Interferon β-1b reduced exacerbations in multiple sclerosis at 2 years
ACP J Club. 1993 Sept-Oct;119:33. doi:10.7326/ACPJC-1993-119-2-033
The IFNB Multiple Sclerosis Study Group. Interferon beta-bis effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993 Apr;43:655-61.
To compare the efficacy and safety of 2 doses of interferon β-1b (IFNB) with placebo for reducing exacerbations in patients with relapsing-remitting multiple sclerosis (MS).
Randomized, double-blind, placebo-controlled trial with 2-year follow up.
11 medical centers in the United States and Canada.
372 patients (mean age 36 y, mean duration of disease 4.4 y, 70% women) with clinically definite or laboratory-supported definite MS. Patients were ambulatory, with Kurtzke Expanded Disability Status Scale (EDSS) scores ≥ 2 acute exacerbations in the previous 2 years; were clinically stable for at least 30 days before entry; had not received adrenocorticotropic hormone or prednisone in the previous 30 days; and had never taken azathioprine or cyclophosphamide.
125 patients received 1.6 million international units (MIU) of IFNB; 124 received 8 MIU of IFNB; and 123 received placebo, all self-administered subcutaneously every other day.
Main outcome measures
Primary end points were annual rate of exacerbations and proportion of exacerbation-free patients. Exacerbations were defined as the appearance or worsening of MS symptoms that were accompanied by a new neurologic abnormality (existing for ≥ 24 h without fever) and were preceded by stability or improvement in the previous 30 days. Secondary end points were time to first exacerbation; duration and severity of exacerbations; changes in EDSS scores; and disease burden and activity as measured by magnetic resonance imaging (MRI).
After 2 years, patients in the placebo group had more exacerbations than those in the 1.6-MIU or 8-MIU groups (1.27, 1.17, 0.84/y, respectively; P < 0.01 for both comparisons with placebo); a higher rate of moderate and severe exacerbations (0.45, 0.32, and 0.23/y, P = 0.007); fewer exacerbation-free patients in the high-dose group, (18, 23, and 36; P = 0.007) (Table); a shortened median time to exacerbation (153, 180, and 295 d; P < 0.05); and a greater mean lesion area (20% increase, 11% increase, and 0.1% decrease, respectively). The groups did not differ for changes in EDSS scores. The dropout rates were similar; more patients taking placebo withdrew because of lack of efficacy, and more patients taking IFNB withdrew because of toxicity.
Interferon β-1b was well tolerated and reduced the rate and severity of exacerbations in patients with relapsing-remitting multiple sclerosis who were followed for 2 years.
Source of funding: In part, Berlex Laboratories (Interferon β-1b).
For article reprint: Dr. W.A. Sibley, University Hospital, Tucson, AZ 85724, USA. FAX 520-626-2111.
Table. Interferon β-1b (1.6 and 8) vs placebo to reduce exacerbations in patients with multiple sclerosis
|Outcomes at 2 years||Interferon dose||Interferon β-1b||Placebo||RBI (95% CI)||NNT (CI)|
|Exacerbation free||1.6 MIU||30.7%||16.1%||29% (-26 to 124)||Not significant|
|Exacerbation free||8 MIU||31.3%||16.1%||95% (19 to 222)||7 (4 to 24)|
*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.
The IFNB Multiple Sclerosis Study Group reports the first convincing evidence of an intervention that alters the natural history of relapsing-remitting MS. The consortium, consisting of 11 medical centers from the United States and Canada, used a double-blind, placebo-controlled trial to show that IFNB reduced several important primary and secondary disease end points, including MRI evidence of plaque burden and severity and frequency of MS exacerbations.
The conduct of the trial was as good as any previous trial in this field. No baseline group differences existed that could have confounded the results. The dropout rate for patients in the placebo group (23 of 123) was similar to that in the 2 treatment groups. A total of 65 patients discontinued treatment in the first 2 years of the 3-year study, and 122 did not complete 3 years. The incidence of severe side effects from IFNB was low. The proposed mechanism of action for IFNB makes biological sense (e.g., IFNB antagonizes the action of interferon gamma that seems to increase attacks) and makes epidemiologic sense (e.g., IFNB may alter the association between viral infections and MS exacerbations). Unfortunately, data about the frequency of viral infections were not reported. Despite its high dropout rate and omission of the viral infection rate, this trial, has undoubtedly produced the most promising data to emerge about MS therapy and is sure to become a benchmark for future research on specific immunomodulatory agents for the treatment of relapsing-remitting MS. Because the clinical improvement from IFNB was modest, the authors correctly urge further research.
John R. Absher, MD
Bowman Gray School of Medicine Winston-Salem, North Carolina, USA