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Editors Selection IGR 7-2

Medical Treatment: Beta-blockers as neuroprotectants

Comment by Stefano Gandolfi on:

21824 Clinical efficacy of topical nipradilol and timolol on visual field performance in normal-tension glaucoma: A multi-center, randomized, double-masked comparative study, Araie M; Shirato S; Yamazaki Y et al., Japanese Journal of Ophthalmology, 2008; 52: 255-264

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Clinical trials in humans on possible 'neuroprotectants' have been awaited for a long time. The multi-center study presented by Araie et al. (1103) belongs to this category. The authors have randomized to two different betablockers (timolol and nipradilol) a reasonably large cohort of patients affected by glaucomatous optic neuropathy and repeatedly showing an IOP < 18 mmHg. The rationale for such an approach is offered by data, collected in animal models of glaucoma, showing a possible non-IOP related protective effect exerted by nipradilol. After a three-year follow up, no statistically significant difference in the number of patients who experienced a documented progression of the field defect(s) was detected between the two cohorts. On top of that, both treatments showed a not greater than 1 mmHg mean decrease of IOP in the enrolled patients, thus confirming that beta-blockers might not be the best ocular hypotensive option in NTG. Publishing a negative result is a commendable effort. However, after reading this well-performed study, some questions do actually arise: 1) Is a three-year follow up long enough to detect possible differences between two treatment modalities in normal-tension glaucomas?; 2) Is a parallel-group, prospective design the most appropriate and convenient approach to evaluate a neuroprotectant in glaucoma?; 3) According to the measured progression rate in both groups, was the study powered enough? In a randomized, prospective, parallel group trial based upon an event-based analysis to detect field progression (the Collaborative Normal Tension Glaucoma Study), the 'intent-to-treat' analysis offered a 60% survival in the untreated vs. A 70% survival in the treated group three years after randomisation.¹ Even after censoring for cataract (and one might discuss how appropriate this method is²), the between-the-groups difference was still not significant. Therefore, with such study design and outcomes, three years might represent a too short time interval to detect a clinically relevant difference on this glaucoma phenotype. While discussing the best design options for clinical trials in neurodegenerations, Cummings stated that 'clinical measures with greater sensitivity than standard trial instruments might represent another strategy applicable to Proof-Of-Concepts studies. Adaptive dose-response designs are being considered as a means of shortening phase Iib studies and creating a seamless interface with phase III.' Practically speaking, the conventional parallel groups, prospective (very) long-term study design does not seem to be the most appropriate and convenient. Alternative approaches, such as (a) adopting biomarkers, or (b) applying the tested compounds only after having measured the degeneration rate in the individual subject, may be more effective. The conventional parallel groups, prospective long term study design does not seem to be the most appropriate and convenient. Finally, the study was powered on (a) an expected progression rate (0.5 dB/yr) that was at least five times greater than the observed one in both groups (0.08-0.09 dB/yr), and (b) on a minimal expected difference (0.25 dB/yr) that was more than twice the measured progression rate. Sizing a trial is particularly difficult and once the trials is completed, as it happened in this case, even the best and evidence-based forecast can be flawed by the observed results.

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