Lipoic Acid for Treatment of Progressive Multiple Sclerosis: A Phase 2 Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: A pilot trial of the antioxidant lipoic acid (LA) in secondary progressive multiple sclerosis (MS) demonstrated a reduction in the whole-brain atrophy, suggesting neuroprotection. This study determined whether LA preserved walking speed, reduced brain atrophy, and was safe in progressive MS (PMS). METHODS: This phase 2, 24-month, randomized, double-blind, placebo-controlled clinical trial (2018-2023) recruited a convenience sample from 10 US sites, including 5 Veterans Affairs medical centers and 1 Canadian site. Inclusion criteria were as follows: age ≥18 years, primary or secondary PMS, Expanded Disability Status Scale (EDSS) score 3.0-6.5, and relapse-independent disability worsening in the previous 2 years. Exclusion criteria were as follows: confounders of mobility outcomes, LA use in the previous 2 years, and MRI contraindications. Concurrent disease-modifying therapy (DMT) was permitted. Participants were block-randomized by site (1:1) to receive 1,200 mg daily oral LA or placebo. The sample size (n = 118) was powered to detect Timed 25-Foot Walk (primary outcome) speed differences, allowing 25% attrition. Secondary outcomes were brain atrophy, other clinical and patient-reported disabilities, and adverse events. Study visits occurred every 6 months. Laboratory monitoring was increased to every 3 months because of treatment-related proteinuria. Intention-to-treat analysis used linear mixed-effects models. RESULTS: Participants in the LA (54) and placebo (61) groups were 54.8% female (age 59.1 (SD 8.5) years), with a disease duration of 16.3 (SD 9.7) years and a median EDSS score of 6.0 (interquartile range 4.0-6.0), and 55.7% were on DMT. Groups were matched at baseline. LA participants discontinued from the study more often (37%) than placebo (17%). LA did not slow declines in walking speed (-0.39 ft/sec vs -0.30 ft/sec; -0.08 [-0.33 to 0.17]), nor showed differences in mobility, other clinical, or patient-reported outcomes from placebo. Whole-brain volume seemed stable in LA participants, whereas it trended toward a decrease in placebo, even after accounting for an increased total T2-weighted lesion volume that was greater in the LA group. Deep gray matter volume remained stable in LA participants and decreased in placebo participants. The LA group experienced more proteinuria and fewer suicidal ideation events than the placebo group. DISCUSSION: LA did not slow decline in walking speed or have other clinical effects different from placebo and was associated with newly described adverse events. Investigating LA mechanisms may help interpretation of volumetric imaging biomarkers in PMS. TRIAL REGISTRATION INFORMATION: NCT03161028. clinicaltrials.gov/study//NCT03161028, first submission May 18, 2017; first patient enrolled August 17, 2018. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with primary or secondary PMS, oral LA did not improve timed walking speed at 24 months compared with placebo.