Open-label Study of Liothyronine in MS

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02506751
• Other study ID #: IRB00061965
• Status: Completed
• Phase: Phase 1
• First received: July 12, 2015
• Last updated: February 8, 2018
• Start date: July 2015
• Est. completion date: September 18, 2017

Study information

• Verified date: February 2018
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: September 18, 2017
• Est. primary completion date: September 18, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 58 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Primary Progressive
• Multiple Sclerosis, Relapsing-Remitting
• Multiple Sclerosis, Secondary Progressive
• Sclerosis

Intervention

Drug:
• liothyronine
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.

Locations

Country	Name	City	State
United States	The Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Johns Hopkins University

Country where clinical trial is conducted

United States, 

References & Publications (9)

Chang A, Tourtellotte WW, Rudick R, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002 Jan 17;346(3):165-73. — View Citation

Harsan LA, Steibel J, Zaremba A, Agin A, Sapin R, Poulet P, Guignard B, Parizel N, Grucker D, Boehm N, Miller RH, Ghandour MS. Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging. J Neurosci. 2008 Dec 24;28(52):14189-201. doi: 10.1523/JNEUROSCI.4453-08.2008. — View Citation

Karampampa K, Gustavsson A, Miltenburger C, Eckert B. Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from five European countries. Mult Scler. 2012 Jun;18(2 Suppl):7-15. doi: 10.1177/1352458512441566. — View Citation

Mowry EM, Pesic M, Grimes B, Deen S, Bacchetti P, Waubant E. Demyelinating events in early multiple sclerosis have inherent severity and recovery. Neurology. 2009 Feb 17;72(7):602-8. doi: 10.1212/01.wnl.0000342458.39625.91. — View Citation

Orme M, Kerrigan J, Tyas D, Russell N, Nixon R. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health. 2007 Jan-Feb;10(1):54-60. — View Citation

Scott TF, Schramke CJ. Poor recovery after the first two attacks of multiple sclerosis is associated with poor outcome five years later. J Neurol Sci. 2010 May 15;292(1-2):52-6. doi: 10.1016/j.jns.2010.02.008. Epub 2010 Mar 4. — View Citation

Sormani MP, Li DK, Bruzzi P, Stubinski B, Cornelisse P, Rocak S, De Stefano N. Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis. Neurology. 2011 Nov 1;77(18):1684-90. doi: 10.1212/WNL.0b013e31823648b9. Epub 2011 Oct 5. — View Citation

van Horssen J, Witte ME, Ciccarelli O. The role of mitochondria in axonal degeneration and tissue repair in MS. Mult Scler. 2012 Aug;18(8):1058-67. doi: 10.1177/1352458512452924. Epub 2012 Jun 21. Review. — View Citation

Witte ME, Bø L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA, Geurts JJ, De Vries HE, van der Valk P, van Horssen J. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol. 2009 Oct;219(2):193-204. doi: 10.1002/path.2582. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence rate of adverse events		26 weeks