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

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA, MS Care of Connecticut, One Towne Park Plaza, Norwich, CT 06360, USA

B Weinstock-Guttman

Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA

J A Cohen

Department of Neurology, Cleveland Clinic, Cleveland, OH, USA

X Wei

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA, Department of Radiology, Seaman Family MR Research Centre, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada

C Gutmann

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

R Bakshi

Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA, Partners MS Center, One Brookline Place, Brookline, MA 02445, USA

M Olek

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA, Multiple Sclerosis Center, Gottschalk Medical Plaza, University of California at Irvine, Irvine, CA 92697, USA

L Stone

Department of Neurology, Cleveland Clinic, Cleveland, OH, USA

S Greenberg

Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA, Johnson & Johnson, Inc., One Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA

D Stuart

Peachtree Neurologic Clinic, Atlanta, GA, USA

J Orav

Department of Epidemiology, Brigham and Women’s Hospital, Boston, MA, USA

W Stuart

Peachtree Neurologic Clinic, Atlanta, GA, USA, MS Center of Atlanta, Atlanta, GA, USA

H Weiner

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA, Department of Radiology, Seaman Family MR Research Centre, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada

Objective: To evaluate the efficacy and safety of combination therapy with pulse cyclophosphamide given with methylprednisolone (MP) and interferon beta (IFNß)-1a in multiple sclerosis (MS) patients with active disease during IFNß monotherapy. Methods: This was a randomized, single-blind, parallel-group, multicenter trial in MS patients with a history of active disease during IFNß treatment. Patients were randomized to either cyclophosphamide 800 mg/m² plus methylprednisolone 1 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 1 g IV at screening and 30 mcg IFNß-1a 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 IFNß-1a decreased the number of Gd+ lesions and slowed clinical activity in patients with previously active disease on IFNß alone.

Key Words: brain atrophy • breakthrough disease • combination therapy • cyclophosphamide • cytotoxic agents • eosinophilia • eosinophils • glucocorticoids • IFNß • IL-4 • methylprednisolone • mitoxantrone • MRI • MS • natalizumab=antegren=tysabri • randomized clinical trial • RRMS • treatment failure

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