. — View Citation

Shen LL, Mangalesh S, McGeehan B, Tai V, Sarin N, El-Dairi MA, Freedman SF, Maguire MG, Toth CA; BabySTEPS Group. Birth Weight Is a Significant Predictor of Retinal Nerve Fiber Layer Thickness at 36 Weeks Postmenstrual Age in Preterm Infants. Am J Ophthalmol. 2021 Feb;222:41-53. doi: 10.1016/j.ajo.2020.08.043. Epub 2020 Sep 4. — View Citation

Smith LEH, Hellstrom A, Stahl A, Fielder A, Chambers W, Moseley J, Toth C, Wallace D, Darlow BA, Aranda JV, Hallberg B, Davis JM; Retinopathy of Prematurity Workgroup of the International Neonatal Consortium. Development of a Retinopathy of Prematurity Activity Scale and Clinical Outcome Measures for Use in Clinical Trials. JAMA Ophthalmol. 2019 Mar 1;137(3):305-311. doi: 10.1001/jamaophthalmol.2018.5984. Erratum In: JAMA Ophthalmol. 2019 Mar 1;137(3):328. — View Citation

Viehland C, Chen X, Tran-Viet D, Jackson-Atogi M, Ortiz P, Waterman G, Vajzovic L, Toth CA, Izatt JA. Ergonomic handheld OCT angiography probe optimized for pediatric and supine imaging. Biomed Opt Express. 2019 Apr 29;10(5):2623-2638. doi: 10.1364/BOE.10.002623. eCollection 2019 May 1. — View Citation

Wang KL, Chen X, Stinnett S, Tai V, Winter KP, Tran-Viet D, Toth CA. Understanding the variability of handheld spectral-domain optical coherence tomography measurements in supine infants. PLoS One. 2019 Dec 11;14(12):e0225960. doi: 10.1371/journal.pone.0225960. eCollection 2019. — View Citation

Zepeda EM, Shariff A, Gillette TB, Grant L, Ding L, Tarczy-Hornoch K, Cabrera MT. Vitreous Bands Identified by Handheld Spectral-Domain Optical Coherence Tomography Among Premature Infants. JAMA Ophthalmol. 2018 Jul 1;136(7):753-758. doi: 10.1001/jamaophthalmol.2018.1509. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Axial length as measured in millimeters (Cohort 1 only)		4.75-year study visit
Other	OCT grading from commercial OCT device	Based on combination of presence or absence of retinal vessel dragging, retinal detachment and fundus pigmentation (blond, medium, dark) from ultra-widefield fundus imaging; and OCT imaging (nerve fiber layer and center foveal thickness).	4.75-year study visit
Other	Reference standard score for ROP vascular severity (Cohort 3 only)	The reference standard is the consensus determination based on a combination of OCT and photographic imaging of the relative retinal vessel tortuosity score & clinical ROP exam determination of plus, pre-plus, neither, and for all 3 assessments extraretinal neovascularization and aggressive ROP.	Up to 42 weeks post-menstrual age
Primary	Optotype Visual acuity scores (Cohort 1 only)	HOTV visual acuity at the 5-year study visit. Visual acuity is recorded as the last line of the HOTV chart on which over 50% of the 4 symbols are identified correctly identified by the participant.; If the participant is not capable of performing HOTV, then Teller cards will be used for preferential-looking visual acuity assessment. With Teller, acuity is determined by the smallest cycles per degree.	5-year study visit
Primary	Visual function scores (Cohort 1 only)	Visual function at the 4.75-year visit is measured by the presence or absence of strabismus, nystagmus, and amblyopia	4.75-year study visit
Primary	Neurodevelopmental scores at 2-year study visit (Cohort 1 only)	Neurodevelopmental testing at the 2-year neurodevelopment study visit: a) Bayley Scales of Infant and Toddler Development: Scores motor skills with the standardized mean motor score of 100; less than 85 indicates mild impairment; less than 70 indicates moderate to severe impairment.	2-year study visit
Primary	Retinal thickness at the fovea and surrounding optic nerve as measured by OCT reading (Cohort 1-3)	Retinal thickness (microns) at the fovea and surrounding optic nerve.	Up to 42 weeks post-menstrual age
Primary	Microanatomy as measured by OCT reading	Combination of presence and severity of: retinal vessel tortuosity, vascular abnormality score by OCT (VASO), aggressive ROP, extra retinal neovascularization, vitreous abnormalities, shunt vessels, retinoschisis and retinal detachment.	Up to 42 weeks post-menstrual age
Primary	Microanatomy as measured by retinal photo reading (Cohort 3 only)	Combination of presence and severity of retinal vessel tortuosity, aggressive ROP, extra retinal neovascularization, shunt vessels, vitreous opacities, vitreous haze, retinoschisis and retinal detachment.	Up 42 weeks post-menstrual age
Primary	Microanatomy as measured by clinical exam (Cohort 1-3)	Clinical determination of combination presence and severity of retinal vessel tortuosity, aggressive ROP, extra retinal neovascularization, shunt vessels, vitreous opacities, vitreous haze, retinoschisis and retinal detachment.	Up to 42 weeks post-menstrual age
Primary	Measurement of stress of imaging (Cohort 3 only)	Assessment of stress and discomfort using modified CRIES score (crying 0-4; facial expression 0-2; heart rate beats per minute; change in respiratory support) during each eye imaging and compared to baseline pre-imaging score adverse events recorded during imaging (bradycardia, tachycardia, desaturation, emesis, and ocular adverse events e.g. conjunctival hemorrhage)	Up to 42 weeks post-menstrual age
Primary	Assessment of ease of imaging (Cohort 3 only)	Based on Likert scales (1-5)	Up to 42 weeks post-menstrual age
Primary	ROP vascular severity score (Cohort 3 only)	Based on a combination of relative retinal vessel tortuosity score, extraretinal neovascularization and aggressive ROP.	Up to 42 weeks post-menstrual age
Secondary	Neurodevelopmental scores at 5-year study visit (Cohort 1 only)	Wechsler Preschool and Primary Scale of Intelligence - 4: Measures specific aspects of working memory. Each subtest produces scaled scores from 1 to 19, with average scores between 7 and 12.	5-year study visit
Secondary	Neurodevelopmental scores at 5-year study visit (Cohort 1 only)	Movement Assessment Battery for Children: Comprehensive measurement of motor skills & is a well-known standardized test for detecting movement difficulty in children. Higher scores reflect more motor impairment.	5-year study visit
Secondary	Neurodevelopmental scores at 5-year study visit (Cohort 1 only)	Developmental Test of Visual Motor Integration: Non-verbal assessment that gauges the degree to which participants can integrate visual and motor abilities. Lower scores reflect more impairment.	5-year study visit
Secondary	Neurodevelopmental parental questionnaires at 5-year study visit (Cohort 1 only)	Child Behavior Checklist: 113 questions scored on a 3-point Likert frequency scale; scores below 93rd% are considered normal, scores 93-97th% are borderline and score above 97th% is in clinical range.	5-year study visit
Secondary	Neurodevelopmental parental questionnaires at 5-year study visit (Cohort 1 only)	Behavior Rating Inventory of Executive Functioning: 75 items in terms of frequency on a 3-point scale; raw scores for each scale are summed and T-scores (performance score where 50 is average and standard deviation is 10 points) are used.	5-year study visit
Secondary	Neurodevelopmental parental questionnaires at 5-year study visit (Cohort 1 only)	Social Communication Questionnaire: Total score is interpreted with a higher score in reference to cut-off (e.g. of 15) to suggest likelihood of autism spectrum.	5-year study visit