Dataset Information

Improving the Feasibility of Glaucoma Clinical Trials Using Trend-Based Visual Field Progression Endpoints.

ABSTRACT: Purpose:There have been concerns that short-term clinical trials for evaluating new treatments in glaucoma would require prohibitively large sample sizes when using visual field endpoints, given that glaucoma is often a slowly progressive disease. This study sought to determine the required sample size for such trials using event-based analyses, and whether it can be reduced using trend-based analyses. Design:Longitudinal, observational study. Participants:321 eyes of 240 glaucoma participants followed under routine clinical care using 242 visual field for an average of 10 years. Methods:Sample size requirements were derived using computer simulations that reconstructed "real-world" visual fields by combining estimates of point-wise variability according to different threshold levels and rates of change obtained from the clinical glaucoma cohort. A clinical trial lasting 2 years with testing every 3 months was simulated, assuming that the new treatment halted visual field change in various percentages of participants (or "responders"). Treatment efficacy was evaluated by: (a) Difference in incidence of point-wise event-based progression (similar to the commercially available Guided Progression Analysis), and (b) Difference in rate of visual field mean deviation (MD) change between groups using linear mixed models (LMMs). Main Outcome Measures:Sample size to detect a statistically significance difference between groups. Results:Between-group trend-based analyses using LMMs reduced sample size requirements by 85-90% across the range of new treatment effects when compared to the conventional point-wise event-based analysis. To detect the effect of a new treatment that halted progression in 30% of the participants under routine clinical care (equal to a 30% reduction in average rate of MD change) with 90% power, for example, 1924 participants would be required per group using event-based analysis, but only 277 participants per group if LMMs were used. Conclusions:The feasibility of future glaucoma clinical trials can be substantially improved by evaluating differences in the rate of visual field change between groups.

SUBMITTER: Wu Z

PROVIDER: S-EPMC7337274 | biostudies-literature | 2019 Mar-Apr

REPOSITORIES: biostudies-literature

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Improving the Feasibility of Glaucoma Clinical Trials Using Trend-Based Visual Field Progression Endpoints.

Wu Zhichao Z Crabb David P DP Chauhan Balwantray C BC Crowston Jonathan G JG Medeiros Felipe A FA

Ophthalmology. Glaucoma 20190117 2

<h4>Purpose</h4>There have been concerns that short-term clinical trials for evaluating new treatments in glaucoma would require prohibitively large sample sizes when using visual field endpoints, given that glaucoma is often a slowly progressive disease. This study sought to determine the required sample size for such trials using event-based analyses, and whether it can be reduced using trend-based analyses.<h4>Design</h4>Longitudinal, observational study.<h4>Participants</h4>321 eyes of 240 g ...[more]

PMID: 32632403

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Project description:ImportanceRates of visual field (VF) progression vary among patients with glaucoma. Knowing the rate of progression of individual patients would allow appropriately aggressive therapy for patients with high rates of visual loss and protect those with low rates from unnecessary therapy.ObjectiveTo compare 3 pointwise methods of estimating the rate of VF progression in glaucoma.Design, setting, and participantsThis retrospective, observational cohort study included 729 eyes of 567 consecutive patients with primary open-angle glaucoma who had at least 6 reliable VFs and at least 3 years of follow-up. One hundred seventy-six patients (257 eyes) were treated at a tertiary glaucoma center; in addition, data were collected from 391 participants (472 eyes) in the Advanced Glaucoma Intervention Study. Data were collected from May 1988 to November 2004 and analyzed from October 2018 to February 2019.ExposuresEstimates of VF progression were measured with guided progression analysis (GPA), pointwise linear regression (PLR), and the glaucoma rate index (GRI). A subgroup analysis was performed in a subset of patients with likely VF progression and likely VF stability.Main outcomes and measuresProportion of VF series detected as progressing, estimates of false-positive proportions, time to detect progression, and agreement among measures.ResultsAmong the 567 patients included in the analysis, mean (SD) age was 65.6 (9.7) years, 300 (52.9%) were female, and 295 (52.0%) were white. The median baseline mean deviation was -6.7 (interquartile range [IQR], -11.6 to -3.5) dB; the median follow-up time, 8.9 (IQR, 7.3-10.4) years. The proportion of eyes labeled as progressing was 27.7% according to the GPA, 33.5% according to the PLR, and 52.9% according to the GRI; pairwise differences for GRI vs PLR were 20% (95% CI, 17%-23%); for GRI vs GPA, 25% (95% CI, 22%-29%); and for PLR vs GPA, 6% (95% CI, 3%-9%; P < .001 for all comparisons, McNemar test). The shortest median time to progression was with the GRI (8.8 [IQR, 2.4-10.5 years), compared with the GPA and PLR (both >16 years). The hazard ratio of VF progression for GRI vs PLR (reference) was 11.3 (95% CI, 9.2-13.7); for GRI vs GPA (reference), 18.1 (95% CI, 14.5-22.6); and for PLR vs GPA (reference), 1.5 (95% CI, 1.3-1.9; P < .001 for all comparisons, Cox proportional hazards regression). These results held in the subgroup with likely progression; the proportions of progressing eyes were 73.7% (115 of 156) for GPA, 81.4% (127 of 156) for PLR, and 92.9% (145 of 156) for GRI. Pairwise difference for GRI vs PLR was 11.5% (95% CI, 7.4%-17.6%; P < .001, McNemar test); for GRI vs GPA, 19.2% (95% CI, 12.6%-26.4%; P < .001, McNemar test); and for PLR vs GPA, 7.7% (95% CI, 0.3%-15.7%; P = .08, McNemar test).Conclusions and relevanceThese results suggest GRI can detect long-term VF progression in glaucoma earlier than PLR or GPA. Validation with prospective designs may strengthen the generalizability and value of this method.

