Phase I randomized trial of liothyronine for remyelination in multiple sclerosis: A dose-ranging study with assessment of reliability of visual outcomes.

BACKGROUND: Thyroid hormone promotes remyelination in multiple sclerosis (MS) animal models through a variety of mechanisms. Liothyronine (L-T3) is a short-acting thyroid hormone with demonstrated safety and tolerability for short-term and chronic use in euthyroid adults with other health conditions, but has not been studied in people with MS. The objectives of this single-center, phase I, placebo-controlled, clinical trial were to determine the safety, tolerability, and optimal dosing of L-T3 in people with MS in preparation for a phase 2 remyelination clinical trial. Secondary goals included exploration of the reliability of functional and clinical measurements of myelination in the anterior visual pathway over one week. METHODS: Groups of six clinically stable people with MS were randomized in a 4:2 ratio to receive L-T3 or placebo. The first group received 50 mcg total daily dose (TDD) of L-T3, with escalating doses of L-T3 in subsequent groups, up to potentially 150 mcg TDD in the final group. Prior to enrollment for the next dose-escalated group, all safety measures for the prior dose were reviewed. The maximum tolerated dose (MTD) was considered to be the dose below which two or more participants experienced dose limiting symptoms or one participant experienced a serious adverse event. After the MTD was reached, no further patients were enrolled. Visual evoked potentials (VEP) P100 latency with two different check sizes (17' and 34') and Sloan low contrast letter acuity (LCLA) were measured pre- and post-treatment. To determine whether there was a treatment effect, the placebo and L-T3 groups were compared using a clustered bootstrap regression estimation. A linear mixed effects model was used to determine test-retest reliability of VEP and LCLA in all eyes. RESULTS: Between May 2016 and November 2016, 15 people with MS were randomized to L-T3 (n = 10) or placebo (n = 5). Subjects were adherent to the study drug and the MTD was 75 mcg TDD. No serious adverse events were observed and the most common adverse events were poor sleep and loose stools. No treatment effect of L-T3 was observed over one week. Therefore, data from patients on L-T3 and placebo were pooled to explore VEP and LCLA reliability. The intraclass correlations of VEP 17', VEP 34' and LCLA were 0.836, 0.860, and 0.932, respectively. The mean differences in values between visits 1 and 2 for VEP 17' and 34' and LCLA were 1.9 ms/eye (SD 6.5), 0.4 ms/eye (6.3), and 0.8/eye (3.6), respectively. CONCLUSIONS: This study confirms the short-term safety and tolerability of L-T3 in people with MS, with 75 mcg TDD as the MTD. Our results also support that, despite small variations over one week, VEP with various check sizes and Sloan LCLA are reliable functional and clinical outcome measures that could be used in remyelination clinical trials in MS. A future phase 2 clinical trial to investigate the efficacy of L-T3 as a remyelination therapy may be warranted. This trial was registered on clinicaltrials.gov (NCT02760056).

Correction to: Dietary Interventions and Multiple Sclerosis.

The original version of this article contains an error in the second sentence of the second paragraph of the Paleolithic Diet section.

Dietary Interventions and Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic, disabling neurologic disease that has its onset in young adulthood. While the knowledge about underlying pathogenesis of MS has improved significantly over the last few decades, the exact cause still eludes us. Despite the availability of several United States Food and Drug Administration-approved disease-modifying therapies (DMT) for MS in the last two decades, the disease remains disabling for many. DMT use is limited by its partial effectiveness, significant side effects in many cases, and high cost that leads people with MS (PwMS) to look for alternative management options. Dietary intervention as a possible mode to help MS seems very appealing to PwMS; however, scientific data supporting this notion remains sparse. New information on the role of various non-MS health factors, especially vascular disease risk factors such as hypertension, hyperlipidemia, salt intake, and obesity, that may play a role in MS pathogenesis appears very intriguing as it may partly explain the heterogeneity seen in MS activity and disability. This review will highlight the emerging information on various dietary approaches that may affect MS and their possible underlying mechanism.

Remyelination and multiple sclerosis: therapeutic approaches and challenges.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. After acute inflammatory mediated demyelination, some remyelination often occurs, but in chronic demyelinated MS plaques, remyelination frequently fails. Chronically demyelinated axons cause a variety of symptoms and probably are more likely to degenerate, leading to irreversible clinical disability. Oligodendrocyte precursor cells (OPCs) present in the adult brain can proliferate and differentiate to remyelinate lesions. Failure of remyelination in the majority of MS patients is secondary to arrest in OPC differentiation. Many therapies have been developed to modulate the immune response in MS, but no neuroprotective or remyelinating therapies are available. Promoting remyelination is a promising avenue for protecting axons, reversing neurologic disability and preventing progressive disease in MS. This review will begin with an overview of remyelination and remyelination failure, consequences of demyelination, and available animal disease models. In addition, preclinical and clinical studies on the most promising potential therapies for inducing remyelination will be described.