Cognition, Multiple Sclerosis
Conditions
Keywords
multiple sclerosis, cognition, clinical trial, thiotic acid, Omega-3 fatty acids
Brief summary
The primary aim is to collect data to determine the correct effect size on the primary outcome to aid in the design of a larger study: The primary outcome is to determine if lipoic acid and omega-3 fatty acids can improve cognitive function in people with multiple sclerosis that have cognitive dysfunction.
Detailed description
The study is designed as a randomized, double-blind, placebo-controlled pilot trial. The primary aim of the study is to determine if lipoic acid and omega-3 fatty acids can improve cognitive function over 12-weeks in people with multiple sclerosis that have a baseline score of at least two standard deviations below normative values on any one of four cognitive tests that include, Paced Auditory Serial Addition Task (PASAT), Stroop Color-Word Test, California Verbal Learning Test-II (CVLT-II), and Controlled Oral Word Association Test (COWAT). The secondary aim is to determine treatment effects on markers of endothelial inflammation, insulin dysregulation, and mitochondrial dysfunction that may be related to cognitive dysfunction by measuring soluble intercellular adhesion molecule-1 (sICAM-1) levels, homeostasis model of insulin resistance (HOMA-IR), and MRI phosphorus imaging in a subset of study participants. The study will also measure safety by adverse event reports and laboratory measures; plasma fatty acid levels; serum lipoic acid levels.
Interventions
DRUGlipoic acid and omega-3 fatty acids
alpha lipoic acid as racemic form at 1,200 mg per day omega-3 fatty acids as fish oil concentrate containing a daily dose of 1.35 grams docosahexanoic acid and 1.95 grams of eicosapentaenoic acid
DRUGPlacebo
placebo lipoic acid and placebo oil
Sponsors
National Multiple Sclerosis Society
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* • A definite diagnosis of multiple sclerosis (MS) with relapsing remitting or secondary progressive course * Age 18 to 65 years, inclusive * A score two or more standard deviations below the mean in one or more of the following cognitive tests: PASAT, COWAT, CVLT -II, Stroop * Expanded Disability Status Scale (EDSS) 0-7.5, inclusive * Suboptimal omega-3 levels (plasma docosahexaenoic acid \[DHA\] + eicosapentaenoic acid \[EPA\] \< 5.0% of total plasma fatty acids) * If taking MS disease modifying medications, on stable dose for \> 6 months preceding enrollment * Able to read and write English
Exclusion criteria
* • Moderate to severe depression (Beck Depression Inventory score \> 19) * Any significant uncontrolled medical problem including diabetes requiring insulin. * MS relapse within the 30 days before screening * Abnormalities of coagulation or current use of prescription anticoagulants or antiplatelet agents. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are not excluded. * Fish intake of one 6 ounce serving \> once a week less than 2 months prior to enrollment * Omega-3 fatty acid supplement intake (e.g. fish oil capsules, cod liver oil) less than 2 months prior to enrollment * Lipoic Acid supplementation less than 1 month prior to enrollment * Taking systemic corticosteroids, neuroleptics, antiparkinsonian agents, and/or narcotic analgesics. Low dose sinemet and dopamine agonist taken once a day for restless leg syndrome is not an exclusion. * Contraindications to MRI, including: subjects with intrathecal pumps, stimulators, pacemakers, aneurysm clips, non-removable hearing aids, or metal fragments in the eyes. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Paced Auditory Serial Addition Task (PASAT) | Baseline to 12 weeks | The PASAT is a measure of working memory and sustained attention frequently used in multiple sclerosis treatment outcome studies. The examinee is presented with a series of numbers at 2 second intervals on an audiotape and responds by always adding the last two numbers on the tape before the next number is presented. The change in total number of correct responses from baseline to 12 weeks is the measurement for the outcome. |
| Stroop Color-Word Test | baseline to 12 weeks | The Stroop test assess attention and executive function.The task consists of 3 tasks with only red, green, and blue colors used. The first task asks the subject to name the colors of spots on cards. If a subject can perform this task the second task is performed in which a subject must read the names of colors listed on cards (which are printed in congruent colors). In the third task, the subject is shown a series of words naming colors but the words and colors are mismatched; so the word yellow may be red, the word blue may be green and so forth. The subject is instructed to ignore the word and name the color. The subject will have the tendency to read the word rather than name the color, the so-called Stroop effect. This third part of the test is referred to as the interference condition and is the critical measurement. The change in time it takes to complete the interference from baseline to 12 weeks is the outcome measure. |
| California Verbal Learning Test-II (CVLT-II) | baseline to 12 weeks | CVLT-II is a measure of verbal learning/memory. It is comprised of lists containing 16 words, each of which fit into one of four categories of shopping list items. Five trials are administered followed by presentation of a different list. Free and cued recall of the original list is assessed. The change in long delay free recall from baseline to 12 weeks will be the measurement used for outcome. |
| Controlled Oral Word Association Test (COWAT) | baseline to 12 weeks | The COWAT is a letter fluency test. Participants are asked to generate as many words as possible beginning with a particular letter of the alphabet during one minute. Alternate versions using 3 letters are used for each examination. The change in total number of words produced for the 3 letters from baseline to 12 weeks will be the outcome. |
Countries
United States
Participant flow
Pre-assignment details
49 participants were excluded from the study for the following: did not meet inclusion criteria (i.e. test scores too high, colorblindness, unclear cognitive status), declined to participate, could not consent, lost to follow-up, and started fish oil.
