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


Therapeutics

Interferon-β1a reduced relapses at 2 years in relapsing-remitting multiple sclerosis

ACP J Club. 1999 May-June;130:68. doi:10.7326/ACPJC-1999-130-3-068

Related Content in this Issue
• Companion Abstract and Commentary: Interferon-beta1b reduced the progression of secondary progressive multiple sclerosis


Source Citation

PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998 Nov 7; 352:1498-504.


Abstract

Question

In patients with relapsing-remitting multiple sclerosis (MS), does interferon-β1a reduce the rate and severity of relapse?

Design

Randomized, double-blind, placebo-controlled trial with 2-year follow-up (Prevention of Relapses and Disability by Interferon β1a Subcutaneously in Multiple Sclerosis [PRISM] Study Group).

Setting

22 centers in Europe, Australia, and North America.

Patients

560 patients (median age 35 y, 69% women, mean duration of MS 5.3 y) with clinically definite or laboratory-supported definite MS (Kurtzke Expanded Disability Status Scale [EDSS] scores 0 to 5.0) who had had ≥ 2 relapses in the previous 2 years. Exclusion criteria were previous systemic treatment with interferons or other immunomodulatory or immunosuppressive treatments. Follow-up was 95%.

Intervention

Patients were assigned to subcutaneous interferon-β1a (Rebif), 6 million IU (22 µg) 3 times/wk (n = 189) or 12 million IU (44 µg) 3 times/wk (n = 184), or placebo (n = 187).

Main outcome measures

Frequency and severity of relapse; progression in disability; and changes in magnetic resonance imaging (MRI), disease activity, and disease burden.

Main results

90% of patients completed treatment. Patients in the interferon groups had fewer relapses, moderate or severe relapses, steroid courses, and hospital admissions for MS and had less increase in disability measured by EDSS score changes than did patients who received placebo (Table). MRI measures of disease burden and activity were lower in treated patients. In patients with entry EDSS scores > 3.5, time to sustained progression was longer only in the high-dose group.

Conclusion

Patients with relapsing-remitting multiple sclerosis who received interferon-β1a had fewer relapses, fewer moderate or severe relapses, less change in EDSS scores, and less worsening on MRI than patients who received placebo.

Source of funding: Ares-Serono International SA.

For correspondence: Dr. G.C. Ebers, London Health Sciences Centre, Division of Neurology, 339 Windermere Road, London, Ontario N6A 5A5, Canada. FAX 519-663-3744.


Table. Mean values per patient for low- and high-dose interferon-β1a vs placebo for relapsing-remitting multiple sclerosis (MS) at 2 years

Variable Low-dose interferon High-dose interferon Placebo
All relapse 1.82 1.73 2.56
Moderate or severe relapses 0.71 0.62 0.99
Steroid courses 0.97 0.75 1.39
Hospitalizations for MS 0.38* 0.25 0.48
Changes in EDSS† 0.23 0.24 0.48

*Not significant.
†EDSS = Expanded Disability Status Score.


Commentary

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


References

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.