Assessment of the Impact of an Endpoint Committee in the Ocular Hypertension Treatment Study.

PURPOSE To assess the impact of a masked Endpoint Committee on estimates of the incidence of primary open-angle glaucoma (POAG) treatment efficacy and statistical power of the Ocular Hypertension Treatment Study-Phase 1, 1994-2002 (OHTS-1). DESIGN Retrospective interrater reliability analysis of endpoint attribution by the Endpoint Committee. METHODS After study closeout, we recalculated estimates of endpoint incidence, treatment efficacy, and statistical power using all-cause endpoints and POAG endpoints. To avoid bias, only the first endpoint per participant is included in this report. RESULTS The Endpoint Committee reviewed 267 first endpoints from 1636 participants. The Endpoint Committee attributed 58% (155 of 267) of the endpoints to POAG. The incidence of all-cause endpoints vs POAG endpoints was 19.5% and 13.2%, respectively, in the observation group and 13.1% and 5.8%, respectively, in the medication group. Treatment effect for all-cause endpoints was a 33% reduction in risk (relative risk = 0.67, 95% confidence interval [CI] of 0.54-0.84) and a 56% reduction in risk for POAG endpoints (relative risk = 0.44, 95% CI of 0.31-0.61). Post hoc statistical power for detecting treatment effect was 0.94 for all-cause endpoints and 0.99 for POAG endpoints. CONCLUSION Endpoint Committee adjudication of endpoints improved POAG incidence estimates, increased statistical power, and increased calculated treatment effect by 23%. An Endpoint Committee should be considered in therapeutic trials when common ocular and systemic comorbidities, other than the target condition, could compromise study results.

[1]  P. Lichter,et al.  The Collaborative Initial Glaucoma Treatment Study: study design, methods, and baseline characteristics of enrolled patients. , 1999, Ophthalmology.

[2]  B. Kahan,et al.  A comparison of approaches for adjudicating outcomes in clinical trials , 2017, Trials.

[3]  T. Dawber,et al.  The Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. , 1980, Survey of ophthalmology.

[4]  M. Bhandari,et al.  Adjudicating outcomes: fundamentals. , 2012, The Journal of bone and joint surgery. American volume.

[5]  E. E. Hartmann,et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. , 2002, Archives of ophthalmology.

[6]  D. Hood,et al.  Challenges to the Common Clinical Paradigm for Diagnosis of Glaucomatous Damage With OCT and Visual Fields , 2018, Investigative ophthalmology & visual science.

[7]  Nicholas G Strouthidis,et al.  Optic disc and visual field progression in ocular hypertensive subjects: detection rates, specificity, and agreement. , 2006, Investigative ophthalmology & visual science.

[8]  Chris A Johnson,et al.  Baseline visual field characteristics in the ocular hypertension treatment study. , 2002, Ophthalmology.

[9]  M. C. Leske,et al.  Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. , 2002, Archives of ophthalmology.

[10]  D E Gaasterland,et al.  The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods and baseline characteristics of study patients. , 1994, Controlled clinical trials.

[11]  M. Kass,et al.  The Ocular Hypertension Treatment Study: design and baseline description of the participants. , 1999, Archives of ophthalmology.

[12]  C. Ramsay,et al.  Outcome Measures in Glaucoma: A Systematic Review of Cochrane Reviews and Protocols , 2015, Journal of glaucoma.

[13]  D P Crabb,et al.  Interobserver agreement on visual field progression in glaucoma: a comparison of methods , 2003, The British journal of ophthalmology.

[14]  Wenle Zhao,et al.  Architecture design of a generic centralized adjudication module integrated in a web-based clinical trial management system , 2016, Clinical trials.

[15]  W. Feuer,et al.  Five-year follow-up optic disc findings of the Collaborative Initial Glaucoma Treatment Study. , 2009, American journal of ophthalmology.

[16]  Jonathan H Seltzer,et al.  Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium , 2017, American heart journal.

[17]  S. Yusuf,et al.  Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs , 2009, Clinical trials.

[18]  Douglas R. Anderson,et al.  The Ocular Hypertension Treatment Study: reproducibility of cup/disk ratio measurements over time at an optic disc reading center. , 2002, American journal of ophthalmology.

[19]  Richard A. Russell,et al.  Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial , 2015, The Lancet.

[20]  J L Keltner,et al.  Confirmation of visual field abnormalities in the Ocular Hypertension Treatment Study. Ocular Hypertension Treatment Study Group. , 2000, Archives of ophthalmology.

[21]  S. Mansberger,et al.  Primary Open-Angle Glaucoma Suspect Preferred Practice Pattern(®) Guidelines. , 2016, Ophthalmology.