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Analysis of the delayed-release Dimethyl Fumarate phase III studies: relapses requiring intravenous steroid use and multiple-sclerosis-related hospitalizations

The purpose was to report the effects of delayed-release Dimethyl fumarate ( DMF; also known as gastro-resistant DMF ) on the number of relapses requiring intravenous ( IV ) steroids and multiple sclerosis-related hospitalizations using integrated data from the phase III DEFINE and CONFIRM studies.

DEFINE and CONFIRM were randomized, double-blind, placebo-controlled, multicenter studies that evaluated the efficacy and safety of Dimethyl fumarate over a 2-year period in patients with relapsing-remitting multiple sclerosis ( RRMS ).
Patients were randomized ( 1:1:1 ) to receive oral Dimethyl fumarate 240 mg BID or TID, placebo, or Glatiramer acetate ( CONFIRM only ). Eligible subjects ( aged 18-55 years ) had an EDSS score of 0-5.0 and experienced either greater than or equal to 1 relapse in the 12 months or had greater than or equal to 1 Gadolinium-enhanced lesion on brain MRI in the 6 weeks, before randomization.

Data DEFINE and CONFIRM were pooled and analyzed using a negative binomial regression model ( adjusted for study and region ). Data obtained after subjects switched to an alternative multiple sclerosis therapy were not included in the analysis. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis of relapses requiring IV steroids.

The study population ( intention-to-treat ) comprised 2301 patients who received either placebo ( n=771 ), Dimethyl fumarate BID ( n=769 ), or Dimethyl fumarate TID ( n=761 ).
Baseline demographic and disease characteristics were generally well balanced among treatment groups.

Throughout the 2-year studies, the total number of relapses treated with Methylprednisolone was 402, 221, and 209 in the placebo, Dimethyl fumarate BID, and Dimethyl fumarate TID groups, respectively.

A smaller proportion of patients in the Dimethyl fumarate BID ( 168 of 769 [ 21.8% ] ) and Dimethyl fumarate TID ( 151 of 761 [ 19.8% ] ) groups experienced greater than or equal to 1 relapse requiring IV steroids compared with the placebo group ( 284 of 771 [ 36.8% ] ).

The total number of multiple sclerosis-related hospitalizations over 2 years was 136, 94, and 74 in the placebo, Dimethyl fumarate BID, and Dimethyl fumarate TID groups.
A smaller proportion of patients in the Dimethyl fumarate BID ( 73 of 769 [ 9.5% ] ) and Dimethyl fumarate TID ( 57 of 761 [ 7.5% ] ) groups had greater than or equal to 1 multiple sclerosis-related hospitalization compared with the placebo group ( 104 of 771 [ 13.5% ] ).

In conclusion, Dimethyl fumarate is an effective and well tolerated therapy for relapsing-remitting multiple sclerosis.
In addition to clinical benefits, the use of Dimethyl fumarate may be associated with reduced patient burden and health economic savings, resulting from a decrease in resource utilization associated with relapses. ( Xagena )

Giovannoni G et al, Clin Ther 2015; Epub ahead of print