Different ranibizumab dosages for retinopathy of prematurity: 5-year follow-up data of the randomised, controlled CARE-ROP Study

Abstract

Background: Data on long-term outcomes of antivascular endothelial growth factor therapy in retinopathy of prematurity (ROP) are still rare. We present 5-year post-treatment ophthalmological and paediatric outcomes of the prospective, multicentre, randomised, double-blinded, controlled pilot study CARE-ROP (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity).

Methods: 14 patients (28 eyes) completed the ophthalmologic and 5 patients completed the paediatric 5-year follow-up assessment. The ophthalmological assessment included best-corrected visual acuity (BCVA), orthoptic status, slit lamp examination, intraocular pressure and funduscopy. The paediatric examination followed the German Neonatal Network protocol and covered cognitive, motor and sensory development.

Results: 17 of 28 eyes exhibited at least one ocular abnormality, such as optic disc pallor or atrophy of the optic nerve head, retinal pigment epithelium (RPE) pigment changes, persistent tortuosity or macular hypoplasia. Despite this, 19 of 26 eyes demonstrated a logarithm of the Minimum Angle of Resolution (logMAR) BCVA of 0.3 or better. Mean refractive error was -0.9 D (±3.4 D) with only two eyes of one infant having high myopia of < -5 D. The neurodevelopmental results were within the expected range for a population of preterm infants with treatment-warranting ROP but need to be interpreted with caution due to the low number of five patients.

Conclusion: The 5-year ophthalmologic and paediatric outcomes of the CARE-ROP study confirm the previous results and add important additional information on long-term safety of 0.12 and 0.20 mg ranibizumab for the treatment of ROP. The ophthalmologic functional outcome regarding BCVA and refraction is promising. These exploratory long-term data, however, need to be interpreted with caution due to the low patient number both in the ophthalmologic and paediatric assessment.

Keywords: Child health (paediatrics); Retina.

Figure 1. Enrolment, allocation into the two study arms during the CARE-ROP core study (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity study), the follow-up at 1 year (±2 months), 2 years (±3 months) and 5 years (±6 months) post initial treatment. *After initial regression of the disease, a regular reinjection of the same dose without unblinding of investigators was allowed per protocol after at least 28 days. ^#A rescue treatment was defined as treatment with laser coagulation or the higher ranibizumab dose after unblinding and was allowed at all timepoints. ∼Patients not present at the 5-year ophthalmological visit were contacted multiple times but parents did not want to participate in this examination. §Pediatric examinations for further six infants (three in each treatment arm) were planned to take place in December 2021, but needed to be cancelled due to the COVID-19 pandemic. ROP, retinopathy of prematurity.

Figure 2. Examples of persistent posterior pole vascular tortuosity (A), optic disc pallor (B), persistent avascular retina (C) and persistent visible remnants of the previous ridge (D) at the 5-year assessment. Visual acuity is given for the respective eye in logMAR or decimals. Note that different from (C), the retinal vessels in (D) proceed beyond the previous ridge into the periphery.

Figure 3. Optical coherence tomography (OCT) images provided by the investigators for the 5-year follow-up. Images are arranged from close to normal foveal curvature (top left) to loss of foveal depression (bottom right). Visual acuity values were overall very good, but tended to be slightly better in eyes with (near) normal foveal configuration. Best-corrected visual acuity values given in logMAR are displayed for each eye next to the OCT scan embedded in the figure.

Figure 4. Distribution of spherical equivalent, astigmatism, intraocular pressure (IOP) and visual acuity by treatment arm at year 5. Values of the two study arms were compared using the Mann-Whitney U test in case of spherical equivalent, IOP and visual acuity due to non-normal distribution of data. An unpaired t-test was used in case of astigmatism. Figure displays all eyes; for statistical comparisons between groups, the mean of the right and left eyes of each patient was used. In (A, C and D), line and whiskers represent median and IQR; in (B), line and whiskers represent mean with SD.

Figure 5. (A) Distribution of refractive error (spherical equivalent) by treatment modality (at year 5). (B) Comparison of refractive error (spherical equivalent) between the 1-year and 5-year follow-up. rbz, ranibizumab; wo, without.