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).