Comparative Trials in Immunomodulating Treatment of Relapsing-remitting Multiple Sclerosis - The Importance of Study Design
Comparative Trials in Immunomodulating Treatment of Relapsing-remitting Multiple Sclerosis - The Importance of Study Design
Several randomised clinical trials have clearly demonstrated that the immunomodulating drugs, human recombinant interferon beta (IFN-ß) and glatiramer acetate (GA) are more effective than placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS).1 These drugs are now the approved treatment for RRMS and clinical practice treatment guidelines have been issued. After many years of effective and safe treatment of RRMS with immunomodulating drugs, several trials have compared the efficacy of the various drugs. However, the results from these trials have been conflicting.
Prospective Randomised Trials
The Independent Comparison of Interferon (INCOMIN) trial is the first prospective randomised directly comparative trial of two IFNs, 250µg IFN- ß-1b once every other day (qod) and 30µg IFN-ß- 1a once weekly (qw).2 It involved 15 MS centres and 188 patients with a two-year prospective follow-up and showed that IFN-ß-1b qod has a greater clinical and magnetic resonance imaging (MRI) efficacy than IFN-ß-1a qw. IFN-ß-1b particularly reduced the risk of disease progression to less than half compared with that of patients treated with IFN-ß-1a qw.
The Evidence for Interferon Dose Effect: European- North American Comparative Efficacy (EVIDENCE) trial is a prospective randomised trial comparing two different protocols of administering 44µg IFN-ß-1a three times weekly (tiw) compared with 30µg qw.3 It involved over 677 patients who were followed up for one year. Again, both clinical and MRI effects favoured the multiple weekly high-dose administration protocol.
In conclusion, both the INCOMIN and EVIDENCE trials confirmed the American Academy of Neurology (AAN) clinical practice treatment guidelines for MS, stating that there is a dose-response curve associated with the effect of IFN-ß in the treatment of MS.1
IFN treatment requires multiple weekly parenteral administrations for an as yet undetermined time period. Some patients may find it hard to cope with such a treatment regimen in the long term and might ask to reduce the dose or the frequency of administrations. The Dose Reduction study was aimed at trying to identify the minimum effective dose and frequency of administration of IFN-ß.4 Patients on chronic 250µg IFN-ß-1b qod who were doing very well (i.e. no relapses or disease progression for at least three years, and no signs of disease activity in two consecutive MRI scans) were randomised to either continue on 250µg IFN-ß-1b qod or be gradually switched to intramuscular (IM) 30µg IFN-ß-1a qw. Patients were followed up for one year and a resumption of the clinical and MRI signs of disease activity was observed in the group of patients who reduced the dose of IFN to 30µg IFN- ß-1a qw.
The latter prospective randomised trial showed that IFN-ß-1b treatment is a chronic treatment to be continued at high dose and with frequent weekly administration. A reduction in the administered weekly dose of IFN-ß-1b is not only not advisable but can also be dangerous – even in patients with prolonged absence of clinical and MRI signs of disease activity.
Observational Non-randomised Trials
The Detroit study, a prospective observational study on 122 patients, confirmed a greater efficacy of IFN- -1b qod and GA, which reduced relapse rate from an untreated control group more than IFN-1a qw (see Figure 1).5
The University of Bari study, a big retrospective observational comparative study, performed in 15 MS centres and involving over 1,000 patients, did not show any significant difference in the reduction in relapse rate from baseline between three different IFN-s (250g IFN--1b qod; 22g IFN--1a tiw; 30g IFN--1a qw) (see Figure 2).6
GA = glatiramer acetate, qod = once every other day, qow = once weekly. Source: Khan et al., Mult Scler (2001);7(6): pp. 349–353.
- Goodin D S, Frohman E M, Garmany G P et al., Disease modifying therapies in multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines , Neurology (2002);58: pp. 169 178.
- Durelli L, Verdun E, Barbero P et al., Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN) , Lancet (2002);359(9,316): pp. 1,453 1,460.
- Panitch H, Goodin D S, Francis G et al., Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial , Neurology (2002);59(10): pp. 1,496 1,506.
- Barbero P, Verdun E, Bergui M et al., High-dose, frequently administered interferon beta therapy for relapsing-remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study , J Neurol Sci (2004);222(1 2): pp. 13 19.
- Khan O A, Tselis A C, Kamholz J A et al., A prospective, open-label treatment trial to compare the effect of IFN ß-1a (Avonex), IFN ß-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis: results after 18 months of therapy , Mult Scler (2001);7(6): pp. 349 353.
- Trojano M, Liguori M, Paolicelli D et al., Interferon beta in relapsing-remitting multiple sclerosis: an independent postmarketing study in southern Italy , Mult Scler (2003);9: pp. 451 457.
- Haas J, Firzlaff M, Twenty-four-month comparison of immunomodulatory treatments a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone) , Eur J Neurol (2005);12: pp. 425 431.
- Limmroth V, Malessa R, Kalski G, Wernsdörfer C, A comparison of the efficacy and tolerability of interferon beta (IFN ß) products used as initial or follow-up therapy for the treatment of relapsing multiple sclerosis: Results from the QUASIMS Study , Neurology (2004);62(suppl. 5): p. A155. <
- Harman R J, The concept and implementation of good clinical practice in trials , The Pharmaceutical Journal (2003);270: pp. 653 657.
- Altman D G, Schulz K F, Moher D et al., The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration , Ann Intern Med (2001);134: pp. 663 694.
- Khaw K T, Bingham S, Welch A et al., Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition , Lancet (2001);357(9,257): pp. 657 663.
- Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial , Lancet (2002);360(9,326): pp. 23 33.
- Stampfer M J, Colditz G A, Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence , Prev Med (1991);20(1): pp. 47 63.
- Beral V, Banks E, Reeves G, Evidence from randomised trials on the long-term effects of hormone replacement therapy , Lancet (2002);360(9,337): pp. 942 944.
- Juni P, Altman D G, Egger M, Systematic reviews in health care: Assessing the quality of controlled clinical trials , BMJ (2001);323(7,303): pp. 42 46.
- Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group, Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results , Neurology (2001);56(11): pp. 1,496 1,504.
