Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 215-216, 15 February 2003

Interferon beta-1a in primary progressive multiple sclerosis

NMR Research Unit, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK

Article Outline

Abstract 

There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.

Keywords:  Interferon beta-1a, Primary progressive multiple sclerosis, Therapeutics

 

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1. Introduction 

Patients with primary progressive multiple sclerosis (PPMS) have atypical clinical and MRI characteristics [1] and as a result have been excluded from the majority of therapeutic trials. Recently, there has been an upsurge of interest in this group and a number of trials have been specifically designed for PPMS. This paper summarises the study design and preliminary results of an exploratory randomised controlled trial of interferon beta-1a in PPMS. To put this trial in context, a brief overview of other trials in PPMS to date is first given.

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2. Background 

Several therapeutic trials have been carried out in secondary progressive MS but only a few of these trials have also studied PPMS and the numbers of patients with PPMS have been small. These include randomised controlled trials of azathioprine (n=51), methotrexate (n=18) and cladribine (n=48) but in all cases no efficacy was seen on the analysis of the PPMS subgroup [2], [3], [4]. The results of a trial of intravenous immunoglobulin in progressive MS including 50 patients with PPMS are awaited [5]. More recent trials, which have been specifically designed for PPMS, are either not yet completed or are awaiting peer-reviewed publication. These include randomised controlled trials of interferon beta-1a (n=50), interferon beta-1b (n=70), mitoxantrone (n=54) and riluzole (n=16) [6], [7], [8], [9]. The results of an ongoing randomised controlled trial of glatiramer acetate in 946 patients are eagerly awaited as this will be the first definitive phase 3 trial to be completed in PPMS [10].

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3. Interferon beta-1a 

The trial of interferon beta-1a in PPMS now discussed was an exploratory double-blind, placebo-controlled trial [6]. The main objectives of the trial were to assess safety and tolerance and to explore the usefulness of a variety of outcome measures in this group; it was not expected to provide significant evidence regarding efficacy. Fifty subjects with PPMS of at least 2 years duration were enrolled. Inclusion criteria were age 18 to 60 years, Expanded Disability Status Scale (EDSS) [11] score of 2.0 to 7.0 inclusive, and at least two lesions on T2 weighted MRI of the brain and/or spinal cord. Subjects were randomised to receive intramuscular interferon beta-1a 30 μg (n=15), interferon beta-1a 60 μg (n=15) or placebo (n=20) once a week for 2 years.

The primary clinical endpoint was time to sustained progression in disability. Progression was defined as a 1.0 point increase in EDSS score for subjects with a baseline score ≤5.0 or a 0.5 point increase for subjects with a baseline score ≥5.5. Secondary clinical outcome measures were the timed 10 m walk and the nine hole peg test. Secondary MRI outcome measures were T2 weighted brain lesion load, new T2 brain lesions, new T2 spinal cord lesions, T1 weighted brain lesion load, new T1 brain lesions, spinal cord cross-sectional area, whole brain volume and, ventricular volume. Tertiary MRI outcome measures included magnetisation transfer ratio of lesions and normal appearing white matter (NAWM) and 1H magnetic resonance spectroscopy measurement of N-acetyl derived groups in NAWM.

Forty-nine subjects completed the 2 years of follow-up. Disease progression was evident with 48% of subjects reaching the primary clinical endpoint. Preliminary results suggest that the 30 μg dose was well tolerated but the 60 μg dose was poorly tolerated due to flu-like reactions and liver enzyme rises. No effect was seen on the primary clinical endpoint nor the majority of the secondary outcome measures but there was a suggestion of an effect on T2 lesion load favouring the 30 μg dose. Further information on outcome measures will be provided when the study is published.

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4. Conclusion 

There is currently no disease-modifying treatment proven to be of efficacy in PPMS. The question as to whether interferon beta-1a may play a role in the treatment of PPMS has not been answered by this exploratory trial and a phase 3 trial would be required to address this further. However, it has shown that it is feasible to carry out therapeutic trials in PPMS. In planning future trials, consideration may want to be given to therapeutic agents directed at neuroprotection as well as inflammation. It is hoped that therapeutics in PPMS will continue to expand and that effective therapeutic agents will be developed.

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References 

  1. Thompson AJ, Polman CH, Miller DH, et al.  Primary progressive multiple sclerosis. Brain. 1997;120:1085–1096
  2. British and Dutch Multiple Sclerosis Azathioprine Trial Group . Double-masked trial of azathioprine in multiple sclerosis. Lancet. 1988;ii:179–183
  3. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al.  Low dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann. Neurol. 1995;37:30–40
  4. Rice GPA, et al.  for the Cladribine MRI Study Group   Cladribine and progressive MS. Clinical and MRI outcomes of a multicenter controlled trial. Neurology. 2000;54:1145–1155
  5. Poehlau D, Federlein J, Postert T, et al.  Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis—outline of a double-blind randomized, placebo-controlled trial. Mult. Scler. 1997;3:149–152
  6. Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ. Interferon β-1a in primary progressive MS: an exploratory randomized controlled trial. Neurology [in press].
  7. Montalban X, Tintore M, Rio J, et al.  Primary progressive multiple sclerosis: description of 121 patients and study design of a controlled trial. Mult. Scler. 1998;4:344; [abstract]
  8. Kalkers NF, Barkhof F, Bergers E, et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult. Scler. [in press].
  9. Kita M, Goodkin DE, Bacchetti P, et al.  A phase II trial of mitoxantrone in patients with primary progressive multiple sclerosis. Neurology. 2000;54(Suppl. 3):A22; [abstract]
  10. Wolinsky JS, Narayana PA  The PROMiSe Trial Study Group . Characteristics at entry into the glatiramer acetate study of primary progressive multiple sclerosis: the PROMiSe trial. J. Neurol. 2001;248(Suppl. 2):134; [abstract]
  11. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33:1444–1452

PII: S0022-510X(02)00350-7

Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 215-216, 15 February 2003

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