A randomized blinded trial of combination therapy with cyclophosphamide in patients with active multiple sclerosis on interferon beta DR Smith* ,1,a , B Weinstock-Guttman 4 , JA Cohen 3 , X Wei 1,b , C Gutmann 1 , R Bakshi 4,c , M Olek 1,d , L Stone 3 , S Greenberg 4,e , D Stuart 5 , J Orav 2 , W Stuart 5,f and H Weiner* ,1,b 1 Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA; 2 Department of Epidemiology, Brigham and Women’s Hospital, Boston, MA, USA; 3 Department of Neurology, Cleveland Clinic, Cleveland, OH, USA; 4 Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA; 5 Peachtree Neurologic Clinic, Atlanta, GA, USA Objective: To evaluate the efficacy and safetyof combination therapy with pulse cyclophosphamide given with methylprednisolone (MP) and interferon beta (IFNb)-1a in multiple sclerosis (MS) patients with active disease during IFNb monotherapy. Methods: This was a randomized, single-blind, parallel-group, multicenter trial in MS patients with a history of active disease during IFNb treatment. Patients were randomized to either cyclophosphamide 800 mg/m 2 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 IFNb-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 IFNb-1a decreased the number of Gd / lesions and slowed clinical activity in patients with previously active disease on IFNb alone. Multiple Sclerosis (2005) 11, 573  /582 Key words: brain atrophy; breakthrough disease; combination therapy; cyclophosphamide; cytotoxic agents; eosinophilia; eosinophils; glucocorticoids; IFNb; IL-4; methylprednisolone; mitoxantrone; MRI; MS; natalizumab  /antegren  /tysabri; randomized clinical trial; RRMS; treatment failure Introduction Multiple sclerosis (MS) is the most common cause of neurologic disability in young adults and current theory regarding its pathogenesis is that MS is a cell-mediated autoimmune disease directed against myelin components of the central nervous system. 1,2 While interferon beta (IFNb) has been shown to reduce relapse rate, disability progression and lesion burden, as measured by MRI in patients with relapsing-remitting MS (RRMS), 3  5 many patients experience active disease (i.e., breakthrough symptoms) during treatment with IFNb. Cytotoxic agents, such as mitoxantrone, 6 and cyclophosphamide, 7,8 have been used by many clinicians to treat patients who experience breakthrough disease during IFNb therapy. Cyclophosphamide has been studied as a treatment for MS for the past 30 years, 8 and is used by physicians in select cases of MS. 9 Studies suggest that cyclophospha- mide is effective in early, aggressive, inflammatory MS, 7 but not in later stages of progressive MS. 10,11 A number of open label studies have reported positive effects of pulses of IV cyclophosphamide in active MS despite immunomodulatory therapy. Gobbini et al . evaluated the response to cyclophosphamide in five patients who showed rapid clinical deterioration and persistent multi- ple gadolinium-enhanced (Gd /) lesions despite treatment with several different therapies. 12 Results showed that pulse cyclophosphamide appeared to produce a reduction in the number of Gd / lesions in all patients after one to five months of treatment. Others have found similar re- sults in small series of treatment resistant patients. 13  15 a MS Care of Connecticut, One Towne Park Plaza, Norwich, CT 06360, USA. b Department of Radiology, Seaman Family MR Research Centre, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada. c Partners MS Center, One Brookline Place, Brookline, MA 02445, USA. d Multiple Sclerosis Center, Gottschalk Medical Plaza, University of California at Irvine, Irvine, CA 92697, USA. e Johnson & Johnson, Inc., One Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA. f MS Center of Atlanta, Atlanta, GA, USA. *Correspondence: Derek Smith, MD, Director, MS Care of Conneticut, One Towne Park Plaza, Norwich, CT 06360, USA, and Howard Weiner, MD, Director, Partners MS Center, One Brookline Plaza, Suite 225, Brookline, MA 02445, USA. Received 14 October 2004; accepted 8 April 2005 Multiple Sclerosis 2005; 11: 573  /582 www.multiplesclerosisjournal.com # 2005 Edward Arnold (Publishers) Ltd 10.1191/1352458505ms1210oa