Project description:BACKGROUND:Primary angle-closure glaucoma is a type of glaucoma associated with a physically obstructed anterior chamber angle. Obstruction of the anterior chamber angle blocks drainage of fluids (aqueous humor) within the eye and may raise intraocular pressure (IOP). Elevated IOP is associated with glaucomatous optic nerve damage and visual field loss. Laser peripheral iridotomy (often just called 'iridotomy') is a procedure to eliminate pupillary block by allowing aqueous humor to pass directly from the posterior to anterior chamber through use of a laser to create a hole in the iris. It is commonly used to treat patients with primary angle-closure glaucoma, patients with primary angle closure (narrow angles and no signs of glaucomatous optic neuropathy), and patients who are primary angle-closure suspects (patients with reversible obstruction). The effectiveness of iridotomy on slowing progression of visual field loss, however, is uncertain. OBJECTIVES:To assess the effects of iridotomy compared with no iridotomy for primary angle-closure glaucoma, primary angle closure, and primary angle-closure suspects. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 9) which contains the Cochrane Eyes and Vision Trials Register; MEDLINE Ovid; Embase Ovid; PubMed; LILACS; ClinicalTrials.gov; and the ICTRP. The date of the search was 18 October 2017. SELECTION CRITERIA:Randomized or quasi-randomized controlled trials that compared iridotomy to no iridotomy in primary angle-closure suspects, patients with primary angle closure, or patients with primary angle-closure glaucoma in one or both eyes were eligible. DATA COLLECTION AND ANALYSIS:Two authors worked independently to extract data on study characteristics, outcomes for the review, and risk of bias in the included studies. We resolved differences through discussion. MAIN RESULTS:We identified two trials (2502 eyes of 1251 participants) that compared iridotomy to no iridotomy. Both trials recruited primary angle suspects from Asia and randomized one eye of each participant to iridotomy and the other to no iridotomy. Because the full trial reports are not yet available for both trials, no data are available to assess the effectiveness of iridotomy on slowing progression of visual field loss, change in IOP, need for additional surgeries, number of medications needed to control IOP, mean change in best-corrected visual acuity, and quality of life. Based on currently reported data, one trial showed evidence that iridotomy increases angle width at 18 months (by 12.70°, 95% confidence interval (CI) 12.06° to 13.34°, involving 1550 eyes, moderate-certainty evidence) and may be associated with IOP spikes at one hour after treatment (risk ratio 24.00 (95% CI 7.60 to 75.83), involving 1468 eyes, low-certainty evidence). The risk of bias of the two studies was overall unclear due to lack of availability of a full trial report. AUTHORS' CONCLUSIONS:The available studies that directly compared iridotomy to no iridotomy have not yet published full trial reports. At present, we cannot draw reliable conclusions based on randomized controlled trials as to whether iridotomy slows progression of visual field loss at one year compared to no iridotomy. Full publication of the results from the studies may clarify the benefits of iridotomy.

Dataset Information

Improving the Feasibility of Glaucoma Clinical Trials Using Trend-Based Visual Field Progression Endpoints.

Publications

Improving the Feasibility of Glaucoma Clinical Trials Using Trend-Based Visual Field Progression Endpoints.

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