Skip to main content
PMC home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2000 Apr;68(4):450–457. doi: 10.1136/jnnp.68.4.450

Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts

C Liu 1, L Blumhardt 1
PMCID: PMC1736854  PMID: 10727480

Abstract

OBJECTIVES—Recent phase III clinical trials of immunomodulatory therapies in relapsing-remitting multiple sclerosis have shown significant benefits of active treatment on relapse related end points, but effects on disability outcomes have been inconsistent. These apparent discrepancies could be due to differences in the clinical end points employed, the behaviour of placebo cohorts, or both.
METHODS—Disability data from the placebo cohorts of two large phase III studies, the United States glatiramer acetate trial (Copolymer 1 Multiple Sclerosis Study Group) and the multinational interferon β-1a trial (PRISMS Study Group) were combined and masked (n=313). Two groups of disability outcome measures were assessed. Firstly, measures of disability change (2 year EDSS difference and area under the EDSS/time curve, AUC) were calculated. Secondly, conventional disease progression end points ("confirmed progression" and "worsening to EDSS 6.0") were evaluated by using Kaplan-Meier analysis and compared with a categorical classification based on EDSS trends.
RESULTS—The average increase in disability for the entire cohort as assessed by mean 2 year EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was small. For the "confirmed progression" end points, increasing the stringency of the definition lowered their incidence (from 32% with 1.0 point at 3 months, to 9% with 2.0 points at 6 months), but did not improve the positive predictive accuracy for "sustained progression" maintained to the end of the study. The error rate for this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable end point, but had even lower sensitivity (incidence <10%). EDSS trend analysis showed markedly heterogeneous disease courses, which were then categorised into "stable" (26%), "relapsing-remitting" (59%), and "progressive" (15%) courses. Patients with the last course had deteriorated considerably by the end of 2 years (mean worsening of 2.0 EDSS points).
CONCLUSION—In relapsing-remitting multiple sclerosis treatment trials, the conventional measure of mean EDSS change has low sensitivity, whereas the widely applied confirmed progression end points have high error rates regardless of their definition stringency. Alternative methods with better data utilisation include AUC summary measures and categorical disease trend analysis. The heterogeneity of disability outcomes in short trials, combined with unreliable clinical end points, diminishes the credibility of therapeutic claims aimed at reducing irreversible neurological deficits. The behaviour of patients treated with placebo should be carefully analysed before conclusions are drawn on the efficacy of putative treatments.



