Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis
- O Andersen1,
- I Elovaara2,
- M Färkkilä4,
- H J Hansen3,
- S I Mellgren5,
- K-M Myhr6,
- M Sandberg-Wollheim7,
- P Soelberg Sørensen8,
- The Nordic SPMS Study Group
- 1Institute of Clinical Neuroscience, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
- 2Neuroimmunology Unit, Department of Neurology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
- 3Neurology Department, Århus Community Hospital, Århus, Denmark
- 4Department of Neurology, Helsinki University, Helsinki, Finland
- 5Department of Neurology, University Hospital of North Norway, Tromsö, Norway
- 6Department of Neurology, Haukeland Hospital, Bergen, Norway
- 7Department of Neurology, University Hospital, University of Lund, Lund, Sweden
- 8Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Correspondence to: Professor Oluf Andersen Institute of Clinical Neuroscience, Neurologen-Sahlgrenska, Sahlgrenska University Hospital, SE 413 45 Göteborg, Sweden; oluf.andersenneuro.gu.se
- Received 12 January 2003
- Accepted 6 August 2003
- Revised 28 July 2003
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.
- EDSS, Expanded Disability Status Scale
- EU-SPMS, European Secondary Progressive Multiple Sclerosis trial
- HR, hazard ratio
- IFN, interferon
- IM, intramuscular
- KFS, Kurtzke Functional System
- MRI, magnetic resonance imaging
- PH, proportional hazard
- RFSS, Regional Functional System Score
- RRMS, relapsing–remitting multiple sclerosis
- SAE, serious adverse event
- SC, subcutaneous
- SPMS, secondary progressive multiple sclerosis
- TTP, time to progression
Footnotes
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Competing interests: All authors have participated in meetings sponsored by and received travel grants from pharmaceutical companies marketing treatments for multiple sclerosis
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An introductory text on the RFSS, its definitions of scoring, and principles of calculation is posted on the following web pages: http://www.neuro.gu.se/swe/forskning/demyel/RFSS%20calculation%20example.xls; http://www.neuro.gu.se/swe/forskning/demyel/RFSS%20overview.doc; http://www.neuro.gu.se/swe/forskning/demyel/RFSS%20recording,%20relationship%20to%20EDSS.ppt; http://www.neuro.gu.se/swe/forskning/demyel/RFSSmanual.pdf; and http://www.neuro.gu.se/swe/forskning/demyel/RFSSscan1-7.doc. An instruction video of the RFSS is available on request to the corresponding author.
