Efficacy and Tolerability of Delayed-release Dimethyl Fumarate in Black, Hispanic, and Asian Patients with Relapsing-Remitting Multiple Sclerosis: Post Hoc Integrated Analysis of DEFINE and CONFIRM

Background: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials. Objective: To evaluate delayed-release DMF in newly diagnosed relapsing–remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM. Methods: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy. Results: The newly diagnosed population comprised 678 patients treated with placebo ( n = 223) or delayed-release DMF 240 mg BID ( n = 221) or TID ( n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% ( p < 0.0001) and 47% ( p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF. Conclusion: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

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Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM

Clinical Therapeutics ◽

10.1016/j.clinthera.2017.06.012 ◽

2017 ◽

Vol 39 (8) ◽

pp. 1671-1679 ◽

Cited By ~ 17

Author(s):

Óscar Fernández ◽

Gavin Giovannoni ◽

Robert J. Fox ◽

Ralf Gold ◽

J. Theodore Phillips ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dimethyl Fumarate ◽

Integrated Analysis ◽

Efficacy And Safety ◽

Delayed Release ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate

International Journal of MS Care ◽

10.7224/1537-2073.2014-069 ◽

2015 ◽

Vol 17 (5) ◽

pp. 236-243 ◽

Cited By ~ 30

Author(s):

J. Theodore Phillips ◽

Krzysztof Selmaj ◽

Ralf Gold ◽

Robert J. Fox ◽

Eva Havrdova ◽

...

Keyword(s):

Multiple Sclerosis ◽

Placebo Group ◽

Dimethyl Fumarate ◽

Integrated Analysis ◽

Eligibility Criteria ◽

Delayed Release ◽

Initial Treatment Period ◽

Relapsing Remitting ◽

Post Hoc ◽

Relapsing Remitting Multiple Sclerosis

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.

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