Why carry out this study?

Normal-tension glaucoma (NTG) is a subtype of primary open-angle glaucoma characterized by optic nerve damage and visual field loss despite normal intraocular pressure (IOP). Although several mechanisms have been proposed, including vascular dysregulation, increased IOP sensitivity, neurodegenerative processes, and altered cerebrospinal fluid dynamics, the underlying pathophysiology of NTG remains unclear, and no reliable animal model exists.

The Collaborative Normal-Tension Glaucoma Study (CNTGS), published in 1998, has long served as the central evidence supporting IOP reduction as an effective treatment for NTG. Given advances in statistical methodology and ongoing discussion about the interpretation of its results, a critical and structured reassessment of the CNTGS is needed to understand how its conclusions follow from the original data and analytic choices.

What was learned from the study?

This study re-evaluates the methodology and statistical analyses of the CNTGS and identifies key post hoc analytical modifications, including a shift of baseline to the point of IOP stabilization and selective censoring of cataract-related visual decline. These choices substantially influenced the estimated treatment effect.

When the CNTGS data are interpreted under the original intention-to-treat (ITT) framework, which follows all randomized eyes from randomization and includes all progression events, no statistically significant effect of IOP reduction is observed.

These findings reinforce the importance for strict adherence to ITT methodology, transparent handling of time-dependent processes, and appropriate modeling of treatment-related events.

Future clinical studies on NTG would benefit from prespecified analysis plans, unbiased time zero definitions, and appropriate competing-risk or time-dependent modeling to clarify the therapeutic role of IOP reduction.