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An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis

From the Division of Neurology (D.B.S.), Duke University Medical Center, Durham, NC; University Division of Neuroscience (I.K.H.), The Walton Centre for Neurology and Neurosurgery, Liverpool, UK; Department of Neuromuscular Diseases (R.M.), "Carlo Besta" Neurological Institute Foundation, Milan, Italy; Aspreva Pharmaceuticals Inc. (S.S.S.), Basking Ridge, NJ; Division of Neurology/Department of Medicine (Z.A.S.), University of Alberta, Edmonton, AB, Canada; Department of Neurology (M.H.V.D.B.), Academical Hospital, Maastricht, The Netherlands; Neurologische Universitatsklinik (A.M.), Eberhard-Karls-Universitat, Tubingen, Germany; University Hospital LHSC (M.W.N.), University of Western Ontario, London, ON, Canada; Aspreva Pharmaceuticals Corp. (N.S.), Victoria, BC, Canada; and Department of Neurology and the Center for Neuroscience (D.P.R.), University of California, Davis.

Address correspondence and reprint requests to Dr. Donald B. Sanders, Box 3403, Duke University Medical Center, Duke University, Durham, NC 27710 Donald.Sanders{at}Duke.edu

Background: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG).

Methods: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety.

Results: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%).

Conclusions: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Abbreviations: AChR = acetylcholine receptor; AUC = area under the time/dose curve; ITT = intention-to-treat; MG = myasthenia gravis; MG-ADL = MG Activities of Daily Living; MGFA = MG Foundation of America; MM = minimal manifestations; MMF = mycophenolate mofetil; PR = pharmacologic remission; QMGS = quantitative MG score; QoL = quality of life; SF-36 = Short-Form 36.

Supplemental data at www.neurology.org

Editorial, page 390

See also page 394

e-Pub ahead of print on April 23, 2008, at www.neurology.org.

Sponsored by F Hoffmann-La Roche Ltd./Inc./AG as part of the Aspreva Pharmaceuticals Corp. Rare Disease Program.

Disclosures: Dr. Sanders has received consultation fees from Sanofi-Aventis and Accordant Health Services. He is on the speaker’s program for Athena Diagnostics and has received research support through his institution from Roche Laboratories and Aspreva Pharmaceuticals. Drs. De Baets and Hart have received grants from F Hoffmann-La Roche Ltd./Inc./AG as part of the Aspreva Pharmaceuticals Corp. Rare Disease Program. Drs. Mantegazza, Melms, and Richman have received honoraria from F Hoffmann-La Roche Ltd./Inc./AG as part of the Aspreva Pharmaceuticals Corp. Rare Disease Program. Drs. Shukla and Solomons are employees of Aspreva Pharmaceuticals. Drs. Nicolle and Siddiqi have nothing to disclose.

Received July 27, 2007. Accepted in final form January 7, 2008.

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