Multiple Sclerosis Express ReportTM
Based on Data Presented October 6–9, 2004 / Vienna, Austria


Updates from the 20th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)


The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) has become one of the largest annual gatherings of professionals in the field of multiple sclerosis (MS). At this year's Congress, more than 600 presentations added insight to the pathogenesis and optimal treatment options for patients with MS. According to data presented at a late-breaking news session, more frequent, higher dosing of interferon beta-1b (Betaferon) every other day was not clinically superior to, but rather comparable to, weekly dosing of interferon beta-1a (Rebif) in preventing relapses and delaying disease progression in patients with MS.1 The frequency of interferon beta dosing and its effect on efficacy continues to be a topic of much debate. This new information lends support to the contention that different interferon beta agents are therapeutically comparable.

For patients with MS who exhibit continuing disease activity in spite of optimal treatment with disease-modifying agents, combination therapy offers a promising alternative. Investigators from the MS Center of Atlanta reported on their experience using intramuscular interferon beta-1a (Avonex) in combination with cyclophosphamide, mycophenolate mofetil, or intravenous methylprednisolone for the treatment of breakthrough disease.2 All combination regimens were safe and effective in stabilizing disease activity.

High-dose versus Low-dose Interferon Beta Therapy

Comparison of interferon beta-1a 22 mcg once a week and interferon beta-1b 250 mcg every other day in a randomized head-to-head study.

Nils Koch-Henriksen, MD, Department of Neurology, Aalborg Hospital North, Aalborg, Denmark

A national, multicenter, randomized, open-label, head-to-head comparison study evaluated the efficacy of high-dose subcutaneous Betaferon 250 mcg every other day against that of low-dose subcutaneous Rebif 22 mcg administered once a week.1 A total of 303 patients with MS who initiated treatment with disease-modifying therapies between June 1996 and November 1999 were enrolled in the study. Inclusion criteria required patients to have at least 2 relapses within the previous 2 years and an Expanded Disability Status Scale (EDSS) score ≤5.5. The primary endpoint of the study was annual relapse rate.

Patients were randomized to receive either subcutaneous Rebif 22 mcg once a week (n = 143) or subcutaneous Betaferon 250 mcg every other day (n = 160) for 24 months. For those patients who declined randomization (n = 130), subcutaneous Betaferon 250 mcg every other day was offered. All patients were subjected to clinical evaluation every 3 months during the 24-month study. Baseline characteristics were similar for all patients.

The results of the study revealed similar outcomes between the 2 randomized treatment arms with respect to annual relapse rates, annual rate of steroid-treated relapses, and mean time to first relapse after the initiation of treatment (Table 1). Interestingly, non-randomized patients who received subcutaneous Betaferon 250 mcg every other day exhibited worse outcomes.

According to lead author Nils Koch-Henriksen, MD, Department of Neurology, Aalborg Hospital North, Aalborg, Denmark, the mean EDSS scores remained essentially unchanged for patients randomized to treatment. In contrast, non-randomized patients had a slight but non-significant increase in EDSS, from 3.0 to 3.5 over 2 years, reported Dr. Koch-Henriksen.

A subset of 96 patients underwent an evaluator-blinded magnetic resonance imaging (MRI) with gadolinium contrast assessment at the initiation of the study with at least one additional MRI at 12 or 24 months. Non-randomized patients were not included in the MRI analyses. During the first 12 months of the study, the increase in total T2 lesion area in Rebif-treated patients was 52% (+414 mm2) compared with 12% (+24 mm2) in Betaferon-treated patients (P = .099). From 12 to 24 months, the respective increases were 10% (+292 mm2) and 4% (+18 mm2) (P = .078). Similarly, the mean number of gadolinium-enhancing lesions was noted to be greater in Rebif-treated patients at 24 months (P = .09).

MRI findings revealed a non-significant trend favoring Betaferon. However, Robert J. Fox, MD, Medical Director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic Foundation, Cleveland, Ohio, pointed out during the discussion period that the higher pre-study disease activity among Rebif patients as measured by baseline MRI may have influenced this finding.

Higher Dosing Was Not Clinically Superior

Investigators concluded that subcutaneous Betaferon 250 mcg every other day was not clinically superior to, but rather, was comparable to subcutaneous Rebif 22 mcg once a week with respect to standard clinical endpoints, despite very different dosage regimens.

Dr. Koch-Henriksen stated, "Betaferon 250 mcg every other day was far from superior to Rebif once weekly in this study in terms of relapse rate, time to first relapse, rate of sustained progression, or time to sustained progression."

The investigators noted that their results did not confirm those from a small number of other comparison studies in which a higher dose and more frequent administration of interferon beta seemed to be more effective in reducing the occurrence of clinical endpoints.3–5

Addressing these differences, Dr. Koch-Henriksen discussed the possibility that the non-blinded study design may have influenced the results. "The investigators and the patients may have anticipated that low-dose Rebif should be as good as [conventional] Betaferon, because it is more convenient and less expensive," suggested Dr. Koch-Henriksen.

