Open-label Study of Liothyronine in MS

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of synthetic T3, liothyronine. It will establish if there are changes in MS symptoms and if there is a positive effect on markers of neuronal health.

Detailed Description
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Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) that is characterized by inflammation, demyelination, and neurodegeneration. It remains the most common non-traumatic cause of neurologic disability in young adults and presents in most patients as relapsing-remitting disease. Relapses, caused by inflammatory demyelination, can result in a significant amount of neurological disability and reduced health-related quality of life, and having frequent early relapses is associated with increased risk of longer-term disability. Clinical recovery from early relapses is incomplete in approximately half of patients with MS. The mechanisms underlying relapse recovery are not completely understood. Remyelination of acutely denuded axons is one mechanism by which relapse recovery may occur. Remyelination is suspected to occur via newly differentiated oligodendrocytes, which are derived from oligodendrocyte precursor cells (OPCs) in the CNS. However, despite the presence of this innate repair mechanism, many patients go on to develop progressive functional disability. This may be due to a failure of remyelination or because of progressive axonal injury. Chronic demyelinating lesions are surrounded by OPCs and premyelinating oligodendrocytes, which suggest that failed remyelination does occur and could be partially due to incomplete oligodendrocyte differentiation. Additionally, recent studies have highlighted the importance of mitochondrial dysfunction, perhaps related to oxidative stress or increased energy demands, in mediating MS disease progression. Mitochondrial dysfunction may drive axonal degeneration with resultant neurodegeneration and progressive neurological decline (progressive MS). While numerous immune modulating therapies exist, currently, there is an urgent need for novel therapies that have neuroreparative and neuroprotective properties. Thyroid hormones may play a direct role in remyelination and repair in the adult CNS by promoting maturation of oligodendrocytes. Further, thyroid hormones have been shown to reduce oxidative stress and thus may have the capacity to prevent mitochondrial dysfunction as well. Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic form of T3) has the potential to induce reparative mechanisms and limit secondary neurodegeneration in MS. In mice, T3 administration has shown to help facilitate recovery from cuprizone-induced demyelination. In this study, the investigators propose to perform a phase 1 study in patients with MS to establish a tolerable dose of liothyronine, evaluate the safety of this medication, determine whether it impacts function, and evaluate if it is associated with changes in neurotrophic and/or inflammatory biomarkers in the cerebrospinal fluid (CSF).

Official Title
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A Phase 1b, Open-label Study to Evaluate the Safety and Tolerability of the Putative Remyelinating Agent, Liothyronine, in Individuals With MS

Conditions
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Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Secondary Progressive, Multiple Sclerosis, Primary Progressive

Intervention / Treatment
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* Drug: liothyronine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must meet 2010 McDonald criteria for clinically definite MS Must be euthyroid Expanded Disability Status Scale (EDSS) 3.0-7.5 Patients may be on MS immunomodulating therapies or immunosuppressant therapies during the study Exclusion Criteria: Known thyroid disease (past or current) Currently on thyroid replacement therapy Steroid use within a month of screening History of coronary artery disease, atrial fibrillation, or other clinically significant cardiac disease History of adrenal insufficiency Ongoing renal and/or liver disease Ongoing severe depression and/or anxiety Use of carbamazepine, phenytoin, phenobarbital, warfarin, antacids, cholestyramine, colestipol, sucralfate, and rifampin Known contraindication to using beta-blocker medications History of alcohol or substance abuse in the past 6 months Pregnant or nursing If the investigator feels that participation in this study is not in the best interest of the subject

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 58 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liothyronine<br>Subjects will take oral liothyronine for a total of 24 weeks following the below titration schedule: 0-6 weeks: liothyronine 10mcg po daily (5mcg po BID) 6-12 weeks: liothyronine 20mcg po daily (10mcg po BID) 12-18 weeks: liothyronine 50mcg po daily (25mcg po BID) 18-24 weeks: liothyronine 1mcg/kg/day (0.5mcg/kg po BID), not to exceed 75mcg po daily | Drug: liothyronine<br>* All eligible subjects will be treated with the study drug as per the standardized dose-escalation protocol. Subjects will be required to report to the study site every six weeks for the duration of the study in order to receive their study drug and to monitor drug safety and tolerability.<br>* Other names: Cytomel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence rate of adverse events |  | 26 weeks |