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David F Garway-Heath, Haogang Zhu, David Paul Crabb, UKGTS Investigators; Observation periods of 1 year for clinical trials of neuroprotective agents in glaucoma are feasible. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3550.
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Before the United Kingdom Glaucoma Treatment Study (UKGTS), a placebo-controlled treatment trial for manifest glaucoma, clinical trials in glaucoma with a visual field (VF) outcome typically had observation periods of 5 years or longer. The UKGTS reported a significant outcome with a 2-year observation period, with the difference between treatment arms evident after only 12 months. The UKGTS was designed to maximize the precision of estimates of progression rate (speed). In this study, the UKGTS data were used as the basis for modelling a trial of neuroprotection.
The assumed study design is a placebo-controlled trial of a neuroprotective agent, with all patients taking latanoprost in addition. The rates of progression from the eye with the worst VF loss at baseline in the latanoprost-treated arm of the UKGTS, with at least 6 months of follow-up, were used for modelling. For patients with less than 12 months follow-up, the rate for the available series was used. The modelling of the UKGTS VF data identified the outcome with greatest power to separate treatment groups as the mean rate of loss at the 10 fastest deteriorating locations in each eye. Progression rates were determined using a technique called ‘ANSWERS’ (Zhu et al. PLoS ONE: in press) and pointwise ordinary least squares linear regression (PLR). ANSWERS is a regression technique which accounts for the increasing variability with declining VF sensitivity. The study sample size was calculated for treatment effects of a 10%, 20% and 30% reduction in progression rate in latanoprost-treated eyes over a 12-month period for power=0.90 and two-sided P=0.05. Sample sizes for pilot studies (power=0.80 and P=0.10) were also calculated.
For a modest treatment effect of 20% rate reduction, 888 patients are needed (Table). For a more clinically significant treatment effect of 30% rate reduction, 390 patients are needed for an observation period of 12 months. For a pilot study, treatment effect of 30% rate reduction, 230 patients are required.
A clinical trial, with a VF outcome and an observation period of only 12 months, for a neuroprotective agent in patients on IOP-lowering treatment for glaucoma is feasible.
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