TY - JOUR
T1 - Safety and efficacy of dimethyl fumarate in ALS
T2 - randomised controlled study
AU - Vucic, Steve
AU - Henderson, Robert D.
AU - Mathers, Susan
AU - Needham, Merrilee
AU - Schultz, David
AU - Kiernan, Matthew C.
AU - the TEALS study group
AU - Mekhael, Linda
AU - Ryder, Julie
AU - Orden, Bronwen
AU - Menon, Parvathi
AU - Pavey, Nathan
AU - Higashihara, Mana
AU - Dharmadasa, Thanuja
AU - Huynh, William
AU - Ramsey, Eleanor
AU - Zoing, Margaret
AU - Mazumder, Srestha
AU - Thornton, Nicolette
AU - Hall, Lesley-Ann
AU - Allcroft, Peter
AU - Toubia, Marie
AU - Hopkins, Susan
PY - 2021/10
Y1 - 2021/10
N2 - Objective: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods: Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life. Results: A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation: Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.
AB - Objective: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods: Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life. Results: A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation: Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.
KW - Neuroinflammation
KW - amyotrophic lateral sclerosis
KW - ALS
KW - pathogenic
KW - dimethyl fumarate
KW - T cells
KW - Tregs
UR - http://www.scopus.com/inward/record.url?scp=85114374830&partnerID=8YFLogxK
U2 - 10.1002/acn3.51446
DO - 10.1002/acn3.51446
M3 - Article
AN - SCOPUS:85114374830
SN - 2328-9503
VL - 8
SP - 1991
EP - 1999
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 10
ER -