Full Text

The Full Text of this article is available as a PDF (202.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALEXANDER L., BERKELEY A. W., ALEXANDER A. M. Prognosis and treatment of multiple sclerosis-quantitative nosometric study. J Am Med Assoc. 1958 Apr 19;166(16):1943–1949. doi: 10.1001/jama.1958.02990160001001. [DOI] [PubMed] [Google Scholar]
  2. Cutter G. R., Baier M. L., Rudick R. A., Cookfair D. L., Fischer J. S., Petkau J., Syndulko K., Weinshenker B. G., Antel J. P., Confavreux C. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999 May;122(Pt 5):871–882. doi: 10.1093/brain/122.5.871. [DOI] [PubMed] [Google Scholar]
  3. Ellison G. W., Myers L. W., Leake B. D., Mickey M. R., Ke D., Syndulko K., Tourtellotte W. W. Design strategies in multiple sclerosis clinical trials. The Cyclosporine Multiple Sclerosis Study Group. Ann Neurol. 1994;36 (Suppl):S108–S112. doi: 10.1002/ana.410360725. [DOI] [PubMed] [Google Scholar]
  4. Fazekas F., Deisenhammer F., Strasser-Fuchs S., Nahler G., Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet. 1997 Mar 1;349(9052):589–593. doi: 10.1016/s0140-6736(96)09377-4. [DOI] [PubMed] [Google Scholar]
  5. Ferguson B., Matyszak M. K., Esiri M. M., Perry V. H. Axonal damage in acute multiple sclerosis lesions. Brain. 1997 Mar;120(Pt 3):393–399. doi: 10.1093/brain/120.3.393. [DOI] [PubMed] [Google Scholar]
  6. Fu L., Matthews P. M., De Stefano N., Worsley K. J., Narayanan S., Francis G. S., Antel J. P., Wolfson C., Arnold D. L. Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain. 1998 Jan;121(Pt 1):103–113. doi: 10.1093/brain/121.1.103. [DOI] [PubMed] [Google Scholar]
  7. Goodkin D. E., Hertsgaard D., Rudick R. A. Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis. Implications for clinical trials. Arch Neurol. 1989 Oct;46(10):1107–1112. doi: 10.1001/archneur.1989.00520460093019. [DOI] [PubMed] [Google Scholar]
  8. Goodkin D. E. Interferon beta therapy for multiple sclerosis. Lancet. 1998 Nov 7;352(9139):1486–1487. doi: 10.1016/S0140-6736(98)00057-9. [DOI] [PubMed] [Google Scholar]
  9. Hughes R. A., Sharrack B. More immunotherapy for multiple sclerosis. J Neurol Neurosurg Psychiatry. 1996 Sep;61(3):239–241. doi: 10.1136/jnnp.61.3.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jacobs L. D., Cookfair D. L., Rudick R. A., Herndon R. M., Richert J. R., Salazar A. M., Fischer J. S., Goodkin D. E., Granger C. V., Simon J. H. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) Ann Neurol. 1996 Mar;39(3):285–294. doi: 10.1002/ana.410390304. [DOI] [PubMed] [Google Scholar]
  11. Johnson K. P., Brooks B. R., Cohen J. A., Ford C. C., Goldstein J., Lisak R. P., Myers L. W., Panitch H. S., Rose J. W., Schiffer R. B. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995 Jul;45(7):1268–1276. doi: 10.1212/wnl.45.7.1268. [DOI] [PubMed] [Google Scholar]
  12. Kurtzke J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444–1452. doi: 10.1212/wnl.33.11.1444. [DOI] [PubMed] [Google Scholar]
  13. Liu C., Blumhardt L. D. Assessing relapses in treatment trials of relapsing and remitting multiple sclerosis: can we do better? Mult Scler. 1999 Feb;5(1):22–28. doi: 10.1177/135245859900500105. [DOI] [PubMed] [Google Scholar]
  14. Liu C., Edwards S., Gong Q., Roberts N., Blumhardt L. D. Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1999 Mar;66(3):323–330. doi: 10.1136/jnnp.66.3.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Liu C., Li Wan Po A., Blumhardt L. D. "Summary measure" statistic for assessing the outcome of treatment trials in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998 Jun;64(6):726–729. doi: 10.1136/jnnp.64.6.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McALPINE D., COMPSTON N. Some aspects of the natural history of disseminated sclerosis. Q J Med. 1952 Apr;21(82):135–167. [PubMed] [Google Scholar]
