Multiple Sclerosis
Conditions
Keywords
multiple sclerosis, magnetic resonance imaging, gait, neuroprotective agents, thioctic acid, alpha-lipoic acid, mobility, chronic progressive multiple sclerosis
Brief summary
The purpose of the study is to determine if lipoic acid can preserve mobility and protect the brain in progressive forms of multiple sclerosis.
Detailed description
This two-year study will determine if daily oral intake of lipoic acid will prove superior to placebo in reducing injury to the brain and maintaining mobility in progressive MS. Mobility will be assessed with the timed 25-foot walk test and 2-minute timed walk test as well as fall counts. Neuroprotection will be measured by the extent of brain volume loss seen on MRI.
Interventions
DRUGLipoic acid
1200 mg taken by mouth daily for two years starting on day one of the study and ending on the last day of study participation.
DRUGPlacebo
The placebo comparator will be taken by mouth daily for two years starting on day one of the study and ending on the last day of study participation
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of progressive MS as defined by the study * Able to give informed consent and to adhere to study procedures. * Expanded Disability Status Scale (EDSS) 3.0 - 6.5: ambulatory for at least 20 meters without rest and use of bilateral aids (canes, crutches, walker) or better.
Exclusion criteria
* A self-reported medical or neurological problem other than MS that is a cause of progressive or fluctuating gait dysfunction * Unable to undergo MRI * Unable to follow directions in English as standardized scales are not all validated in other languages. * Current major disease or disorder other than MS (e.g., cancer, renal disease, end-stage cardiopulmonary disease, post-traumatic stress disorder, etc.) that may interfere with study procedures. Note: Stable abnormal laboratory values of no more than Grade 1 determined to not be of clinical significance to the primary treating physician for that condition may be permitted per local site investigator discretion. * Pregnant or breast-feeding. * Insulin-dependent diabetes or diabetes not controlled on oral diabetes medications. * Scheduled (every 3 months or more frequently) IV or oral steroids in the year prior to enrolment. * IV or oral steroids in the 60 days prior to enrolment. * Use of LA in the prior 2 years exceeding the equivalent of 1200mg daily for 3 months. * Participation in the pilot LA in SPMS trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mobility: Timed 25 Foot Walk | 24 months | T25FW was transformed to walking speed by dividing 25 feet by the completion time in seconds (ft/sec). The change in walking speed across 24 months was compared between treatment groups using a mixed models analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mobility: 2-minute Timed Walk | 24 months | The score is the distance, in meters, the subject walks in 2 minutes. The change in walking distance across 24 months was compared between treatment groups using a mixed models analysis. |
| Mobility: Fall Count | 24 months | Change in number of falls recorded from Baseline to year 2 |
| Brain Atrophy by MRI | 24 months | Change in whole brain volume from baseline to 24 months |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety: Adverse Event Monitoring | 24 months | Participants with at least 1 treatment-emergent AE |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were recruited from 5 Veteran Affairs Medical Centers, 1 Medical Health System, and 5 US and Canada University Hospitals. The first participant was enrolled on August 17, 2018 and the last participant was enrolled in January 2022.
Participants by arm
| Arm | Count |
|---|---|
| Lipoic Acid Participants received 1200mg daily lipoic acid orally for 24 months. Lipoic acid: 1200 mg capsule | 54 |
| Placebo Participants received placebo capsule matching lipoic acid orally for 24 months.
Placebo: lipoic acid placebo capsule | 61 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative PD/UP | 4 | 2 |
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Study drug side effects | 2 | 2 |
| Overall Study | Unable to comply with procedures | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Total | Lipoic Acid | Placebo |
|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 8.5 | 59.6 years STANDARD_DEVIATION 9.5 | 58.6 years STANDARD_DEVIATION 7.7 |
| EDSS | 6.0 score | 6.0 score | 6.0 score |
| MS Subtype Primary progressive MS (PPMS) | 34 Participants | 16 Participants | 18 Participants |
| MS Subtype Secondary progressive MS (SPMS) | 81 Participants | 38 Participants | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 105 Participants | 50 Participants | 55 Participants |
| Region of Enrollment Canada | 15 Participants | 8 Participants | 7 Participants |
| Region of Enrollment United States | 100 Participants | 46 Participants | 54 Participants |
| Sex: Female, Male Female | 63 Participants | 29 Participants | 34 Participants |
| Sex: Female, Male Male | 52 Participants | 25 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 1 / 61 |
| other Total, other adverse events | 35 / 54 | 30 / 61 |
| serious Total, serious adverse events | 11 / 54 | 7 / 61 |
Outcome results
Primary
Change in Mobility: Timed 25 Foot Walk
T25FW was transformed to walking speed by dividing 25 feet by the completion time in seconds (ft/sec). The change in walking speed across 24 months was compared between treatment groups using a mixed models analysis.
Time frame: 24 months
Population: Intent to Treat Population (all participants assigned to lipoic acid or placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lipoic Acid | Change in Mobility: Timed 25 Foot Walk | -0.39 feet per second |
| Placebo | Change in Mobility: Timed 25 Foot Walk | -0.30 feet per second |
Comparison: For the model evaluating the primary outcome (change in T25FW), T25FW was transformed to walking speed by dividing 25 feet by the completion time in seconds (ft/sec). Any participants who were unable to complete the T25FW at any timepoint after baseline were assigned a value of 199 seconds, a statistical technique known as Winsorizing.p-value: 0.51Mixed Models Analysis
Secondary
Brain Atrophy by MRI
Change in whole brain volume from baseline to 24 months
Time frame: 24 months
Population: Intent to Treat Population (all participants assigned to lipoic acid or placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lipoic Acid | Brain Atrophy by MRI | -0.58 cm3 |
| Placebo | Brain Atrophy by MRI | -7.18 cm3 |
p-value: 0.084Mixed Models Analysis
Secondary
Change in Mobility: 2-minute Timed Walk
The score is the distance, in meters, the subject walks in 2 minutes. The change in walking distance across 24 months was compared between treatment groups using a mixed models analysis.
Time frame: 24 months
Population: Intent to Treat Population (all participants assigned to lipoic acid or placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lipoic Acid | Change in Mobility: 2-minute Timed Walk | -7.25 meters |
| Placebo | Change in Mobility: 2-minute Timed Walk | -8.02 meters |
p-value: 0.902Mixed Models Analysis
Secondary
Mobility: Fall Count
Change in number of falls recorded from Baseline to year 2
Time frame: 24 months
Population: Intent to Treat Population (all participants assigned to lipoic acid or placebo).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lipoic Acid | Mobility: Fall Count | 0.65 Falls |
| Placebo | Mobility: Fall Count | 0.63 Falls |
p-value: 0.9Mixed Models Analysis
Other Pre-specified
Safety: Adverse Event Monitoring
Participants with at least 1 treatment-emergent AE
Time frame: 24 months
Population: Intent to Treat Population (all participants assigned to lipoic acid or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lipoic Acid | Safety: Adverse Event Monitoring | 35 Participants |
| Placebo | Safety: Adverse Event Monitoring | 30 Participants |
p-value: 0.134Chi-squared