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Reassessment of the Collaborative Normal-Tension Glaucoma Study: Statistical Evidence and Implications for Current
Hanspeter E Killer1, Achmed Pircher2, Daniel J Stekhoven3,4
1Department of Biomedicine, University of Basel, Basel, Switzerland.
Ophthalmology and Therapy
|January 9, 2026
Summary
Re-examining the Collaborative Normal-Tension Glaucoma Study (CNTGS) reveals its conclusions on intraocular pressure (IOP) reduction are questionable. Methodological issues, including immortal time bias, obscured the true treatment effect in normal-tension glaucoma (NTG).
Area of Science:
- Ophthalmology
- Clinical Trials
- Biostatistics
Background:
- The Collaborative Normal-Tension Glaucoma Study (CNTGS) is often cited to support intraocular pressure (IOP) reduction for normal-tension glaucoma (NTG).
- This study critically evaluates the statistical methods used in the CNTGS.
- The aim is to determine the validity of the study's conclusions regarding IOP reduction's efficacy in NTG management.
Purpose of the Study:
- To re-examine the statistical methodology of the CNTGS.
- To assess the impact of analytical choices on the reported treatment effect.
- To clarify the role of IOP reduction in normal-tension glaucoma management.
Main Methods:
- Review of the CNTGS design, focusing on survival analysis techniques.
- Analysis of time zero definition, censoring rules, and intention-to-treat (ITT) versus per-protocol analyses.
- Evaluation of post hoc baseline redefinition and handling of cataract-related visual decline.
Main Results:
- The CNTGS analysis introduced immortal time bias by shifting the baseline for the treatment group.
- Cataract-related visual decline in the treatment group was inappropriately censored.
- The statistically significant treatment effect observed in per-protocol analysis vanished in the original intention-to-treat (ITT) analysis.
Conclusions:
- The reported treatment benefit in CNTGS relied heavily on post hoc modifications.
- The original ITT analysis did not demonstrate a statistically significant IOP reduction effect.
- Future NTG trials require transparent methods, adherence to ITT, and appropriate handling of biases and events.
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