Skip to main content
Log in

Multiple sclerosis trial designs for the 21st century: Building on recent lessons

  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Starting with the first positive pilot study of glatiramer acetate, trial design in multiple sclerosis has advanced considerably over the past two decades, successively building and improving on previous successes in the implementation and analysis of new clinical trials. Most of these trials have been successful and this has led to the regulatory approval and commercial availability of six agents for the treatment of multiple sclerosis. During this period, outcome measures have been validated to determine the efficacy and safety of such agents, notably those useful in reducing the inflammatory aspects of disease. These include measurements of relapse reduction (annualized relapse rate, time to first relapse, proportion of subjects relapse free), disability (change in EDSS score, change in MSFC score) and MRI metrics (measurements of gadolinium-enhancing lesions, T1 and T2 lesion load). Recent trial design has shown that one can answer some clinical questions after one year on study and that these results may be predictive of more robust two-year trial data. The other important recent lesson involves emergence of rare complications of immunomodulatory therapy, namely progressive multifocal leucoencephalopathy with natalizumab that blocks the access of immune cells to the nervous system. In addition to the increased need for enhanced safety assessment, this issue will have an impact both on the study of combination therapies and on the use of combinations in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bornstein MB, Miller A, Slagle S, et al. (1987) A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 317:408–414

    PubMed  Google Scholar 

  2. Brex PA, Ciccarelli O, O’Riordan JI, et al. (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164

    Article  PubMed  Google Scholar 

  3. Cohen JA, Cutter GR, Fischer JS, et al. (2002) Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 59:679–687

    PubMed  Google Scholar 

  4. Comi G, Filippi M, Wolinsky JS, et al. (2001) The European/Canadian multicenter, double-blind, randomised placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing and remitting multiple sclerosis. Ann Neurol 49:290–297

    Article  PubMed  Google Scholar 

  5. Cutter GR, Baier ML, Rudick RA, et al. (1999) Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122:871–882

    Article  PubMed  Google Scholar 

  6. European Study Group on Interferon β–1b in Secondary Progressive MS (1998) Placebo-controlled multicentre randomised trial of interferon β–1b in treatment of secondary progressive multiple sclerosis. Lancet 352:1491–1497

    Article  PubMed  Google Scholar 

  7. Filippi M, Rovaris M, Rocca MA, et al. (2001) Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57:731–733

    PubMed  Google Scholar 

  8. Ford C, Johnson K, Brooks B, et al. (2003) Sustained efficacy and tolerability of glatiramer acetate in relapsing-remitting multiple sclerosis patients for over ten years. Multiple Sclerosis 9(Suppl 1):S120

    Google Scholar 

  9. Jacobs LD, Cookfair DL, Rudick RA, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39:285–294

    Article  PubMed  Google Scholar 

  10. Johnson KP, Brooks BR, Cohen JA, et al. (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45:1268–1276

    PubMed  Google Scholar 

  11. Johnson KP, Brooks BR, Ford CC, et al. (2000) Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 6:255–266

    Article  PubMed  Google Scholar 

  12. Kappos L, Moeri D, Radue EW, et al. (1999) Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Lancet 353:964–969

    Article  PubMed  Google Scholar 

  13. Kurtzke JF (1983) Rating neurological impairment in MS: an expanded disability status scale (EDSS).Neurology 33:1444–1452

    PubMed  Google Scholar 

  14. Lublin FD, Baier M, Cutter G (2003) Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 61:1528–1532

    PubMed  Google Scholar 

  15. Lublin FD, Cutter G, Elfont R, et al. (2001) A trial to assess the safety of combining therapy with interferon beta-1a and glatiramer acetate in patients with relapsing-remitting MS. Neurology 56(Suppl):S20.002

    Google Scholar 

  16. Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911

    PubMed  Google Scholar 

  17. Mainero C, De Stefano N, Iannucci G, et al. (2001) Correlates of MS disability assessed in vivo using aggregates of MR quantities. Neurology 56:1331–1334

    PubMed  Google Scholar 

  18. McDonald WI, Compston A, Edan G, et al. (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    Article  PubMed  Google Scholar 

  19. Noseworthy JH, O’Brien P, Erickson BJ, et al. (1998) The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis. Neurology 51:1342–1352

    PubMed  Google Scholar 

  20. O’Riordan JI, Thompson AJ, Kingsley DP, et al. (1998) The prognostic value of brain MRI in clinically isolated syndromes of the CNSA 10-year follow-up. Brain 121:495–503

    Article  PubMed  Google Scholar 

  21. Panitch H, Goodin DS, Francis G, et al. (2002) Evidence of Interferon Dose-response: European North American Comparative Efficacy; University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59:1496–1506

    PubMed  Google Scholar 

  22. Panitch H, Miller A, Paty D, Weinshenker B (2004) North American Study Group on Interferon beta-1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 63:1788–1795

    PubMed  Google Scholar 

  23. Polman C, O’Connor P, Havrdova E, et al. (2005) Clinical results from AFFIRM: a randomised, double-blind, placebo-controlled,multicenter trial to determine the efficacy and safety of natalizumab in patients with relapsing-remitting multiple sclerosis (MS). Neurology 64(Suppl 1):S16.003

    Google Scholar 

  24. Poser CM, Paty DW, Scheinberg I, et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231

    Article  PubMed  Google Scholar 

  25. Rovaris M, Agosta F, Sormani MP, et al. (2003) Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain 126:2323–2332

    Article  PubMed  Google Scholar 

  26. Rudick R, Stuart W, Calabresi P, et al. (2005) SENTINEL: a randomised, double-blind, placebo-controlled, multicenter trial to determine the efficacy and safety of natalizumab when added to intramuscular interferon-β 1a in patients with relapsing-remitting multiple sclerosis (MS). One year clinical and MRI results. Neurology 64(Suppl 1):S36.001

    Google Scholar 

  27. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group (1995) Interferon beta-1 β in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45:1277–1285

    PubMed  Google Scholar 

  28. The PRISMS STUDY GROUP and the University of British Columbia MS/MRI Analysis Group (2001) PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 56:1628–1636

    PubMed  Google Scholar 

  29. van Waesberghe JH, Kamphorst W, de Groot CJ, et al. (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754

    Article  PubMed  Google Scholar 

  30. van Walderveen MAA, Barkhof F, Hommes OR, et al. (1995) Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short TR/short TE (T1-weighted) spin-echo images. Neurology 45:1684–1690

    PubMed  Google Scholar 

  31. Weinshenker BG, Bass B, Rice GP, et al. (1989) The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 112:1419–1428

    PubMed  Google Scholar 

  32. Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers GC (1991) The natural history of multiple sclerosis: a geographically based study. 3.Multivariate analysis of predictive factors and models of outcome. Brain 114:1045–1056

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fred Lublin M. D..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lublin, F. Multiple sclerosis trial designs for the 21st century: Building on recent lessons. J Neurol 252 (Suppl 5), v46–v53 (2005). https://doi.org/10.1007/s00415-005-5008-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-005-5008-1

Key words

Navigation