Yasuko Asahina

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid OCH-NCNP1 (OCH) exerts an immunoregulatory action that suppresses Th1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. Objective: This trial investigates the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. The protocol was also designed to confirm exploratory biomarkers of T cells and natural killer cells that fluctuated in the Phase I trial, as well as efficacy-related clinical endpoints, including relapses, disability, magnetic resonance imaging changes, and their association with combined endpoints. Methods: This protocol describes a double-blind, multicenter, placebo-controlled, randomized, phase II clinical trial conducted in September 2019. The duration of the trial was 24 weeks. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group for the 24-week duration. Outcome measures included the primary outcome of magnetic resonance imaging changes and secondary outcomes including annual relapse rate, relapse-free period, sustained reduction in disability occurrence rate, period until sustained reduction in disability, no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). Results: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021, and the study analysis was planned to end in March 2023. Conclusions: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. Clinical Trial: ClinicalTrials.gov Trial registration ID#: NCT04211740

BACKGROUND Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell–mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica–immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. CLINICALTRIAL ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/46709