Multiple Sclerosis
Conditions
Keywords
Thyroid hormone, Remyelination
Brief summary
This is a phase 1 study evaluating the safety and maximum tolerated dose of Liothyronine (T3) in subjects with multiple sclerosis
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
Interventions
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.
DRUGPlacebo
Patient will receive a matching placebo to take twice daily for one week.
Sponsors
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind, randomized, controlled
Intervention model description
Dose escalation with monitoring for safety and tolerability, as well as reliability of VEP testing.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 10 |
| Placebo 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. | 5 |
| Total | 15 |
Baseline characteristics
| Characteristic | Placebo | Total | Liothyronine (Cytomel) |
|---|---|---|---|
| Age, Continuous | 38.4 years | 38.8 years | 39 years |
| MS Subtype Relapsing Remitting Multiple Sclerosis | 5 Participants | 14 Participants | 9 Participants |
| MS Subtype Secondary Progressive Multiple Sclerosis | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 5 |
| other Total, other adverse events | 6 / 10 | 2 / 5 |
| serious Total, serious adverse events | 0 / 10 | 0 / 5 |
Outcome results
Primary
Determine the Maximum Tolerated Dose (MTD) of Oral L-T3 in Subjects With MS
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
Population: Participants with MS taking L-T3 (10) excluding those taking placebo (5)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liothyronine (Cytomel) | Determine the Maximum Tolerated Dose (MTD) of Oral L-T3 in Subjects With MS | 75 mcg daily with BID dosing |
Secondary
Reliability of Visual Evoked Potential (VEP) Testing (ICC)
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
Population: Participants with MS taking L-T3 or placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liothyronine (Cytomel) | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Left Eye | 0.746 Intraclass Coefficient (ICC) |
| Liothyronine (Cytomel) | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Right Eye | 0.852 Intraclass Coefficient (ICC) |
| Liothyronine (Cytomel) | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC- Mixed Model | 0.889 Intraclass Coefficient (ICC) |
| Placebo | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Left Eye | 0.966 Intraclass Coefficient (ICC) |
| Placebo | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Right Eye | 0.679 Intraclass Coefficient (ICC) |
| Placebo | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC- Mixed Model | 0.963 Intraclass Coefficient (ICC) |
| All Participants | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Right Eye | 0.824 Intraclass Coefficient (ICC) |
| All Participants | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC- Mixed Model | 0.924 Intraclass Coefficient (ICC) |
| All Participants | Reliability of Visual Evoked Potential (VEP) Testing (ICC) | ICC - Left Eye | 0.845 Intraclass Coefficient (ICC) |