The OCTOPUS trial, a multi-site, multi-arm study evaluating R/S alpha-lipoic acid and metformin in patients with progressive multiple sclerosis (MS), is progressing well, according to an update presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The trial aims to complete the first stage of recruitment, targeting 375 participants, by December of this year.
Recruitment and Patient Demographics
As of March 25, 2024, 189 of 237 screened participants have been randomized, representing approximately 49% of the planned stage 1 recruitment. Among these participants, 63% (119 individuals) were diagnosed with secondary progressive MS. The average time since MS onset was 20.6 years (SD, 10.5 years; range, 2.4-45.2 years), with 14.8 years since MS diagnosis (SD, 9.2; range, 0.9-44.1 years) and 10.6 years since the onset of MS progression (SD, 6.6; range, 2.2-30.1 years).
The study population predominantly consists of White participants (94.2%), with smaller representation from Asian (3.7%) and Black (1.1%) patients. Baseline Extended Disability Status Scale (EDSS) scores indicated that 18.5% of randomized participants had scores less than 5.5, while 81.5% had scores greater than 6.0. Over 5,271 participants completed the initial online survey, with 2,958 deemed eligible for telephone screening.
Trial Design and Objectives
OCTOPUS is the first multi-site, multi-arm multi-stage (MAMS) trial in progressive MS designed to compare multiple treatment arms simultaneously. The trial randomizes 125 patients to each treatment arm: R/S alpha-lipoic acid, metformin, or placebo. A two-stage process will determine the continuation of treatment arms. Stage 2 will require 600 participants per arm and will assess confirmed disability progression using a composite score based on the Extended Disability Status Scale (EDSS), 9-hole peg test, and timed 25-foot walk.
Rationale for Investigated Treatments
The OCTOPUS trial addresses a critical unmet need in progressive MS, where treatment options are limited. Currently, ocrelizumab is the only FDA-approved therapy for progressive MS. Researchers hypothesize that lipoic acid, administered orally, may modulate the immune system, reducing the number of immune cells that attack and damage myelin. Metformin, typically used to treat type 2 diabetes, may promote myelin repair by stimulating myelin-making cells to fully develop.
Supporting Preclinical Evidence
Preclinical studies have suggested the potential of metformin in promoting myelin repair. A 2019 study demonstrated that metformin could restore the regenerative capacity of aged oligodendrocyte progenitor cells (OPCs) in rats, improving remyelination following focal demyelination. The study indicated that metformin reversed age-related changes in OPC differentiation potential, suggesting synergistic effects of rejuvenation and pro-differentiation therapies.
Concurrent Lipoic Acid Trial
Lipoic acid is also being investigated in the phase 2 LAMPS trial (NCT03161028) for progressive MS. This 2-year trial, involving approximately 115 participants, assesses mobility using the 25-foot walk test and 2-minute timed walk test, along with fall counts. The LAMPS trial also includes MRI assessments to evaluate neuroprotection by measuring brain volume loss.
