|Title||Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Naismith RT, Ashokkumar A, Barnes J, Ecklund D, Klingner E, Koepp M, Long JD, Natarajan S, Thornell B, Yankey J, Bermel RA, Debbins JP, Huang X, Jagodnik P, Lowe MJ, Nakamura K, Narayanan S, Sakaie KE, Thoomukuntla B, Zhou X, Krieger S, Alvarez E, Apperson M, Bashir K, Cohen BA, Coyle PK, Delgado S, L Dewitt D, Flores A, Giesser BS, Goldman MD, Jubelt B, Lava N, Lynch SG, Moses H, Ontaneda D, Perumal JS, Racke M, Repovic P, Riley CS, Severson C, Shinnar S, Suski V, Weinstock-Guttman B, Yadav V, Zabeti A|
|Corporate Authors||NN102/SPRINT-MS Trial Investigators|
|Journal||N Engl J Med|
|Date Published||2018 08 30|
|Keywords||Adult, Atrophy, Brain, Depression, Diffusion Tensor Imaging, Disease Progression, Double-Blind Method, Female, Gastrointestinal Diseases, Headache, Humans, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive, Phosphodiesterase Inhibitors, Pyridines|
BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.
METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.
RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.
CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).
|Alternate Journal||N. Engl. J. Med.|
|PubMed Central ID||PMC6172944|
|Grant List||U01 NS077179 / NS / NINDS NIH HHS / United States |
UL1 TR002369 / TR / NCATS NIH HHS / United States
KL2 TR001080 / TR / NCATS NIH HHS / United States
U01 NS082329 / NS / NINDS NIH HHS / United States
U10 NS077265 / NS / NINDS NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
UL1 TR000448 / TR / NCATS NIH HHS / United States
UL1 TR001425 / TR / NCATS NIH HHS / United States
UL1 TR002556 / TR / NCATS NIH HHS / United States
U01 NS077352 / NS / NINDS NIH HHS / United States
UL1 TR002345 / TR / NCATS NIH HHS / United States
U24 NS107128 / NS / NINDS NIH HHS / United States
U24 NS107182 / NS / NINDS NIH HHS / United States
U10 NS077260 / NS / NINDS NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
U24 NS107165 / NS / NINDS NIH HHS / United States