MST3K: Thyroid Hormone for Remyelination in Multiple Sclerosis (MS): A Safety and Dose Finding Study

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02760056
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Actual Duration (Months): 7.2
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This is a phase 1 study evaluating the safety and maximum tolerated dose of Liothyronine (T3) in subjects with multiple sclerosis

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Liothyronine sodium; Drug: Placebo	Phase 1

Detailed Description

This is a pilot, phase I, placebo controlled clinical trial of short-term high-dose thyroid hormone to promote remyelination in MS. Permanent clinical disability in MS is likely caused by the neuronal damage and degeneration that follows recurrent demyelination with progressive failure of remyelination. Thyroid hormone (TH) is required for central nervous system (CNS) myelination during development, and CNS remyelination in animal models of MS, a process similar to developmental myelination, has also been found to be promoted by TH. This study will ascertain the safety, tolerability and maximum tolerated dose of TH in people with MS, explore reliability for a potential signal of treatment efficacy and mechanism, and optimize procedures for a full scale clinical trial to evaluate the efficacy of pulsed TH for promotion of remyelination in MS.

The safety and tolerability of this treatment will be assessed using subjects' self-report of symptoms, the validated Hyperthyroid Symptom Scale (HSS), and blood pressure measurements. a

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose escalation with monitoring for safety and tolerability, as well as reliability of VEP testing.Dose escalation with monitoring for safety and tolerability, as well as reliability of VEP testing.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind, randomized, controlled
• Primary Purpose: Treatment
• Official Title: Thyroid Hormone for Remyelination in Multiple Sclerosis (MS): A Safety and Dose Finding Study
• Actual Study Start Date: Jun 6, 2016
• Actual Primary Completion Date: Jan 10, 2017
• Actual Study Completion Date: Jan 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Liothyronine (cytomel) Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week	Drug: Liothyronine sodium; Subjects will be divided into 4 groups of progressively escalating doses. Each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.; Other Names: Cytomel
Placebo Comparator: Placebo Subject will take matching placebo twice a day for one week	Drug: Placebo; Patient will receive a matching placebo to take twice daily for one week.

Outcome Measures

Primary Outcome Measures

1. Determine the Maximum Tolerated Dose (MTD) of Oral L-T3 in Subjects With MS [1 week]

   MTD per protocol (dose level one category below dose at which study was stopped due to intolerance or meeting criteria for cessation)

Secondary Outcome Measures

1. Reliability of Visual Evoked Potential (VEP) Testing (ICC) [1 week]

   P100 latency will be compared before and after treatment with L-T3 in subjects receiving the active treatment to assess reliability of the test for future assessment of treatment effect.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of MS of any type

• Age 18 to 50 years

• Weight range 45-90 kg (100-200 lbs)

• Lesions on brain MRI

Exclusion Criteria:

• History of hypo or hyperthyroidism and a normal TSH

• History of high blood pressure (hypertension) [

• Resting blood pressure greater than 150/95, resting heart rate greater than 100

• History of coronary artery disease or clinically significant arrhythmia, clinically significant abnormalities on EKG

• History of diabetes

• History of anemia or renal (kidney) disease

• Clinically significant abnormalities on metabolic panel or serum hematocrit below 32 %

• History of atrophic gastritis

• History of anxiety disorder or bipolar disorder

• Serious psychiatric or medical conditions that would preclude reliable participation in the study

• Use of illicit substances or alcohol abuse

• Current use of fingolimod (Gilenya)

• Current or prior use of mitoxantrone (Novantrone)

• Current use of stimulants (methylphenidate, atomoxetine, dextroamphetamine,phentermine)

• Current use of any blood thinners such as warfarin or apixaban (Aspirin is ok)

• Medications which would metabolized faster in the presence of thyroid hormone (Insulin, oral hypoglycemic agents and oral anticoagulants)

• Severe head tremors (which would impair the ability to perform VEPs)

• Present or recent use of medications that could interact with the thyroid hormone (iodine containing agents such as kelp supplements, amiodarone, iodinated contrast given for CT or xray), P450 stimulants (phenytoin, carbamazepine, phenobarbital, and rifampin)

• Corrected visual acuity worse than 20/50 in either eye or other eye issues that would prevent reading of a standard eye chart

• Head tremors or other tremors that would prevent sitting relatively still for a vision test

• Patients taking proton pump inhibitors (PPIs) or H2 blockers will be excluded unless they can safely not take these medications during the week of study drug administration.

• Patients taking Ampyra (dalfampridine) will be excluded unless they can safely not take these medications during the week of study drug administration.

