Repeatability of Quantitative Autofluorescence Imaging in a Multicenter Study Involving Patients With Recessive Stargardt Disease 1.

Purpose: This study assesses the repeatability of quantitative autofluorescence (qAF) in a multicenter setting and evaluates qAF as the end point for clinical trials in recessive Stargardt disease 1 (STGD1). Methods: A total of 102 patients with STGD1 underwent qAF imaging as part of the Stargardt Remofuscin Treatment Trial (STARTT; EudraCT No. 2018-001496-20). For 166 eyes, we obtained qAF imaging at 2 visits, with 2 recordings per visit. The qAF8 values were independently determined by the study site and a central reading center. Intra- and inter-visit reproducibility, as well as interobserver (study site versus reading center) reproducibility were obtained using intraclass correlation (ICC), one-sample t-test, and Bland-Altman coefficient of repeatability. Results: The qAF repeatability was ± 26.1% for intra-visit, ± 40.5% for inter-visit, and ± 20.2% for the interobserver reproducibility measures. Intra-visit repeatability was good to excellent for all sites (ICC of 0.88-0.96). Variability between visits was higher with an overall ICC of 0.76 (0.69-0.81). We observed no significant difference in qAF values across sites between visits (7.06 ± 93.33, P = 0.238). Conclusions: Real-life test-retest variability of qAF is higher in this set of data than previously reported in single center settings. With improved operator training and by selecting the better of two recordings for evaluation, qAF serves as a useful method for assessing changes in autofluorescence signal. Translational Relevance: The qAF can be adopted as a clinical trial end point, but steps to counterbalance variability should be considered.

The STArgardt Remofuscin Treatment Trial (STARTT): design and baseline characteristics of enrolled Stargardt patients.

Background: This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT). Methods: In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF 8). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP),  spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index. Results: Mean age of participants was 35±11 years with 49 (56%) female. Median qAF 8 value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 µm (range 72-265) and median macular volume of 1.65 mm 3 (range 1.13-2.19). Compared to persons without vision impairment, both reading performance and patient-reported visual function were significantly lower (p<0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6. Conclusions: This trial design may serve as reference for future clinical trials as it explores the utility of qAF 8 as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1. EudraCT registration: 2018-001496-20 (09/05/2019).

α5ß1-Integrin inhibitor (CLT-28643) effective in rabbit trabeculectomy model.

PURPOSE: Glaucoma filtration surgery (GFS) fails due to fibrosis. The α5ß1-integrin plays a pivotal role in fibrosis, angiogenesis and inflammation. This is the first experiment evaluating the prevention of fibrosis after GFS by a specific small molecule α5ß1-integrin inhibitor (CLT-28643). METHODS: Twenty-four rabbits received trabeculectomy on their right eyes. The rabbits were randomized into three groups of eight eyes each. CLT-28643 was given as a single subconjunctival injection intraoperatively to two of the right eye groups followed by postoperative vehicle eye drops (CLT+ group) or CLT-28643 eye drops 4 times daily (CLT++ group). A third group received mitomycin-C (MMC) intraoperatively (sponge application, 0.04%, 2 min) followed by vehicle eye drops postoperatively. The control-surgery group consisted of 12 left eyes having trabeculectomy with no adjunctive therapy. The remaining 12 left eyes formed the untreated group. Clinical assessment included intraocular pressure (IOP) measurement, slit-lamp examination (including bleb survival and morphology) and bleb photography. The rabbits were killed after four weeks for histology. RESULTS: Both CLT-28643-treated groups showed significantly prolonged bleb survival, and better bleb score compared to the control-surgery group. At end of the study, most functioning blebs were found in the MMC group (MMC group 75%; CLT+ group 12.5%, CLT++ group 25%; CLT+ group 12.5%, control-surgery group 0%). CLT-28643 was non-toxic and well tolerated. CONCLUSIONS: This rabbit GFS study indicates that inhibition of α5ß1-integrin by the novel α5ß1-integrin antagonist CLT-28643 significantly improved the outcome. The effect of a single intro-operative application of CLT-28643 seems to be inferior to 0.04% MMC.

Incidence of conjunctival exposure following drainage device implantation in patients with glaucoma.

PURPOSE: To evaluate prior studies including a glaucoma drainage device and to describe the timing and incidence of conjunctival exposure. A meta-analysis of previously published articles. METHODS: Articles included were prospective, single cohort, or comparative parallel design, with a mean treatment period of at least 3 months and at least 30 patients per treatment arm. We limited our analysis to studies that evaluated the most common devices, including Ahmed, Baerveldt, and Molteno. RESULTS: We included 38 studies containing 45 treatment arms (16 Ahmed, 12 Baerveldt, and 17 Molteno). These studies included 3,105 patients and 3,255 eyes with an average follow-up of 26.1+/-3.3 months. The overall incidence of exposure was 2.0+/-2.6% (n=64) of eyes with an average exposure/month of 0.09+/-0.14%. There was no significant correlation between study length and incidence of exposure (p=0.11), although multivariate regression analysis identified length of follow-up as a risk factor for exposure (p=0.001). Among individual drainage devices, there was no significant difference in the incidence of exposure (p=0.22) or percent exposure per month (p=0.18). In addition, no difference existed in the incidence of exposure between sizes for the Baerveldt 250, 350 or 500 mm (p=0.7), number of plates for the Molteno Single or Double (p=0.3), nor between the composition of the Ahmed Silicone or Polypropylene (p=0.7). CONCLUSIONS: This study suggests that tube exposure of glaucoma implants is unusual and the incidence does not differ between the Ahmed, Baerveldt, and Molteno implants. However, exposure appears to occur at any time within the first 5 years following implantation.