  17. Morrissey S. P., Miller D. H., Kendall B. E., Kingsley D. P., Kelly M. A., Francis D. A., MacManus D. G., McDonald W. I. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study. Brain. 1993 Feb;116(Pt 1):135–146. doi: 10.1093/brain/116.1.135. [DOI] [PubMed] [Google Scholar]
  18. Rice G., Ebers G. Interferons in the treatment of multiple sclerosis: do they prevent the progression of the disease? Arch Neurol. 1998 Dec;55(12):1578–1580. doi: 10.1001/archneur.55.12.1578. [DOI] [PubMed] [Google Scholar]
  19. Rudick R. A., Goodkin D. E., Jacobs L. D., Cookfair D. L., Herndon R. M., Richert J. R., Salazar A. M., Fischer J. S., Granger C. V., Simon J. H. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1997 Aug;49(2):358–363. doi: 10.1212/wnl.49.2.358. [DOI] [PubMed] [Google Scholar]
  20. Rudick R., Antel J., Confavreux C., Cutter G., Ellison G., Fischer J., Lublin F., Miller A., Petkau J., Rao S. Clinical outcomes assessment in multiple sclerosis. Ann Neurol. 1996 Sep;40(3):469–479. doi: 10.1002/ana.410400321. [DOI] [PubMed] [Google Scholar]
  21. Rudick R., Antel J., Confavreux C., Cutter G., Ellison G., Fischer J., Lublin F., Miller A., Petkau J., Rao S. Recommendations from the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force. Ann Neurol. 1997 Sep;42(3):379–382. doi: 10.1002/ana.410420318. [DOI] [PubMed] [Google Scholar]
  22. Runmarker B., Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain. 1993 Feb;116(Pt 1):117–134. doi: 10.1093/brain/116.1.117. [DOI] [PubMed] [Google Scholar]
  23. Sharrack B., Hughes R. A., Soudain S., Dunn G. The psychometric properties of clinical rating scales used in multiple sclerosis. Brain. 1999 Jan;122(Pt 1):141–159. doi: 10.1093/brain/122.1.141. [DOI] [PubMed] [Google Scholar]
  24. Sharrack B., Hughes R. A. The Guy's Neurological Disability Scale (GNDS): a new disability measure for multiple sclerosis. Mult Scler. 1999 Aug;5(4):223–233. doi: 10.1177/135245859900500406. [DOI] [PubMed] [Google Scholar]
  25. Simonian N. A., McAllister A., Lull J. "Summary measure" statistic for assessing the outcome of treatment trials in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 1999 Apr;66(4):553–554. doi: 10.1136/jnnp.66.4.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Trapp B. D., Peterson J., Ransohoff R. M., Rudick R., Mörk S., Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278–285. doi: 10.1056/NEJM199801293380502. [DOI] [PubMed] [Google Scholar]
  27. Weinshenker B. G., Bass B., Rice G. P., Noseworthy J., Carriere W., Baskerville J., Ebers G. C. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989 Dec;112(Pt 6):1419–1428. doi: 10.1093/brain/112.6.1419. [DOI] [PubMed] [Google Scholar]
  28. Weinshenker B. G., Bass B., Rice G. P., Noseworthy J., Carriere W., Baskerville J., Ebers G. C. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989 Feb;112(Pt 1):133–146. doi: 10.1093/brain/112.1.133. [DOI] [PubMed] [Google Scholar]
  29. Weinshenker B. G., Issa M., Baskerville J. Long-term and short-term outcome of multiple sclerosis: a 3-year follow-up study. Arch Neurol. 1996 Apr;53(4):353–358. doi: 10.1001/archneur.1996.00550040093018. [DOI] [PubMed] [Google Scholar]
  30. Weinshenker B. G., Issa M., Baskerville J. Meta-analysis of the placebo-treated groups in clinical trials of progressive MS. Neurology. 1996 Jun;46(6):1613–1619. doi: 10.1212/wnl.46.6.1613. [DOI] [PubMed] [Google Scholar]
  31. Weinshenker B. G., Rice G. P., Noseworthy J. H., Carriere W., Baskerville J., Ebers G. C. The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials. Brain. 1991 Apr;114(Pt 2):1057–1067. doi: 10.1093/brain/114.2.1057. [DOI] [PubMed] [Google Scholar]
  32. Whitaker J. N., McFarland H. F., Rudge P., Reingold S. C. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler. 1995 Apr;1(1):37–47. doi: 10.1177/135245859500100107. [DOI] [PubMed] [Google Scholar]
  33. Wingerchuk D. M., Noseworthy J. H., Weinshenker B. G. Clinical outcome measures and rating scales in multiple sclerosis trials. Mayo Clin Proc. 1997 Nov;72(11):1070–1079. doi: 10.4065/72.11.1070. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES