MN-166

The amyotrophic lateral sclerosis functional rating scale-revised, or ALSFRS-R, measures the functional status of subjects with ALS. It is based on 12 items, each of which is rated on a 5-point scale (0 to 4). The rate of total functional disability thus ranges from 0 (maximum disability) to 48 (normal function) points.

Heavy drinking days defined as 5+ drinks for men and 4+ for women. Reported outcome measures are proportions of heavy drinking days.

Participants were considered "responders" if they did not meet the need for supplemental oxygen requirements (invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or ECMO, CPAP, BiPAP, nasal cannula) at the end of the 7-day double-blind treatment.

Number (percentage) of participants with at least a 1-point improvement in clinical status on Day 7. Clinical status is measured by the National Institute of Allergy and Infectious Disease (NIAID) 8-Point Ordinal Scale: 1=Not hospitalized, no limitations on activities; 2=Not hospitalized, limitation on activities and/or requiring home oxygen; 3=Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4=Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 5=Hospitalized, Hospitalized, requiring supplemental oxygen; 6=Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7=Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8=Death.

Safety will be assessed by monitoring and recording all treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) and discontinuations due to TEAEs and Additional assessments will include regular monitoring of hematology, blood chemistry, and urine values, regular measurement of vital signs, ECGs, medical history, physical and neurological examinations.

To evaluate the activity of ibudilast (100 mg/day) versus placebo at 96 weeks as measured by quantitative magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF), calculated as the ratio of brain parenchymal tissue volume to the total volume contained within the brain surface contour.

Safety Measures: percentage of participants who experienced treatment-emergent adverse events, clinically significant abnormal laboratory and electrocardiogram results.

Determine the proportion of patients with * Treatment-emergent adverse events (TEAEs) as measured by the CTCAE v4.0 and * Treatment discontinuations due to TEAEs and Dose-Limiting Toxicities (DLTs).

Proportion of patients who are progression free at 6 months (PFS6) using the RANO criteria.

Glial activation will be estimated in eligible participants in the Regular arm by combined magnetic resonance positron emission tomography (MR-PET) using the \[11C\]-PBR28 radioligand. \[11C\]-PBR28 uptake is quantified as the ratio of the standardized uptake value (SUVR). An independent neuroimaging rater blinded to the clinical data will assess for quality control of the PBR28-PET images and SUVR. The primary analysis will be performed on the modified Intent-to-Treat (mITT) population. The median (90% confidence interval \[CI\]) changes from baseline in SUVR from pre- to post-treatment visit will be presented.

Mean change from baseline (pre-dose) to Week 36 in blood biomarkers for neuroinflammation, including macrophage migration inhibitory factor (MIF), tumor necrosis factor (TNF)-alpha, and neurofilament light (NfL). All blood biomarkers are measured in picograms/milliliter (pg/mL).

Insomnia, Nicotine craving, Gastrointestinal upset, Headache, Musculoskeletal pain, Pain at IV site, Rash, Vivid dreams, Constipation, Dizziness, Dysuria, Ectopic heart beats, Fever/chills/hot flashes, Pruritis, Sore throat, Tinnitus, Backache, Chest congestion, Sedation, or other reported by patient or observed by clinician

Systolic and diastolic blood pressure, heart rate, and an EKG "rhythm strip"