Lessons from randomised direct comparative trials.

Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel-Aviv University, Israel.
Journal of the Neurological Sciences (Impact Factor: 2.24). 03/2009; 277 Suppl 1:S19-24. DOI: 10.1016/S0022-510X(09)70007-3
Source: PubMed

ABSTRACT For over a decade, four immunomodulatory therapies have been available for the treatment of relapsing remitting multiple sclerosis. However, few direct comparative data were available to facilitate the choice of treatment. This choice has been influenced by the perception that interferon-beta preparations have greater efficacy than glatiramer acetate, due to apparently more rapid and robust reduction of gadolinium-enhancing lesions seen on magnetic resonance imaging in the pivotal trials of these agents. This situation has changed in the last year, with the outcomes of three randomised clinical trials comparing the efficacy and safety of glatiramer acetate with that of a high-dose interferon-beta in relapsing remitting multiple sclerosis. These are the REGARD, BEYOND and BECOME trials. In the REGARD trial, 764 patients were randomised to treatment with either interferon-beta 1a sc 44 microg or glatiramer acetate for 96 weeks; no significant difference in the time to first relapse was observed. The largest of the three comparative studies, the BEYOND trial, compared treatment with interferon-beta 1b sc 500 microg, interferon-beta 1b sc 250 microg or glatiramer acetate for two years in 2,244 patients. The hazard ratio for multiple relapses was close to unity for comparisons between all groups, indicating equivalent efficacy in all three treatment arms. Relapse rates (around 0.3 relapses/year) in all these studies were much lower than anticipated and lower than those reported a decade previously in the pivotal trials of beta-interferons and glatiramer acetate. No unexpected safety issues were identified in any of these studies. The completion of these direct comparative studies has considerably enriched the clinical evidence database by contributing large numbers of patients. This provides an invaluable contribution for helping the physician make an informed choice about treatment. The results of the direct comparative studies provide evidence that glatiramer acetate and high-dose interferon-beta preparations have comparable clinical efficacy.

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    ABSTRACT: Recent clinical studies in multiple sclerosis have provided new data on glatiramer acetate, interferon-beta preparations and natalizumab, which will have important implications for optimising patient care. Once a diagnosis has been made with confidence, early initiation of immunotherapy is warranted because of the presence of continuous inflammatory disease activity. Approval for therapy in patients with a clinically isolated syndrome has been granted to several first-line treatments, and most recently to glatiramer acetate. The utility of systematic frequent MRI monitoring of disease activity and response to therapy is not yet clearly established. Treatment efficacy after initiating therapy at the first demyelinating episode has to be followed carefully and re-evaluated whenever necessary. The occurrence of further relapses, confirmed disability progression or MRI evidence of persistent or aggravated disease activity would be regarded as evidence for an inadequate treatment response. However, limitations of clinical scores in faithfully reflecting disease activity at all times, as well as uncertainties about the discriminatory capacity of surrogate measures such as MRI, need to be clarified before clear-cut recommendations on treatment failure can be advocated. Escalation therapy is reserved for patients presenting with 'aggressive disease', which can be operationally defined as the occurrence of two severe relapses within twelve months, together with either MRI evidence for persistent disease activity or a two-point progression of disability on the EDSS.
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