Multiple Sclerosis
Conditions
Keywords
Multiple sclerosis, Lithium
Brief summary
The purpose of this study is to determine whether lithium carbonate is safe, well-tolerated, and effective at treating progressive forms of multiple sclerosis.
Detailed description
In progressive multiple sclerosis (MS), patients experience worsening disability through a combination of inflammatory and neuro-degenerative processes. To test whether low-dose lithium carbonate ameliorates disability accumulation in progressive MS, patients with progressive MS were randomly assigned to take lithium in either the first or second year of a two-year trial. The trial was designed as a cross-over study to maximize exposure to lithium to for two reasons: 1) To increase the number of persons with MS exposed to lithium for purposes of assessing safety and tolerance; and 2) To increase the power to detect changes in the primary radiological outcome (change in brain volume) and also in secondary clinical outcomes (disability, mood, fatigue, cognition).
Interventions
DRUGLithium Carbonate
Lithium carbonate is dosed at 150 or 300 mg daily, as tolerated by study subjects, for one year's time.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Each study participant agreed to a two-year enrollment commitment. Each subject was asked to take lithium for one year and to be observed for one year. Randomization was used to determine the sequence of lithium vs. observation (year 1 or year 2).
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of a progressive subtype of multiple sclerosis by revised 2005 McDonald Criteria. * EDSS of 3.0-6.5 * Ages 30-65 * Must be mentally capable of providing informed consent and following study guidelines.
Exclusion criteria
* Relapse or steroid treatment within 1 month of trial entry. * Any current or previous treatment with mitoxantrone, azathioprine, methotrexate, mycophenolate, cyclophosphamide, or any experimental therapy. * Women who are pregnant, wishing to become pregnant in the coming 30 months, or are breastfeeding. * Sexually active women unwilling to use reliable contraception (oral contraceptives, condom, IUD). * Patients with known kidney dysfunction or creatinine \>1.4; known cardiac arrhythmia or significant conduction abnormality on EKG; uncontrolled thyroid disease or TSH \>20% above the upper limit of normal; uncontrolled psoriasis, HIV, or any other severe medical condition. * Patients with a history of unstable psychiatric illness or active severe depression. * Patients with a history of seizure. * Concurrent use of any of the following medications: Antipsychotics, diuretics, digoxin, or iodide salts. * Use of non-steroidal anti-inflammatory drugs (NSAIDs) 5 or more days a week. * Patients with a history of substance abuse in the past year. * Patients sensitive to gadolinium, or who are unable to undergo the required number of MRI scans. * Unable to speak or understand sufficient English to consent or complete study procedures. * Patients unable or unwilling to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Brain Parenchymal Fraction | 2 years | Paired comparison of change in brain parenchymal fraction during Lithium treatment and during observation period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Relapses | 2 years | Total number of relapses which occurred during the Li-treatment and observation study phases. |
| Change in Expanded Disability Status Scale Score | 2 years | The Expanded Disability Status Scale (EDSS) is an ordinal scale ranging from 0 to 10 used to assess disability in multiple sclerosis (MS). A score of 0 denotes no neurological impairments and no neurological exam abnormalities, while a score of 10 denotes death due to MS. The EDSS is derived from subscales called Functional System Scales at the lower range of the EDSS, and from ambulatory impairments and overall functional impairment at higher ranges of the scale. The Functional System scores (Vision, Brainstem, Pyramidal, Sensory, Cerebellar, Cognitive, Bladder and Bowel) are used to generate the EDSS based on pre-specified rules that determine the overall EDSS score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lithium Then Observation Lithium carbonate was dosed at 150 or 300 mg daily, as tolerated by study subjects, for one year's time.
During observation subjects continued on their standard of care disease modifying agent (or no agent at all if judged not appropriate by the treating physician). | 11 |
| Observation Then Lithium During observation subjects continued on their standard of care disease modifying agent (or no agent at all if judged not appropriate by the treating physician).
Lithium carbonate was dosed at 150 or 300 mg daily, as tolerated by study subjects, for one year's time. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Lithium Then Observation | Total | Observation Then Lithium |
|---|---|---|---|
| Age, Continuous | 55.4 years STANDARD_DEVIATION 4.6 | 51.0 years STANDARD_DEVIATION 7.8 | 47.1 years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 22 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 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 | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 8 Participants | 16 Participants | 8 Participants |
| Region of Enrollment United States | 11 Participants | 23 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 23 | 0 / 18 |
| serious Total, serious adverse events | 1 / 23 | 1 / 18 |
Outcome results
Primary
Rate of Change in Brain Parenchymal Fraction
Paired comparison of change in brain parenchymal fraction during Lithium treatment and during observation period
Time frame: 2 years
Population: Due to this being a crossover study design, each participant's data was evaluated for each phase of the trial (Li treatment and observation). Only subjects who completed both years (and thus both phases) of the study were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lithium | Rate of Change in Brain Parenchymal Fraction | 0.107 percentage of change in brain volume | Standard Error 0.38 |
| Observation | Rate of Change in Brain Parenchymal Fraction | -0.355 percentage of change in brain volume | Standard Error 0.22 |
p-value: 0.346t-test, 2 sided
Secondary
Change in Expanded Disability Status Scale Score
The Expanded Disability Status Scale (EDSS) is an ordinal scale ranging from 0 to 10 used to assess disability in multiple sclerosis (MS). A score of 0 denotes no neurological impairments and no neurological exam abnormalities, while a score of 10 denotes death due to MS. The EDSS is derived from subscales called Functional System Scales at the lower range of the EDSS, and from ambulatory impairments and overall functional impairment at higher ranges of the scale. The Functional System scores (Vision, Brainstem, Pyramidal, Sensory, Cerebellar, Cognitive, Bladder and Bowel) are used to generate the EDSS based on pre-specified rules that determine the overall EDSS score.
Time frame: 2 years
Population: Due to this being a crossover study design, each participant's data was evaluated for each phase of the trial (Li treatment and observation). Only subjects who completed both years (and thus both phases) of the study were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lithium | Change in Expanded Disability Status Scale Score | 0 Units on a scale |
| Observation | Change in Expanded Disability Status Scale Score | 0.5 Units on a scale |
p-value: 0.013Wilcoxon (Mann-Whitney)
Secondary
Total Relapses
Total number of relapses which occurred during the Li-treatment and observation study phases.
Time frame: 2 years
Population: Due to this being a crossover study design, each participant's data was evaluated for each phase of the trial (Li treatment and observation). Only subjects who completed both years (and thus both phases) of the study were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lithium | Total Relapses | 2 relapses |
| Observation | Total Relapses | 5 relapses |