Design, methods, and conduct of the optic neuritis treatment trial

Cleary, Patricia A.; Beck, Roy W.; Anderson, Malcolm M.; Kenny, David J.; Backlund, Jye‐Yu C.; Gilbert, Peter R.

doi:10.1016/0197-2456(93)90015-6

Cited by 74 publications

(40 citation statements)

References 14 publications

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“…The presence of prior AON was assessed in the subject's Electronical Medical Record, using the criteria from the Optic Neuritis Treatment Trial [10] and confirmed Fig. 1 The color vision pathway.…”

Section: Clinical Evaluationmentioning

confidence: 99%

Color vision impairment in multiple sclerosis points to retinal ganglion cell damage

et al. 2015

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Multiple Sclerosis (MS) results in color vision impairment regardless of optic neuritis (ON). The exact location of injury remains undefined. The objective of this study is to identify the region leading to dyschromatopsia in MS patients' NON-eyes. We evaluated Spearman correlations between color vision and measures of different regions in the afferent visual pathway in 106 MS patients. Regions with significant correlations were included in logistic regression models to assess their independent role in dyschromatopsia. We evaluated color vision with Hardy-Rand-Rittler plates and retinal damage using Optical Coherence Tomography. We ran SIENAX to measure Normalized Brain Parenchymal Volume (NBPV), FIRST for thalamus volume and Freesurfer for visual cortex areas. We found moderate, significant correlations between color vision and macular retinal nerve fiber layer (rho = 0.289, p = 0.003), ganglion cell complex (GCC = GCIP) (rho = 0.353, p < 0.001), thalamus (rho = 0.361, p < 0.001), and lesion volume within the optic radiations (rho = -0.230, p = 0.030). Only GCC thickness remained significant (p = 0.023) in the logistic regression model. In the final model including lesion load and NBPV as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia [OR = 0.88 95 % CI (0.80-0.97) p = 0.016]. This association remained significant when we also added sex, age, and disease duration as covariates in the regression model. Dyschromatopsia in NON-eyes is due to damage of retinal ganglion cells (RGC) in MS. Color vision can serve as a marker of RGC damage in MS.

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Section: Clinical Evaluationmentioning

confidence: 99%

Color vision impairment in multiple sclerosis points to retinal ganglion cell damage

et al. 2015

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“…Unfortunately, however, these reanalyses almost always introduce considerable bias. A good example of the difficulties produced by such methods is the optic neuritis treatment trial (ONTT) [20][21][22], in which the authors made several such errors [23]. Thus, after the trial was over and the findings on the primary and secondary endpoints were found to be disappointing, the ONTT authors changed the a priori analysis plan of the trial from one-tailed to two-tailed in order to focus attention on the unexpected tertiary outcome of increased recurrent optic neuritis in the oral prednisone group [20,22,23].…”

Section: ■ Re-analysis Biasmentioning

confidence: 99%

“…A good example of the difficulties produced by such methods is the optic neuritis treatment trial (ONTT) [20][21][22], in which the authors made several such errors [23]. Thus, after the trial was over and the findings on the primary and secondary endpoints were found to be disappointing, the ONTT authors changed the a priori analysis plan of the trial from one-tailed to two-tailed in order to focus attention on the unexpected tertiary outcome of increased recurrent optic neuritis in the oral prednisone group [20,22,23]. They also re-analysed the baseline status of patients (without informing readers in the text of the article) and, in addition, excluded certain individuals from analysis (in a seemingly arbitrary manner) in order to demonstrate an effect of intravenous steroids on another tertiary outcome (development of MS), which was non-significant when analysed initially [21,23].…”

Section: ■ Re-analysis Biasmentioning

confidence: 99%

Disease-modifying therapy in MS: a critical review of the literature

Goodin

2004

J Neurol

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Several types of errors are commonly made during the conduct, analysis, and interpretation of clinical trials in multiple sclerosis (MS). These include statistical errors of overestimating the significance of trial results, particularly when multiple endpoints are evaluated. They also include errors arising from the use of inappropriate covariate analyses, meta-analyses, and post hoc subgroup analyses. Interpretation of trial results can also be confounded by regression to the mean, by post hoc data re-analysis, and by the use of a non-concurrent control population. As these kinds of errors continue to plague the medical literature, it has become important for physicians to be able to assess critically the reports of clinical trial results. In turn, this has made it necessary for physicians to become familiar with the rudiments of the fields of statistics, epidemiology, and trial design. It is the purpose of this manuscript, therefore, to provide an overview of these principles through a detailed analysis of these kinds of clinical trial errors, together with examples that have actually occurred in the recently published MS literature.

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“…Lumbar puncture was optional and performed in 133 of 457 (29.1%) of the cohort. 65,84 Two of 457 patients were eventually discovered to have compressive ON.…”

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confidence: 99%

“…The use of a placebo IV group was not included because study organizers could not justify, ethically or financially, hospitalizing patients for 3 days of sham IV therapy. 65,84 The study was designed to determine speed and level of recovery and complications of therapy. Visual acuity, visual fields, contrast sensitivity, and color vision were measured at study entry and at seven follow-up visits during the first 6 months, at 1 year, and then annually for 5 years.…”

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confidence: 99%