Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Abstract

Objective: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study.

Methods: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort).

Results: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance.

Conclusions: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS.

Classification of evidence: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

Figure 1. Patient flow

Final intent-to-treat population of patients who were enrolled in the MRI cohort and then randomized and received at least 1 dose of study treatment was n = 681. AE = adverse event; DMF = delayed-release dimethyl fumarate (also known as gastro-resistant DMF); GA = glatiramer acetate; MS = multiple sclerosis; QD = once daily; SC = subcutaneous.

Figure 2. Lesion number (A–C) and volume (D–F) of T2 lesions, T1-hypointense lesions, and Gd+ lesions over time

Patient numbers refer to those who provided data both at baseline and at each scheduled MRI analysis. Relative reductions (vs placebo) in the risk of having a greater number of gadolinium-enhancing (Gd+) lesions were based on the odds ratio from the prespecified analysis model of ordinal logistic regression (a conservative method, chosen to minimize undue influence of outlier Gd+ lesion counts on the estimated treatment effect), for categories of patients with 0, 1, 2, 3–4, and ≥5 lesions. Comparisons vs placebo were based on ^anegative binomial regression, adjusted for region and baseline lesion volume; ^bordinal regression, adjusted for region and baseline lesion number; and ^canalysis of covariance on ranked data, adjusted for region and baseline lesion volume. ^dThe comparison vs placebo of mean Gd+ lesion volume at postbaseline timepoints was a post hoc analysis (change from baseline was the prespecified analysis). ^ep < 0.0001; ^fp < 0.01; ^gp < 0.05; ^hp < 0.001 for comparison vs placebo. CI = confidence interval; DMF = delayed-release dimethyl fumarate (also known as gastro-resistant DMF); GA = glatiramer acetate.

Figure 3. Effect of treatment on brain atrophy

Measured using the structural image evaluation, using normalization, of atrophy method. *DMF = delayed-release DMF (also known as gastro-resistant DMF); GA = glatiramer acetate.