The Italian Journal of Neurological Sciences

, Volume 17, Issue 2, pp 135–139

Does a placebo-effect exist in clinical trials on multiple sclerosis? Review of the literature

  • Mantia L. La 
  • Eoli M. 
  • Salmaggi A. 
  • Milanese C. 
Original Articles

Abstract

To verify whether the outcome in placebo-treated MS patients actually corresponds to that expected on the basis of the natural history and pretrial evolution of the disease, we here review the results of clinical trials conducted according to a placebo-controlled, randomized design, regardless of the experimental therapy used.

The frequency of relapse in remitting-relapsing patients decreases during follow-up, and disability in progressive cases increases more slowly than before enrollment. These data should be borne in mind when evaluating the impact of experimental drugs on the natural course of the disease.

Key Words

Multiple Sclerosis Trials Review Placebo treatment 

Sommario

Sono stati rivisti i trials clinici condotti in pazienti affetti da SM secondo un disegno randomizzato e controllato con placebo, per verificare se i pazienti trattati con placebo evolvono meno rapidamente rispetto alla storia naturale e all'andamento pretrial. La maggioranza degli studi suggerisce che la frequenza di riaccensioni e l'accumulo di disabilità è inferiore rispetto alle condizioni pre-arruolamento. Questi dati vanno considerati nella valutazione dell'impatto di farmaci sperimentali sul decorso naturale della malattia.

