Current issues of ACP Journal Club are published in Annals of Internal Medicine


Interferon-β1b reduced the progression of secondary progressive multiple sclerosis

ACP J Club. 1999 May-June;130:69. doi:10.7326/ACPJC-1999-130-3-069

Related Content in this Issue
• Companion Abstract and Commentary: Interferon-b1a reduced relapses at 2 years in relapsing-remitting multiple sclerosis

Source Citation

European Study Group on Interferon β-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet. 1998 Nov 7;352:1491-7.



In patients with secondary progressive multiple sclerosis (MS), does interferon-β1b delay the 3-year progression of MS?


Randomized, double-blind, placebo-controlled trial.


32 European centers.


768 outpatients were screened, and 718 were studied (mean age 41 y, 61% women, mean duration of disease 13 y). Inclusion criteria were clinically or laboratory-confirmed MS that was considered to be secondary progressive (a period of deterioration, independent of relapses, sustained for ≥ 6 mo after a period of relapsing-remitting MS), age 18 to 55 years, baseline Kurtzke Expanded Disability Status Scale (EDSS) score 3.0 to 6.5, and a history of ≥ 2 relapses or an increase in ≥ 1 point on the EDSS in the previous 2 years. Patients were excluded if they had recently used immunosuppressive or immunomodulatory treatment or other putative agents for MS. Steroids could be used for relapses. Follow-up was 92%.


360 patients were allocated to subcutaneous interferon, 4 million IU every other day for 2 weeks and then 8 million IU every other day for 33 months. 358 patients were allocated to placebo.

Main outcome measures

Time to confirmed progression of disability that was sustained for ≥ 3 months (≥ 1.0 point on the EDSS scale for patients with a baseline score of < 6.0 or a 0.5-point increase for patients with a baseline score of 6.0 or 6.5).

Main results

270 patients in the interferon group and 261 in the placebo group completed treatment. Fewer patients had confirmed progression during follow-up (P < 0.001) (Table) and the time to progression was longer in the interferon group than in the placebo group (median 644 vs 403 d, P < 0.001). The effect was independent of baseline EDSS scores and occurrence of relapses in the 2 years before or during the study. Patients in the interferon group also had longer time to and less chance of becoming wheelchair bound (P = 0.01), less change in EDSS scores (P = 0.03), fewer relapses (P < 0.001), fewer moderate or severe relapses (44% vs 54%, P = 0.008), less steroid use (54% vs 68%, P < 0.001), fewer hospital days (P = 0.04), and more adverse effects (13 measures).


Patients with secondary progressive MS were less likely to have disease progression with interferon-β1b.

Source of funding: Schering AG, Berlin.

For correspondence: Professor L. Kappos, Department of Neurology, University Hospital Basel, Kantonsspital, Petersgraben 4, CH-4031 Basel, Switzerland.

Table. Interferon-β1b vs placebo in secondary progressive multiple sclerosis*

Outcome at 33 mo Interferon-β1b Placebo RRR (95% CI) NNT (CI)
Progression 39.1% 49.7% 21.3% (7.2 to 33.5) 9 (6 to 30)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


These 2 studies will likely be landmarks in the history of MS treatment trials: The PRISMS study establishes the importance of β-interferon dose in treatment efficacy, and the European Study Group trial is the first to show the effectiveness of β-interferon in secondary progressive MS.

The PRISMS study convincingly shows that β-interferons reduce relapse frequency and severity and slow disability progression and worsening on MRI in relapsing-remitting MS. Given the data from these studies and 2 other large clinical trials (1, 2), no doubt remains that these drugs work in MS. The clinical effects are modest but consistent, and the beneficial MRI effects are typically greater in magnitude.

An interesting aspect of the PRISMS study relates to the importance of interferon-β1a dose on participants with higher disability (EDSS scores > 3.5) at baseline. Time-to-disability progression was longer in patients in the higher disability group who received the higher dose. The number of active T2 lesions on MRI was also lower in the higher-disability, high-dose subgroup of patients. The usual precautions about subgroup analysis apply here, but patients with higher levels of disability may benefit from higher doses of interferon.

Neurologists have 3 available and effective treatments for relapsing-remitting MS: interferon-β1a, which comes in 2 different brands (Avonex or Rebif); interferon-β1b (Betaseron); and copolymer-1 (Copaxone). No simple answer on prescribing is available. Besides considering information on relapse frequency, disability changes, and MRI changes, physicians and their patients must consider frequency and route of drug administration, drug dose, side effects, safety, and cost. Patient disability level at entry may be another important consideration; more disabled patients may benefit from higher doses of β-interferons.

The European Study Group trial has convincingly shown that the drug can modestly decrease disability development in secondary progressive MS. Over 2 to 3 years, the proportion of treated patients who had sustained worsening of disability was lower by about 21% than patients who received placebo, and the median time to progression increased from 403 to 644 days. Interferon-β1b also reduced relapse frequency and severity and had favorable effects on MRI. The authors were careful to include patients who were progressing and were able to show that the treatment effect on progression was similar regardless of baseline EDSS scores or relapses.

Clinical trialists should note 2 strategies that helped a clinically modest effect attain a high degree of statistical significance: a large sample size for a 2-arm study and the practice of sending examiners off to “EDSS school” so that the neurologic end point determination would be standardized and less prone to variability.

This study does not resolve the controversy over the importance of antibody development with β-interferon. Neutralizing antibodies were seen in 28% of treated patients, usually in the first 6 months of therapy. Many of these patients, however, subsequently had ≥ 1 negative antibody test results. Oddly, patients who were antibody positive tended to lose the beneficial therapeutic effect of Betaseron on relapse rate, but no change in disability was seen over time. It seems fair to say that although antibody development may not be bad, it is unlikely to be good.

The ideal dose of interferon-β1b also remains to be identified. The upcoming results of the North America Betaseron Secondary-Progressive MS trial may provide this information. We can also look forward to data from the Rebif Secondary-Progressive MS trial (Europe and Canada) and the Avonex Secondary-Progressive MS trial (North America). The long-term efficacy of these drugs will not be assessed by these short-term clinical trials. But for patients struggling with secondary progressive MS, these studies provide reason for hope.

Paul O'Connor, MD, MSc
St. Michael's Hospital
Toronto, Ontario, Canada


1. Jacobs LD, Cookfair DL, Rudick RA, et al. Ann Neurol. 1996;39:285-94. Erratum. Ann Neurol. 1996;40:480.

2. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1995; 45:1277-85.