• Pregnancy, breastfeeding, or intention to become pregnant in the following month

• Inability to receive an MRI (e.g. implanted metal device)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health and Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Oregon Health and Science University

Investigators

• Principal Investigator: Michelle Cameron, MD, OHSU Department of Neurology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michelle Cameron, Chair and Roy & Eulalia Swank Family Research Professor, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT02760056
• Other Study ID Numbers: IRB 15101
• First Posted: May 3, 2016
• Last Update Posted: Nov 19, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Michelle Cameron, Chair and Roy & Eulalia Swank Family Research Professor, Oregon Health and Science University: Thyroid hormone; Remyelination
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Liothyronine (Cytomel)	Placebo
Arm/Group Description	Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week Liothyronine sodium: Subjects will be divided into 4 groups of progressively escalating doses. If the study is fully enrolled, each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.	Subject will take matching placebo twice a day for one week Placebo: Patient will receive a matching placebo to take twice daily for one week.
Period Title: Overall Study
STARTED	10	5
COMPLETED	10	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Liothyronine (Cytomel)	Placebo	Total
Arm/Group Description	Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week Liothyronine sodium: Subjects will be divided into 4 groups of progressively escalating doses. Each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.	Subject will take matching placebo twice a day for one week Placebo: Patient will receive a matching placebo to take twice daily for one week.	Total of all reporting groups
Overall Participants	10	5	15
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	39	38.4	38.8
Sex: Female, Male (Count of Participants)
Female	4 40%	2 40%	6 40%
Male	6 60%	3 60%	9 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 10%	0 0%	1 6.7%
White	9 90%	4 80%	13 86.7%
More than one race	0 0%	1 20%	1 6.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
MS Subtype (Count of Participants)
Relapsing Remitting Multiple Sclerosis	9 90%	5 100%	14 93.3%
Secondary Progressive Multiple Sclerosis	1 10%	0 0%	1 6.7%

Outcome Measures

1. Primary Outcome

Title	Determine the Maximum Tolerated Dose (MTD) of Oral L-T3 in Subjects With MS
Description	MTD per protocol (dose level one category below dose at which study was stopped due to intolerance or meeting criteria for cessation)
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

Participants with MS taking L-T3 (10) excluding those taking placebo (5)

Arm/Group Title	Liothyronine (Cytomel)
Arm/Group Description	Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week Liothyronine sodium: Subjects will be divided into 4 groups of progressively escalating doses. Each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.
Measure Participants	10
Number [mcg daily with BID dosing]	75

2. Secondary Outcome

Title	Reliability of Visual Evoked Potential (VEP) Testing (ICC)
Description	P100 latency will be compared before and after treatment with L-T3 in subjects receiving the active treatment to assess reliability of the test for future assessment of treatment effect.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

Participants with MS taking L-T3 or placebo

Arm/Group Title	Liothyronine (Cytomel)	Placebo	All Participants
Arm/Group Description	Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week Liothyronine sodium: Subjects will be divided into 4 groups of progressively escalating doses. Each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.	Subject will take matching placebo twice a day for one week Placebo: Patient will receive a matching placebo to take twice daily for one week.	Measure value across cohorts.
Measure Participants	10	5	15
ICC - Right Eye	0.852	0.679	0.824
ICC - Left Eye	0.746	0.966	0.845
ICC- Mixed Model	0.889	0.963	0.924

Adverse Events

Time Frame	1 week
Arm/Group Title	Liothyronine (Cytomel)		Placebo
Arm/Group Description	Subjects will be divided into 4 groups. The first group will take 25 mcg twice daily for one week. The second group will take 37.5 mcg twice daily for one week. The third group will take 50 mcg twice daily for one week. The firth group will take 75 mcg twice daily for one week Liothyronine sodium: Subjects will be divided into 4 groups of progressively escalating doses. Each group will have 6 subjects 4 will receive the active treatment and 2 will receive the placebo. The first group will receive 25 mcg twice daily for one week. The second group will receive 37.5 mcg twice daily for one week. The third group will receive 50 mcg twice daily for one week. The forth group will receive 75 mcg twice daily for one week.		Patient will receive a matching placebo to take twice daily for one week.
All Cause Mortality
	Liothyronine (Cytomel)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)
Serious Adverse Events
	Liothyronine (Cytomel)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Liothyronine (Cytomel)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/10 (60%)		2/5 (40%)
Cardiac disorders
Tachycardia	1/10 (10%)	2	1/5 (20%)	7
Gastrointestinal disorders
Loose Stool	5/10 (50%)	5	0/5 (0%)	0
Abdominal Pain	1/10 (10%)	1	0/5 (0%)	0
Yellow stool	1/10 (10%)	1	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Pain	1/10 (10%)	1	0/5 (0%)	0
Psychiatric disorders
Anxiety	1/10 (10%)	1	0/5 (0%)	0
Poor Sleep	4/10 (40%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Increased severity in post-Tecfidera flushing	1/10 (10%)	1	0/5 (0%)	0

Limitations/Caveats

Self-reporting of BP, HR. 1 missed dose in the drug arm. VEP testing was conducted by multiple technicians and read by multiple attending physicians; though visit one and two were more often conducted by the same tech/attending.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.