Effects of delayed-release dimethyl fumarate on MRI measures in the Phase 3 DEFINE study

Abstract

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing–remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-014-7412-x) contains supplementary material, which is available to authorized users.

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

“…Reductions in brain atrophy with dimethyl fumarate (DMF) in comparison to placebo did not reach statistical significance in the CONFIRM study [103], while in the DEFINE study a relative reduction in the progression of brain atrophy from baseline to year 2 (21% reduction; p = 0.0449) and from month 6 to year 2 (30% reduction; p = 0.0214) was observed and was statistically significant [104].…”

Treating relapsing–remitting multiple sclerosis: therapy effects on brain atrophy

“…Results of brain atrophy for both phase III clinical trials with dimethyl-fumarate have been recently published [31,32]. In the DEFINE clinical trial, comparing dimethyl-fumarate versus placebo in RRMS, and using the 6-month MRI as baseline for BV estimation, dimethyl-fumarate administered twice a day (BID) significantly reduced BV loss as compared to placebo; surprisingly, results for the three times a day (TID) posology on brain atrophy resulted negative [31].…”

“…In the DEFINE clinical trial, comparing dimethyl-fumarate versus placebo in RRMS, and using the 6-month MRI as baseline for BV estimation, dimethyl-fumarate administered twice a day (BID) significantly reduced BV loss as compared to placebo; surprisingly, results for the three times a day (TID) posology on brain atrophy resulted negative [31]. In the CONFIRM trial, BV loss was analysed at different time-points: from baseline to the end of the trial (2 years), from baseline to year 1 and from year 1 to year 2.…”

Whole‐brain atrophy assessed by proportional‐ versus registration‐based pipelines from 3TMRIin multiple sclerosis

“…Investigators have applied a myriad of published proprietary and open‐source methods to quantify brain volume loss (Giorgio, Battaglini, Smith, & De Stefano, 2008), leading to heterogeneous segmentation procedures across sites and studies, without any agreed‐upon standard approach (Bermel & Bakshi, 2006). This heterogeneity is brought to the surface by the regular incorporation of whole‐brain atrophy as a supportive outcome measure in Phase III MS therapeutic clinical trials, in which registration‐based {affine‐fit to an external multiple subject brain size atlas, e.g., normalized brain parenchymal volume [BPV; OPERA I/II (Hauser et al., 2017), FREEDOMS (De Stefano et al., 2016), ALLEGRO (Comi et al., 2012), DEFINE (Arnold et al., 2014)]}, or proportional‐based {scaled to the subject's own intracranial cavity, e.g., brain parenchymal fraction [BPF; CARE‐MS I/II (Arnold et al., 2016), AFFIRM (Miller et al., 2007), TEMSO (O'Connor et al., 2011)]} methods have been employed. Moreover, this challenge is amplified by the observations that the analysis of the same MRI image sets using different segmentation pipelines can produce conflicting findings (O'Connor et al., 2011; Radue et al., 2017; Rovaris, Comi, Rocca, Wolinsky, & Filippi, 2001; Sormani et al., 2004), which hamper the ability to draw firm conclusions on therapeutic effects, and may invalidate the comparison of results across trials.…”