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Show Journal of Neuro- Ophthalmology 21( 4): 310, 2001. © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Letter to the Editor Comparison of the ONTT Intravenous Group and the CHAMPS Placebo Group To the Editor: I have been asked on numerous occasions how the outcome data regarding development of multiple sclerosis ( MS) from the Optic Neuritis Treatment Trial ( ONTT)( l) compare with the outcome data from the CHAMPS trial ( 2). In particular, how does the risk of development of clinical definite MS ( CDMS) in the ONTT intravenous group patients with two or more brain magnetic resonance imaging ( MRI) lesions compare with the risk of CDMS in the CHAMPS placebo group patients who presented with optic neuritis ( and according to entry criteria had two or more brain MRI lesions)? In both trials, the aforementioned groups received a course of intravenous methylprednisolone ( IVMP) 1000 mg/ d for 3 days followed by oral prednisone 1 mg/ kg/ d for 11 days, followed by a short taper. In the ONTT, the intravenous therapy was administered in four doses of 250 mg/ d, whereas in CHAMPS 1000 mg was administered in a single daily dose. Treatment was initiated in the ONTT after an average of 4 days ( maximum 8 days) of symptoms, compared with 9 days ( maximum 14 days) in CHAMPS. In order to compare the CDMS rates between the two trials, several differences in the study design and analytic approach must be accounted for. First, the definition of CDMS in the ONTT did not include fellow eye optic neuritis, whereas in CHAMPS the occurrence of optic neuritis in the fellow eye was considered sufficient for a diagnosis of CDMS. Second, ONTT patients had formal protocol- specified neurologic exams only at baseline, and 6, 12, and 24 months, whereas in CHAMPS protocol- specified exams were performed at 6- month intervals plus at times of new onset of symptoms. Thus, some patients in the ONTT who were classified as probable MS ( meaning that symptoms consistent with a demye-linating event lasting more than 24 hours occurred but abnormality was not documented on a subsequent exam) likely would have been classified as CDMS if a protocol examination had been performed at the time of symptoms. Third, the life- table estimates in CHAMPS and the ONTT were computed differently: in CHAMPS, the life- table analysis of time to CDMS began 30 days after the onset of study drug ( Avonex [ Biogen; Cambridge, MA] or placebo) because by the protocol CDMS could not occur before this time point ( which on average was 49 days from the start of symptoms), whereas the ONTT analysis used the randomization date as the starting point ( which on average was 4 days from the start of symptoms). The 2- year cumulative probability of CDMS was 37% in the 97 CHAMPS placebo group patients presenting with optic neuritis. In the ONTT, after adjusting the life-table estimate for the 37 MRI- positive intravenous group patients so as to be more consistent with the CHAMPS CDMS diagnostic criteria and the life- table analytic method, the 2- year estimate of CDMS is 28%. The 95% confidence interval for this estimate is 14 to 44%, which includes the CHAMPS estimate of 37% ( P value comparing the CHAMPS and ONTT estimates = 0.31) Thus, much of the difference in the 2- year rates of CDMS in the ONTT and CHAMPS is accounted for by differences in study design. The remaining difference is consistent with chance, which is not surprising considering the relatively small number of ONTT patients suitable for a comparison with the CHAMPS cohort. Whether there could be any difference related to the earlier onset of treatment in the ONTT or the dosage schedule cannot be determined. Finally, although I conclude that there is unlikely to be a true difference in the rates of CDMS comparing the ONTT and CHAMPS, one must always be cautious in comparing results from treatment groups in nonconcurrent studies because this can lead to erroneous conclusions ( 3,4). Roy W. Beck, MD, PhD Jaeb Center for Health Research Tampa, Florida REFERENCES 1. Beck RW, Cleary PA, Trobe JD, ET AL. Optic Neuritis Study Group. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. New Engl J Med 1993; 329: 1764- 69. 2. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta- 1 a therapy initiated during a first demyelinating event in multiple sclerosis. New Engl J Med 2000; 343: 898- 904. 3. Sacks H, Chalmers TC, Smith H. Randomized versus historical controls for clinical trials. Am J Med 1982; 72: 233^ t0. 4. Micciolo R, Valagussa P, Marubini E. The use of historical controls in breast cancer: an assessment in three consecutive trials. Contr Clin Trials 1985; 6: 259- 70. 310 |