Outer Segment Thickness Predicts Visual Field Response to QLT091001 in Patients with RPE65 or LRAT Mutations

Abstract

Purpose: To determine whether the degree of change in Goldmann visual fields (GVFs) following oral administration of QLT091001 was related to baseline measures of retinal structure.

Methods: Oral QLT091001 was administered once daily for 7 days in all study patients. Comprehensive ophthalmic testing, including spectral-domain optical coherence tomography (SD-OCT), was conducted in 14 patients with Leber congenital amaurosis (LCA) and 18 patients with retinitis pigmentosa (RP) at seven international sites. Average thickness of the outer segment (OS) layer was calculated over central 20°. Both eyes of each subject were evaluated separately.

Results: Nineteen of 28 eyes (68%) with LCA and 13 of 36 eyes (36%) with RP responded to QLT091001. Among these responders, the average baseline thickness of the OS layer (central 20°) was 13.5 μm in the LCA cohort and 11.7 μm in the RP cohort. Nonresponders had average baseline OS thickness of less than 4.6 μm in both cohorts. The OS thickness in the central 20° was significantly shorter in nonresponders than responders in the LCA cohort (P = 0.01, t-test) and in the RP cohort (P = 0.02, Wilcoxon rank sum test). The OS thickness in the central 20° did not change significantly from baseline during the first 2 months (P = 0.09, t-test, paired).

Conclusions: The present findings suggest that there is a close parallel between the thickness of the photoreceptor layer and the potential for functional improvement in these patients.

Translational relevance: SD-OCT thickness in the central retina may be useful for predicting the visual field response in the peripheral retina to QLT091001. (https://ichgcp.net/clinical-trials-registry/NCT01014052 number, NCT01014052).

Keywords: Leber congenital amaurosis; clinical trial; layer thickness; retinal degeneration; retinitis pigmentosa; segmentation; spectral-domain optical coherence tomography; visual fields.

Figures

Figure 1

(A) Leber congenital amaurosis cohort: The average OS thickness in the central 20° was significantly shorter in nonresponders than responders (P = 0.01, t-test; equal variance, F test, P = 0.88). (B) RP cohort: The average OS thickness in central 20° was significantly shorter in nonresponders than responders (P = 0.02, Wilcoxon rank test; unequal variance, F test, P < 0.001). (C) Retinal degeneration (RD; combined): The average OS thickness in the central 20° was significantly shorter in nonresponders than responders (P < 0.001, Wilcoxon rank test) in the combined group (unequal variance, F test, P = 0.004).

Figure 2

(A) SD-OCT foveal scan (upper) and GVF (lower) in a responder at the screening visit. The average thickness of the OS layer in the central 20° was 13.8 μm. The subject is an 11-year-old male patient with RP associated with RPE65 mutation. (B) SD-OCT foveal scan (upper) and GVF (lower) in the responder (shown in [A]) at day 60 after the start of the treatment. The GVF shows more than 20% gain in area 2 months later (B vs. A). (C) SD-OCT foveal scan (upper) and GVF (lower) in a nonresponder at screening visit. The average thickness of the OS layer in the central 20° was 5.54 μm. The subject is a 42-year-old male patient with RP associated with LRAT mutation. (D) SD-OCT foveal scan (upper) and GVF (lower) in the nonresponder shown in (C) at 2 months after treatment. GVF shows less than 20% gain at 2 months (D vs. C).

Figure 3

Receiver operating characteristic (ROC) curve (whole RD group, 64 eyes) was plotted to find the best criterion to separate responder and nonresponder groups using thickness measurement (micrometers). It was found that 7 μm is the optimum criterion, with a combination of high sensitivity and high specificity.