Participants by arm
| Arm | Count |
|---|---|
| Lipoic Acid and Omega-3 Fatty Acids lipoic acid and omega-3 fatty acids
Alpha lipoic acid and omega-3 fatty acids: alpha lipoic acid as racemic form at 1,200 mg per day omega-3 fatty acids as fish oil concentrate containing a daily dose of 1.35 grams docosahexanoic acid and 1.95 grams of eicosapentaenoic acid | 26 |
| Placebo placebo oil and placebo lipoic acid
Placebo: placebo lipoic acid and placebo oil | 28 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Lipoic Acid and Omega-3 Fatty Acids | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 25 Participants | 28 Participants |
| Age, Continuous | 51.22 years STANDARD_DEVIATION 9.97 | 49.34 years STANDARD_DEVIATION 10.91 | 52.96 years STANDARD_DEVIATION 8.85 |
| Region of Enrollment United States | 54 participants | 26 participants | 28 participants |
| Sex: Female, Male Female | 44 Participants | 23 Participants | 21 Participants |
| Sex: Female, Male Male | 10 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 28 |
| other Total, other adverse events | 21 / 26 | 12 / 28 |
| serious Total, serious adverse events | 2 / 26 | 0 / 28 |
Outcome results
Primary
California Verbal Learning Test-II (CVLT-II)
CVLT-II is a measure of verbal learning/memory. It is comprised of lists containing 16 words, each of which fit into one of four categories of shopping list items. Five trials are administered followed by presentation of a different list. Free and cued recall of the original list is assessed. The change in long delay free recall from baseline to 12 weeks will be the measurement used for outcome.
Time frame: baseline to 12 weeks
Population: Only participants who completed CVLT-II at baseline and 12 weeks were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lipoic Acid and Omega-3 Fatty Acids | California Verbal Learning Test-II (CVLT-II) | 1.57 correct responses | Standard Deviation 1.85 |
| Placebo | California Verbal Learning Test-II (CVLT-II) | 1.65 correct responses | Standard Deviation 2.44 |
Primary
Controlled Oral Word Association Test (COWAT)
The COWAT is a letter fluency test. Participants are asked to generate as many words as possible beginning with a particular letter of the alphabet during one minute. Alternate versions using 3 letters are used for each examination. The change in total number of words produced for the 3 letters from baseline to 12 weeks will be the outcome.
Time frame: baseline to 12 weeks
Population: Only participant who completed COWAT at both baseline and 12 weeks were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lipoic Acid and Omega-3 Fatty Acids | Controlled Oral Word Association Test (COWAT) | 0.70 words | Standard Deviation 7.71 |
| Placebo | Controlled Oral Word Association Test (COWAT) | 0.39 words | Standard Deviation 7.14 |
Primary
Paced Auditory Serial Addition Task (PASAT)
The PASAT is a measure of working memory and sustained attention frequently used in multiple sclerosis treatment outcome studies. The examinee is presented with a series of numbers at 2 second intervals on an audiotape and responds by always adding the last two numbers on the tape before the next number is presented. The change in total number of correct responses from baseline to 12 weeks is the measurement for the outcome.
Time frame: Baseline to 12 weeks
Population: Only participants who completed PASAT at both baseline and 12 weeks were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lipoic Acid and Omega-3 Fatty Acids | Paced Auditory Serial Addition Task (PASAT) | 2.24 correct responses | Standard Deviation 4.69 |
| Placebo | Paced Auditory Serial Addition Task (PASAT) | 3.38 correct responses | Standard Deviation 5.46 |
Comparison: With the initial sample size plan of 53 subjects, we expect an 80% power to detect a significant difference in PASAT score with a mean difference of 8.3 points between the treatment and placebo group.p-value: 0.0595% CI: [-2.03, 4.32]t-test, 2 sided
Primary
Stroop Color-Word Test
The Stroop test assess attention and executive function.The task consists of 3 tasks with only red, green, and blue colors used. The first task asks the subject to name the colors of spots on cards. If a subject can perform this task the second task is performed in which a subject must read the names of colors listed on cards (which are printed in congruent colors). In the third task, the subject is shown a series of words naming colors but the words and colors are mismatched; so the word yellow may be red, the word blue may be green and so forth. The subject is instructed to ignore the word and name the color. The subject will have the tendency to read the word rather than name the color, the so-called Stroop effect. This third part of the test is referred to as the interference condition and is the critical measurement. The change in time it takes to complete the interference from baseline to 12 weeks is the outcome measure.
Time frame: baseline to 12 weeks
Population: Analysis occurs only for participants who completed Stroop at both baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lipoic Acid and Omega-3 Fatty Acids | Stroop Color-Word Test | -5.59 seconds | Standard Deviation 12.77 |
| Placebo | Stroop Color-Word Test | -2.87 seconds | Standard Deviation 7.01 |