Table 4.

Clinical trials investigating the role of ibudilast in neurodegenerative diseases.

Neurodegenerative Disease	Clinical Trial	Study Design	Study Objectives	Main Findings	Reference
Amyotrophic Lateral Sclerosis	NCT02238626	Randomized placebo-controlled Phase 1b/2a clinical trial	To evaluate the tolerability, safety, and clinical efficacy of ibudilast (60 mg/day) as an adjunct therapy to the standard riluzole treatment	-In the early cohort, ibudilast was safe and well-tolerated over a twelve-month period. -No significant difference in clinical progression was detected between ibudilast and placebo groups, as assessed by ALSFRS-R, hand-held dynamometry and ALSAQ-5. -Subgroup analysis demonstrated that ibudilast might provide more benefit for ALS patients with upper limb or bulbar onset, and possibly delay the progression of the disease if administered at an early stage, particularly if the onset of symptoms at screening was less than 17.1 months.	[35,82]
	NCT02714036	Open-label phase 1b clinical trial	To measure the impact of ibudilast on inflammation and axonal loss	-Ibudilast (up to 100 mg/day) was ineffective in inhibiting microglia activation in the primary motor cortex of ALS patients as evaluated by PBR28-PET over 12–24 weeks, and serum neurofilament light chain (NfL) levels, an indicator of neuronal axonal loss, remained unchanged over 36–40 weeks. -Most participants experienced at least one possibly ibudilast-related adverse event: about one-third of the patients required dosage reduction, while about another one-third discontinued ibudilast treatment because of ibudilast-related adverse events.	[49]
	NCT04057898	Phase 2b/3 randomized, double-blind, placebo-controlled clinical trial	To evaluate the safety, tolerability, and efficacy of ibudilast (up to 100 mg/day) for twelve months, followed by an open-label extension phase for six months in patients with ALS		Ongoing
Progressive Multiple Sclerosis	NCT01982942	Phase 2 randomized placebo-controlled clinical trial	To evaluate the safety, tolerability, and activity of ibudilast administered twice daily over a 96- week period in subjects with primary or secondary progressive multiple sclerosis	-Ibudilast (up to 100 mg/day) over a period of 96 weeks was associated with slower progression of the whole-brain atrophy and gray matter atrophy of patients with primary and secondary progressive MS. -Ibudilast was not associated with fewer new or enlarging T2-weighted or new T1-weighted MRI lesions. -Ibudilast treatment could also potentially attenuate retinal thinning on OCT. -Disability progression was similar between the ibudilast and placebo groups. -No significant alterations in NfL levels in the serum and CSF between ibudilast and placebo groups. -Most common adverse events in this study were gastrointestinal complains, headache, and depressive symptoms. -The overall treatment effect of ibudilast in brain atrophy was mainly driven by patients with primary progressive MS and not secondary progressive MS.	[18,36,95,96,97]

ALSFRS-R: ALS Functional Rating Scale-revised; ALSAQ-5: ALS Assessment Questionnaire-5 items; MS: multiple sclerosis; OCT: optical coherence tomography; PET: positron emission tomography; NfL: neurofilament light; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid.