By Chris Berrie
PRAGUE, CZECH REPUBLIC -- October 18, 2007 -- Mitoxantrone induction in combination with methylprednisone prior to interferon beta (IFNbeta) treatment in patients with aggressive relapsing-remitting multiple sclerosis (RRMS) reduces the risk of developing fixed disability and increases relapse-free periods when compared with IFNbeta prior to methylprednisone.
These findings are from a multicentre, randomised, prospective, controlled, study presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The study's principal investigator, Gilles Edan, MD, and Professor of Neurology, Istitut des Neurosciences Cliniques de Rennes, Rennes, France, presented the findings on behalf of the French-Italian Mitoxantrone-Interferon-beta-1b Study Group.
Although IFNbeta-1b can reduce relapse frequencies and new lesions on magnetic resonance imaging (MRI), the magnitude of these effects remains small, providing around 30% benefit. Furthermore, in the longer term of 3 to5 years, these beneficial effects can be lost, particularly for the 35% of patients with RRMS who develop neutralizing antibodies while under IFNbeta treatment.
"Mitoxantrone has a strong, rapid and sustained impact on the inflammatory processes, but its potential toxicity limits the duration of its prescription," Dr. Edan said. Therefore, Dr. Edan and colleagues conducted a study to determine whether the use of mitoxantrone induction prior to IFNbeta-1b therapy can provide further clinical benefits.
The main inclusion criteria were age 18 to 45 years, confirmed diagnosis of MS using Poser criteria and as defined by MRI. For disease status of aggressive RRMS, there was the requirement for two or more relapses in the preceding 12 months, at least one Gd+ lesion on MRI, and an expanded disability status scale (EDSS) score of 2.5 to 5.5 (significant disability).
Exclusion criteria were pregnancy and breast feeding, nonuse of efficient contraception, previous global immunosuppression, use of other specific agents, and associated disease.
The primary endpoint was time to 1 or greater-point increase on the EDSS during the 3 years of the study. There were also secondary endpoints of relapse frequency, relapse-free patients, time to first relapse after inclusion, and safety.
Of 123 patients randomized in the study, 109 were treated and analyzed, constituting the intention-to-treat population. The study design provided randomization to one of two treatment arms after 12 months of followup.
The 55 patients in the first arm started at baseline with mitoxantrone 20 mg/month plus methylprednisone 1 g/month for the first 6 months of treatment. They then had a 3-month break from treatment (months 7-9), followed by interferon 250 mcg SC every other day from months 10 to 36.
The 54 patients in the second arm started at month 0 with methylprednisone 1 g/month in combination with IFNbeta-1b. As with group 1, methylprednisone was stopped after 6 months, while IFNbeta-1b continued for the full 36 months of the study.
Patients in the two groups had similar mean ages (33.2 vs 32.2 years, respectively) and gender distribution (male 34.6% vs 33.3%, respectively).
At baseline, the disease characteristics across treatment groups 1 and 2, respectively, were not significantly different, including duration of MS (6.6 vs 5.1 years), time from last relapse to M0 (3 vs 3 months), annual relapse rate (2.65 vs 2.83) and EDSS score (4.1 vs 3.8).
The primary endpoint was time for a 1-point increase in EDSS (acquisition of fixed disability) within the 36 months of the trial. "This time was clearly longer in the group of patients using mitoxantrone and interferon beta," Dr. Edan said, and thus, there was mitoxantrone group obtained significant benefit compared with group 2 (P =.008). As only five of the total 19 patients who acquired this fixed disability by month 36 were in group 1, this represented a significant 65% reduction in clinical worsening in the mitoxantrone-pretreated patients (P <.024).
When variations in EDSS score were analyzed from baseline to the last recorded scores during the treatment period, the mitoxantrone group saw a small but significant decrease in mean EDSS score from 4.1 to 3.6 (P <.006), whereas in the absence of mitoxantrone there was no significant change (from 3.8 to 3.7).
For the annual relapse rate under study treatment, there was again a large, 61.5%, significant benefit with the use of mitoxantrone (annual relapse rate: group 1, 0.44; group 2, 1.14; P <.003). When further analyzed as annual relapse rate during the IFNbeta-1b alone treatment, benefits for mitoxantrone were again seen compared with treatment without mitoxantrone (group 1, 0.50; group 2, 1.14; P <.007).
Patients in the mitoxantrone group also had significantly improved time to first relapse from baseline (P <.002). Similarly, there was a significant increase in the percentage of relapse-free patients in group 1 over group 2 (53% vs 26%; P =.01).
Finally, the researchers also tested mitoxantrone benefits at the patient disability levels. Although not a pre-planned analysis, this was achieved in a subgroup analysis of EDSS at baseline, divided according to an EDSS of 4.0, and demonstrated a significant benefit for both the use of mitoxantrone and an EDSS score less than 4 at baseline (P <.02).
The safety analysis showed significantly more adverse events in the mitoxantrone group compared with the group not treated with mitoxantrone. These comprised upper respiratory tract infection (45.4% vs 24.1%, respectively; P <.02), leucopenia (36.4% vs 16.7%, respectively; P <.02) and nausea (21.8% vs 7.4%, respectively; P <.02).
"However, these [adverse effects] are exactly what you might expect from adding mitoxantrone to this treatment, and there was no serious adverse effect in this study," added Dr. Edan.
Thus, he concluded, this induction treatment of mitoxantrone combined with methylprednisone provides clinical benefits for patients with aggressive RRMS that include decreases in both acquisition of fixed disability and relapse rates.
[Presentation title: Comparison of Two Therapeutic Strategies in Aggressive Relapsing-Remitting MS: Mitoxantrone as Induction for 6 Months Followed by Interferon Beta-1b Versus Interferon Beta-1b. A 3-Year Randomised Trial. Abstract 74]
