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European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis §

Authors

  • Giancarlo Comi MD,

    Corresponding author
    1. Clinical Trials Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy
    • Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Via Olgettina 60, 20132 Milan, Italy
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    • G. Comi, M. Filippi, J. S. Wolinsky, D. Ladkani, and S. Kadosh were involved in the data analyses and interpretation, and in writing the manuscript.

  • Massimo Filippi MD,

    1. Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy
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    • G. Comi, M. Filippi, J. S. Wolinsky, D. Ladkani, and S. Kadosh were involved in the data analyses and interpretation, and in writing the manuscript.

  • Jerry S. Wolinsky MD

    1. University of Texas–Houston, Health Science Center, Houston, TX
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    • G. Comi, M. Filippi, J. S. Wolinsky, D. Ladkani, and S. Kadosh were involved in the data analyses and interpretation, and in writing the manuscript.


  • Members of the Advisory Committee were reimbursed for their specific services as members of the independent data safety monitoring committee on a contractual basis by Teva Pharmaceutical, Ltd. Dr Johnson has an ongoing consultant agreement with Teva Pharmaceutical, Ltd.

  • Members of the Clinical Steering Committee, MRI Steering Committee, and academicians on the Organizing Committee were reimbursed for their specific services on a contractual basis by Teva Pharmaceutical, Ltd.

  • §

    Drs Stark, Gurevich, Kadosh, Zak, Pinchassi, and Ladkani are employees of Teva Pharmaceutical, Ltd., involved in trial design and execution, study management, database management, and statistical analysis.

  • The paper was distributed for comments and approval to all study trialists through the principal investigators at each participating site before finalized.

  • The members of the European/Canadian Glatiramer Acetate Study Group are: D. Guillaume, J. B. D'Harcour, C. J. M. Sindic, T. P. J. Duprez, L. Truyen, G. Nagels, P. M. Parizel, E. A. C. M. Sanders, R. J. Versteylen, C. P. Hawkins, N. Haq, D. Barnes, A. Clifton, D. Bates, A. Coulthard, G. Perkin, I. Colquhoun, C. A. Young, T. Nixon, D. Francis, D. Yates, D. Neary, A. Jackson, L. D. Blumhardt, T. Jaspan, O. Lyon-Caen, A. Tourbah, M. Bataillard, I. R. Kraehenbuhl, E. A. Cabanis, S. Bracard, M. Debouverie, R. Anxionnat, C. Fieschi, S. Bastianello, R. Capra, R. Gasparotti, G. L. Mancardi, M. Inglese, F. Sardanelli, M. Zaffaroni, M. Rovaris, G. Comi, M. Filippi, B. Storch-Hagenlocher, K. Sartor, W. Gehlen, A. Schmidt, C. Weiller, W. Behrendt, G. Rice, K. Kennedy; L. Metz, D. Patry, M. Yeung, A. Davis; S. Curtis, G. Francis, D. L. Arnold, G. Leroux, V. Cosi, C. Uggetti, F. Zappoli, R. Brenner, A. Valentine, I. Pye, G. Cherryman. Principal Investigators: D. Guillaume, J. B. D'Harcour, C. J. M. Sindic, T. P. J. Duprez, L. Advisory Committee: K. P. Johnson, O. Hommes, P. Feigin. Clinical Steering Committee: G. Comi, D. Bates, O. Lyon-Caen, G. Rice, J. S. Wolinsky. MRI Steering Committee: M. Filippi, F. Barkhof, D. L. Arnold, M. A. Horsfield, J. S. Wolinsky. Organizing Committee: G. Comi, M. Filippi, J. S. Wolinsky, Y. Stark, M. Gurevich, S. Kadosh, B. Zak, I. Pinchassi, D. Ladkani. Coordinating center: Clinical Trials Unit and Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy: G. Comi, M. Filippi, L. Minicucci, M. A. Rocca, M. Rodegher, M. Rovaris.

Abstract

Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (−10.8, 95% confidence interval −18.0 to −3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden. Ann Neurol 2001;49:290–297

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