Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2004 May;75(5):706–710. doi: 10.1136/jnnp.2003.010090

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis

O Andersen 1, I Elovaara 1, M Farkkila 1, H Hansen 1, S Mellgren 1, K Myhr 1, M Sandberg-Wollheim 1, S Soelberg 1
PMCID: PMC1763573  PMID: 15090564

Abstract

Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose–response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 µg subcutaneously once weekly, in patients with secondary progressive MS.

Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 µg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate.

Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 µg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted.

Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose–response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Full Text

The Full Text of this article is available as a PDF (302.2 KB).

Selected References

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

  1. Barnes D., Hughes R. A., Morris R. W., Wade-Jones O., Brown P., Britton T., Francis D. A., Perkin G. D., Rudge P., Swash M. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997 Mar 29;349(9056):902–906. doi: 10.1016/s0140-6736(96)06453-7. [DOI] [PubMed] [Google Scholar]
  2. Clanet M., Radue E. W., Kappos L., Hartung H. P., Hohlfeld R., Sandberg-Wollheim M., Kooijmans-Coutinho M. F., Tsao E. C., Sandrock A. W., European IFNbeta-1a (Avonex) Dose-Comparison Study Investigators A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002 Nov 26;59(10):1507–1517. doi: 10.1212/01.wnl.0000032256.35561.d6. [DOI] [PubMed] [Google Scholar]
  3. Cohen J. A., Cutter G. R., Fischer J. S., Goodman A. D., Heidenreich F. R., Kooijmans M. F., Sandrock A. W., Rudick R. A., Simon J. H., Simonian N. A. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002 Sep 10;59(5):679–687. doi: 10.1212/wnl.59.5.679. [DOI] [PubMed] [Google Scholar]
  4. Comi G., Filippi M., Barkhof F., Durelli L., Edan G., Fernández O., Hartung H., Seeldrayers P., Sørensen P. S., Rovaris M. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001 May 19;357(9268):1576–1582. doi: 10.1016/s0140-6736(00)04725-5. [DOI] [PubMed] [Google Scholar]
  5. Jacobs L. D., Beck R. W., Simon J. H., Kinkel R. P., Brownscheidle C. M., Murray T. J., Simonian N. A., Slasor P. J., Sandrock A. W. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000 Sep 28;343(13):898–904. doi: 10.1056/NEJM200009283431301. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Li D. K., Paty D. W. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multiple Sclerosis. Ann Neurol. 1999 Aug;46(2):197–206. doi: 10.1002/1531-8249(199908)46:2<197::aid-ana9>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  8. Li D. K., Zhao G. J., Paty D. W., University of British Columbia MS/MRI Analysis Research Group. The SPECTRIMS Study Group Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology. 2001 Jun 12;56(11):1505–1513. doi: 10.1212/wnl.56.11.1505. [DOI] [PubMed] [Google Scholar]
  9. Lycke J., Svennerholm B., Hjelmquist E., Frisén L., Badr G., Andersson M., Vahlne A., Andersen O. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol. 1996 Mar;243(3):214–224. doi: 10.1007/BF00868517. [DOI] [PubMed] [Google Scholar]
  10. Munafo A, Trinchard-Lugan I, I, Nguyen TX, Buraglio M. Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol. 1998 Mar;5(2):187–193. doi: 10.1046/j.1468-1331.1998.520187.x. [DOI] [PubMed] [Google Scholar]
  11. Panitch H., Goodin D. S., Francis G., Chang P., Coyle P. K., O'Connor P., Monaghan E., Li D., Weinshenker B., EVIDENCE Study Group. EVidence of Interferon Dose-response: Europian North American Compartative Efficacy Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002 Nov 26;59(10):1496–1506. doi: 10.1212/01.wnl.0000034080.43681.da. [DOI] [PubMed] [Google Scholar]
  12. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Weiner H. L., Mackin G. A., Orav E. J., Hafler D. A., Dawson D. M., LaPierre Y., Herndon R., Lehrich J. R., Hauser S. L., Turel A. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology. 1993 May;43(5):910–918. doi: 10.1212/wnl.43.5.910. [DOI] [PubMed] [Google Scholar]

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

RESOURCES