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References

  1. [1]
    Austims Research Group:Interferon alpha and transfer factor in the treatment of multiple sclerosis: a double-blind, placebo-controlled trial. J. Neurol. Neurosurg. Psychiatry, 52: 566–574, 1989.CrossRefGoogle Scholar
  2. [2]
    Bornstein M.B., Miller A., Slagle S., Weitzman M., Crystal H., Drexler E., Keilson M., Merriam A., Wassertheil-Sommer S., Spada V., Weiss W., Arnon R., Jacobsohn I., Teitelbaum D., Sela M.:A pilot trial of Cop 1 in exacerbating- remitting multiple sclerosis. N. Engl. J. Med. 317: 408–414, 1987.CrossRefPubMedGoogle Scholar
  3. [3]
    Bornstein M.B., Miller A., Slagle S., Weitzman M., Drexler E., Keilson M., Spada V., Weiss W., Appel S., Rolak L., Harati Y., Brown S., Arnon R., Jacobsohn I., Teitelbaum D., Sela M.:A placebo-controlled, double-blind, randomized, two-center, pilot trial of cop 1 in chronic progressive multiple sclerosis. Neurology 41: 533–539, 1991.CrossRefPubMedGoogle Scholar
  4. [4]
    British and Dutch Multiple Sclerosis Azathioprine trial group:Double — masked trial of azathioprine in Multiple Sclerosis. Lancet ii: 178–183, 1988.Google Scholar
  5. [5]
    Camenga D.L., Johnson K.P., Alter M., Engelhardt C.D., Fishman P.S., Greenstein J.I., Haley A.S., Hirsch R.L., Kleiner J.E., Kofie V.Y., Koski C.L., Margilies S.L., Panitch H.S., Valero R.:Systemic recombinant alpha-2 interferon therapy in relapsing Multiple Sclerosis. Arch. Neurol. 43: 1239–1246, 1986.CrossRefPubMedGoogle Scholar
  6. [6]
    Ellison G.W., Myers L.W., Mickey M.R., Graves M.C., Tourtellotte W.W., Syndulko K., Holevoet-Howson M.I., Lerner C.D., Frane M.V., Pettler-Jennings P.:A placebo-controlled, randomized, doublemasked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in Multiple Sclerosis. Neurology 39: 1018–1026, 1989.CrossRefPubMedGoogle Scholar
  7. [7]
    Goodin D.S.:The use of immunosuppressive agents in the treatment of MS: a critical review. Neurology 41: 980–985, 1991.CrossRefPubMedGoogle Scholar
  8. [8]
    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. 46: 1107–1112, 1989.CrossRefPubMedGoogle Scholar
  9. [9]
    Goodkin D.E., Baily R.C., Teetzen M.L., Hertsgaard D., Beatty W.W.:The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology 41: 20–25, 1991.CrossRefPubMedGoogle Scholar
  10. [10]
    Goodkin D.E., Rudick R.A., Mendendorp S.V., Daughtry M.M., Schwetz K.M., Fischer J., Van Dyke C.:Low dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann. Neurol. 37: 30–40, 1995.CrossRefPubMedGoogle Scholar
  11. [11]
    Jacobs L., Salazaar A.M., Herndon R., Reese P.A., Freeman A., Jozefowicz R., Cuetter A., Husain F., Smith W.A., Ekes R., O'Malley J.A.:Intratechally administered natural human fibroblast interferon reduces exacerbations of multiple sclerosis. Arch. Neurol., 44: 589–595, 1987.CrossRefPubMedGoogle Scholar
  12. [12]
    Killian J.M., Bressler R.B., Armstrong R.M., Huston D.P.:Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch. Neurol. 45: 27–30, 1988.CrossRefPubMedGoogle Scholar
  13. [13]
    Kurtzke J.F.,Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 33: 1444–1452, 1983.CrossRefPubMedGoogle Scholar
  14. [14]
    Likoski W.H., Fireman B., Elmore R., Eno G., Gale K., Goode G.B., Ikeda K., Laster J., Mosher C., Rozance J., Richmon J., Rosennberg S., Samman A., Sternbach R., Whaley J., Fehrenbacher L.:Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J. Neurol. Neurosurg. Psychiatry, 54: 1055–1060, 1991.CrossRefGoogle Scholar
  15. [15]
    Milanese C., Salmaggi A., La Mantia L., Campi A., Eoli M., Savoiardo M., Banchi G., Nespolo A.:Double-blind study of intrathecal beta-interferon in multiple sclerosis: clinical and laboratory results. J. Neurol. Neurosurg Psychiatry 53: 554–557, 1990.CrossRefPubMedPubMedCentralGoogle Scholar
  16. [16]
    Milanese C., La Mantia L., Salmaggi A., Eoli M.:A double-blind study of azathioprine efficacy in multiple sclerosis: final report. J. Neurol. 240: 295–298, 1993.CrossRefPubMedGoogle Scholar
  17. [17]
    Myers L.W., Ellison G.W., Leake B.D.:Sample size estimates for therapeutic trials for multiple sclerosis. Ann. Neurol. 32(2): 258, 1992.Google Scholar
  18. [18]
    Noseworthy J.H., Vanderwoort M.K., Wong C.J., Ebers G.C., and the Canadian Cooperative MS Study Group:Inter-rater variability with the expanded Disability Status Scale (EDSS) and Functional System (FS) in a multiple sclerosis clinical trial. Neurology 40: 971–975, 1990.CrossRefPubMedGoogle Scholar
  19. [19]
    Schumacher G.A., Beebe G.W., Kibler R.F., Kurland L.T., Kurtzke J.F., McDowell F., Nagler B., Sibley A.W., Tourtellotte W.W., Willmont L.:Problems of experimental trials of therapy in multiple sclerosis. Ann. NY Acad. Sci. 122: 552–568, 1965.CrossRefPubMedGoogle Scholar
  20. [20]
    The Canadian Cooperative Multiple Sclerosis Study Group:The Canadian Cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 337: 441–446, 1991.Google Scholar
  21. [21]
    The IFNB Multiple Sclerosis Study Group:Interferon beta-1 b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43: 655–661, 1993.CrossRefGoogle Scholar
  22. [22]
    The Multiple Sclerosis Study Group:Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann. Neurol., 27: 591–605, 1990.CrossRefGoogle Scholar
  23. [23]
    Van Haver H., Lissoir F., Ketelaer P., Van Hees J., Theys P., Vervliet G., Claeys H., Gautama K., Vermylen C., Carton H.:Transfer factor therapy in multiple sclerosis: a three-year prospective double-blind clinical trial. Neurology 36: 1399–1402, 1986.CrossRefPubMedGoogle Scholar
  24. [24]
    Weinshenker B.G., Ebers G.C.:The natural history of Multiple Sclerosis. Can. J. Neurol. Sci., 14: 255–261, 1987.PubMedGoogle Scholar
  25. [25]
    Weinshenker B.G., Bass B., Rice G.P.A., Noseworthy J., Carriere W., Baskerville J., Ebers G.C.:The natural history of multiple sclerosis: a geographically based study; l. Clinical course and disability. Brain 112: 133–146, 1989.CrossRefPubMedGoogle Scholar
  26. [26]
    Weinshenker B.G., Rice G.P.A., 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 114: 1057–1067, 1991.CrossRefPubMedGoogle Scholar
  27. [27]
    Whitaker J.N.:Expanded clinical trials of treatment for multiple sclerosis. Ann. Neurol., 34(6): 755–756, 1993.CrossRefPubMedGoogle Scholar
  28. [28]
    Yudkin P.L., Ellison G.W., Ghezzi A., Goodkin D.E., Hughes R.A.C., McPherson K., Mertin J., Milanese C.:Overview of azathioprine treatment in multiple sclerosis. The Lancet 338: 1051–1055, 1991.CrossRefGoogle Scholar

Copyright information

© Masson S.p.A 1996

Authors and Affiliations

  • Mantia L. La 
    • 1
  • Eoli M. 
    • 1
  • Salmaggi A. 
    • 1
  • Milanese C. 
    • 1
  1. 1.Istituto Nazionale Neurologico “C. Besta”MilanoItaly

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