J. Theodore Phillips, Krzysztof Selmaj, Ralf Gold, Robert J. Fox, Eva Havrdova, Gavin Giovannoni, Heather Abourjaily, Amy Pace, Mark Novas, Christophe Hotermans, Vissia Viglietta, and Leslie Meltzer (2015) Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate. International Journal of MS Care: September/October 2015, Vol. 17, No. 5, pp. 236-243.
From the Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
Correspondence: J. Theodore Phillips, MD, PhD, Multiple Sclerosis Program, Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204; e-mail: j.theod.phillips@gmail.com.
Background: In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0−3) with the recommended DMF dosage (240 mg twice daily).
Methods: Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks.
Results: The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation.
Conclusions: This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.
When choosing among treatments for relapsing-remitting multiple sclerosis (MS), health-care providers and patients must weigh factors such as efficacy, safety, tolerability, and convenience. Newer therapeutics are attractive owing to their convenience, but the current lack of long-term experience with these agents may limit their use compared with traditional agents with well-established safety and tolerability profiles.
Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is one of the newest oral therapeutics. In the phase 3 DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS)1 and CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis)2 trials, DMF 240 mg twice daily and three times daily demonstrated efficacy on clinical and neuroradiologic measures across diverse subgroups of patients.3,4 The most common adverse events associated with DMF treatment were flushing and gastrointestinal (GI) events, including abdominal pain, nausea, vomiting, and diarrhea. Other safety signals of note included decreases in mean white blood cell and lymphocyte counts and transient elevations in mean liver enzyme levels. There was no overall increased risk of infections, serious infections, opportunistic infections, or malignancies in DMF-treated patients.
Flushing and GI events are likely to be of concern when considering treatment with DMF. To further investigate the incidence, severity, duration, management, and outcome of these events as recorded by investigators at monthly clinic visits, a post hoc analysis of integrated data from DEFINE and CONFIRM was conducted. The analysis focused on the initial treatment period (months 0−3) with the recommended dosing regimen of DMF (240 mg twice daily).
Materials and Methods
Patients and Study DesignMethodological details of the phase 3 DEFINE (NCT00420212) and CONFIRM (NCT00451451) studies have been described previously.1,2 Briefly, eligible patients were aged 18 to 55 years, had a diagnosis of relapsing-remitting MS per the McDonald criteria5 and an Expanded Disability Status Scale (EDSS) score6 of 0 to 5.0, and had either 1 or more clinically documented relapses within 1 year before randomization and a previous cranial magnetic resonance image showing lesions consistent with MS or a brain magnetic resonance image obtained within 6 weeks before randomization showing at least one gadolinium-enhancing lesion.
DEFINE and CONFIRM were 2-year, multicenter, randomized, double-blind, placebo-controlled clinical trials. In DEFINE, patients were randomized 1:1:1 to receive placebo, DMF 240 mg twice daily, or DMF 240 mg three times daily (408, 410, and 416 patients, respectively, in the safety population, defined as patients who received at least one dose of study treatment) for up to 96 weeks. In CONFIRM, patients were randomized 1:1:1:1 to receive treatment with placebo, DMF 240 mg twice or three times daily, or glatiramer acetate (a reference comparator; safety population = 363, 359, 344, and 351 patients, respectively) for up to 96 weeks.
All patients provided written informed consent. The studies were approved by central and local ethics committees and were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice 7 and the Declaration of Helsinki.8
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