Design and Baseline Characteristics of a Pilot Trial of Lithium for Progressive Multiple Sclerosis

Background:

Progressive forms of multiple sclerosis (MS) are a major cause of MS-related disability.  Despite advances in the treatment of relapsing MS, progressive MS remains refractory to existing disease modifying therapies (DMTs).  Lithium (Li) has shown promise as a drug with possible immune modulating and independent neuroprotective qualities.  However, its safety, tolerance, and efficacy have not been previously demonstrated in an MS cohort.

Objectives:

1. Demonstrate the feasibility of using Li carbonate to treat subjects with progressive MS.
2. Present baseline characteristics of enrolled subjects, and preliminary data on Li tolerance.

Methods:

Subjects with >1 year of progressive disease were recruited from MS clinics at the Birmingham VA and the University of Alabama at Birmingham.  Consenting subjects who completed screening were enrolled in a two-year crossover study.  Subjects were randomly assigned to take fixed-dose Li in either year 1 or year 2. Comprehensive evaluations at baseline and at years 1 and 2 include MRI, Expanded Disability Status Scale, MS Functional Composite, and scales to assess mood, fatigue, and quality of life.  Paired comparisons between on- and off-Li periods will be used to assess clinical and MRI outcomes.  The primary outcome measures for the study are 1) Safety and tolerance of Li, as evidenced by adverse events (AEs), side effects, and study withdrawals; and 2) Evidence of disease progression, as evidenced by intra-individual changes in brain atrophy rates.  Secondary outcomes include changes in MRI lesion burden, relapses, and changes in disability, fatigue, mood, and quality of life.

Results:

We consented 24 subjects, of whom 23 successfully completed screening.  The cohort is 62.5% male, with a mean age of 51.5 (SD 7.5) years at enrollment and mean disease duration of 14.8 (SD 10.4) years.  Subjects are 87.5% secondary progressive, 12.5% primary progressive.  Median EDSS is 4.0 (IQR 3.5, 6).  Nineteen subjects are taking a DMT.  Of the 17 subjects exposed to Li to date, 8 have completed a full year of Li, 4 are currently taking Li, and 5 have discontinued the study:  3 due to AEs (worsening gait) and 2 for personal reasons.  One subject on Li has experienced a relapse requiring outpatient steroids, but remains enrolled and on Li.  Cumulative Li exposure to date for all subjects is 141 months.  After study initiation, maximum daily Li was reduced from 600 to 300 mg due to frequent side effects, which improved overall tolerance.  The most common AEs reported to date have all been mild and include increased thirst (11/17), polyuria (9/17), and fatigue (7/17).  Efficacy endpoints will be analyzed upon study completion in 2015.

Conclusions:

Low-dose Li is safe and well-tolerated in this cohort of progressive MS subjects.  Major changes in disease activity, mood, and fatigue have not been noted to date.  Deterioration in gait may limit Li treatment in a subset of MS patients.