"But, if there is a bias due to lack of blinding, then it is peculiar and unlikely that we would arrive at a completely even distribution between the two randomized treatment arms," proffered Dr. Koch-Henriksen. "There is not just a 'tendency', but there is an exact and even distribution of the attack rate and other outcomes between the randomized treatment arms. It is difficult to explain why a bias in the study would result in this finding."

Dr. Fox explained that the more likely bias, if one existed, would be that "more is better." Elaborating, Dr. Fox stated, "Even if there is the potential for bias, the study found no differences between the agents. This is another study that suggests therapeutic similarity between weekly versus three-times-weekly dosing."

The findings from the study also suggest that the clinical behavior of MS patients included in randomized studies may be different from those treated in routine clinical practice [non-randomized patients], even though pretreatment parameters are comparable. The most reliable data can be expected from studies that are randomized, blinded, head-to-head comparisons, and this design should be the standard according to study investigators.

Advances in Treating Breakthrough Disease

Treatment of disease progression in relapsing multiple sclerosis (RMS) with combination therapy of interferon (IFN) beta-1a (Avonex) plus pulse steroids, cyclophosphamide, and/or mycophenolate mofetil.

William H. Stuart, MD, Medical Director, MS Center of Atlanta, Atlanta, Georgia

The heterogeneous nature of relapsing MS suggests that the best treatment approach for breakthrough disease may be to use a combination of agents. A large study conducted by William H. Stuart, MD, Medical Director, MS Center of Atlanta, Atlanta, Georgia, evaluated the safety and efficacy of several agents in combination with Avonex in treating MS patients with breakthrough disease.2 The retrospective chart review analyzed data from approximately 1,300 patients treated at the MS Center of Atlanta.

Patients were eligible for study inclusion if they had a diagnosis of clinically definite MS, had been treated with Avonex for at least 12 months before initiating a combination approach for breakthrough disease, had been on a combination therapy for breakthrough disease, and their medical records contained data on relapses, EDSS scores, MRI scans, laboratory values, and adverse events for ≥12 months prior to, and 12 months after, initiation of combination therapy. A total of 46 patients were evaluable for the study with a mean age of 47.2 years and duration of disease ranging from 3 to 9 years.

Patients received 1 of 3 add-on therapies:

•Pulse steroids only (intravenous methylprednisolone given either as 1 g once a month, or in a repeating pattern 1 g/day for 3 consecutive days for 1 month [3 grams total], followed by 1 g once a month for 2 months).

•Cyclophosphamide (given as 80% of 0.8 g/m2 titrated to 0.8 g/m2 to an absolute neutrophil count between 1000-3000/mm3, also 1 g of methylprednisolone was given as part of the cyclophosphamide protocol).

•Mycophenolate mofetil (1 g/day).

"All the treatment regimens were effective in suppressing disease activity," explained Jeffrey B. English, MD, Associate Director of Research, MS Center of Atlanta, Atlanta, Georgia, who presented the study results. "Each had essentially the same effect on decreasing the relapse rate. Any of these agents can be safely and effectively added to Avonex," advised Dr. English, noting further that the study was not powered to determine the superiority of any one treatment regimen over another.

The annualized relapse rate was significantly reduced with all combination regimens (Table 2). EDSS scores and disease activity on MRI scans remained stable during treatment with all combination regimens. The mean change in T2 lesion load was -0.4, 0.2, and 0.0, for combination therapy with mycophenolate mofetil, cyclophosphamide, and combined corticosteroids, respectively. In addition, a substantial, though not statistically significant, decrease in the number of gadolinium-enhancing lesions with combination treatment was observed. Relatively few adverse events were observed.

Because all the treatment approaches proved safe and effective, Dr. English explained that he generally selects a regimen by "escalating therapy" – using corticosteroids as a first-line treatment option in patients with milder forms of breakthrough disease, cyclophosphamide for rapid disease progression, and mycophenolate mofetil for disease activity that falls between these extremes. Dr. English also stated that he tends to treat younger, more active adults more aggressively. Patients are periodically monitored for adverse events and reassessed clinically after 1 year of combination treatment.


1. Koch-Henriksen N, Sorensen P, Christensen T. Comparison of interferon-beta-1a 22 mcg once a week and interferon-beta-1b 250 mcg every other day in a randomized head-to-head study. Mult Scler. 2004;10(suppl 2):S240. Abstract P576.
2. Stuart WH, English JB, Court D. Treatment of disease progression in relapsing multiple sclerosis (RMS) with combination therapy of interferon (IFN) beta-1a (Avonex) plus pulse steroids, cyclophosphamide, and/or mycophenolate mofetil. Mult Scler. 2004;10(suppl 2):S265. Abstract P666.
3. The Once Weekly Interferon for MS Study Group. Evidence for interferon beta-1a dose response in relapsing MS: the OWIMS study. Neurology. 1999;53:679-686.
4. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology. 2002;2:1496-1506.
5. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1b for multiple sclerosis: results of a 2-year prospective randomized multicenter study (INCOMIN). Lancet. 2002;359:1453-1460.

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