A randomized blinded trial of combination therapy with cyclophosphamide in patients with active multiple sclerosis on interferon beta

Objective: To evaluate the efficacy and safety of combination therapy with pulse cyclophosphamide given with methylprednisolone (MP) and interferon beta (IFNβ)-Ia in multiple sclerosis (MS) patients with active disease during IFNβ monotherapy. Methods: This was a randomized, single-blind, parallel group, multicenter trial in MS patients with a history of active disease during IFNβ treatment. Patients were randomized to either cyclophosphamide 800 mg/m² plus methylprednisolone I g IV (CY/MP) or methylprednisolone once a month for six months and then followed for an additional 18 months. All patients received three days of methylprednisolone I g IV at screening and 30 mcg IFNβ-Ia IM weekly for the entire 24 months. The primary endpoint was change from baseline in the mean number of gadolinium-enhancing (Gd+) lesions. Secondary clinical endpoints included time to treatment failure. Results: Fifty-nine patients were randomized to treatment: 30 to CY/MP and 29 to MP. Change from baseline in the number of Gd+ lesions was significantly different between treatment groups at three (P = 0.01), six (P = 0.04) and 12 months (P = 0.02), with fewer lesions in the CY/MP group. The cumulative rate of treatment failure was significantly lower in the CY/MP group compared with the MP group (rate ratio = 0.30; 95% confidence interval, 0.12-0.75, P = 0.011). CY/MP treatment was well tolerated. Conclusion: Combination therapy with CY/MP and IFNβ-Ia decreased the number of Gd+ lesions and slowed clinical activity in patients with previously active disease on IFNβ alone.