Multiple Sclerosis, Cognitive Ability, General
Conditions
Keywords
Ginkgo biloba, Multiple Sclerosis, Cognition, Neuropsychological Tests, Neurobehavioral Manifestations, Quality of life, Randomized Controlled Trials, Placebos, Double-Blind Method
Brief summary
The purpose of this study is to see if treatment with Ginkgo improves cognitive function in people with multiple sclerosis who have cognitive problems.
Detailed description
Objectives: Primary objective: Determine the difference between subjects treated with Ginkgo biloba (GB) and subjects treated with placebo for 12 weeks on the performance of a battery of neuropsychological tests that are frequently impaired in Multiple Sclerosis (MS): the Stroop test, the Paced Auditory Serial Addition Test (PASAT), the California Verbal Learning Test (CVLT-II), and the Controlled Oral Word Association Test (COWAT). Secondary objectives: Determine the difference between the two groups after treatment in the following outcomes: 1) incidence of treatment related side effects, 2) cognitive performance as reported by the subjects on the Perceived Deficits Questionnaire, 3) cognitive performance as reported by the subject's family members or caregivers as measured on the Multiple Sclerosis Neuropsychological Screening Questionnaire and 4) community integration as measured with the Community Integration Questionnaire. Research plan: This will be a randomized double blind placebo controlled trial of GB 120 mg twice a day for 12 weeks. Methods: One hundred fifty-eight subjects (79 per group) will be randomly assigned to placebo or GB. Subjects will be evaluated at baseline and exit with the cognitive test battery and the self report measures detailed above. For the primary outcome, multivariate analysis of covariance (MANCOVA) will be used to analyze the changes in all the cognitive tests simultaneously. This analysis will be followed by the analysis of covariance (ANCOVA) for each of the cognitive tests in the battery. The sample size we selected has a power of 0.80 with an alpha level of 0.05 on the overall MANCOVA and for each of the ANCOVA's after Bonferroni's correction. The self report measures will be analyzed using ANCOVA with baseline responses as covariates. Safety evaluations will include complete blood count and metabolic panel as well as physical exams at baseline and at exit. The physical exam will include the Expanded Disability Scale (EDSS). Telephone follow-ups will be done monthly while on treatment and one month after exiting the study to review study procedures and assess side effects. Adverse reactions will be classified using the categories and grading in the Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria (CTC) Version 3.0 and reported to the Institutional Review Board (IRB) following the institutions guidelines. A Data Safety Management Board (DSMB) will oversee the study.
Interventions
DRUGGinkgo biloba
120 mg orally twice a day for 12 weeks
DRUGPlacebo
One capsule orally twice a day for 12 weeks
Sponsors
US Department of Veterans Affairs
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 65 Years
Healthy volunteers
No
Inclusion criteria
* A diagnosis of multiple sclerosis by McDonald's criteria * Age 18 to 65 years, inclusive * A score minus one standard deviation below the mean on one or more of the following tests: PASAT, COWAT, CVLT-II, Stroop * EDSS 0 - 7.5, inclusive * No Ginkgo biloba in preceding 30 days * Native English speaker
Exclusion criteria
* Current substance abuse disorder, psychosis, or significant depression (score on the Beck Depression Inventory II (BDI -II) greater than 28 * Any significant uncontrolled medical problem including diabetes requiring insulin * Relapse of multiple sclerosis within the 30 days before screening * Abnormalities of coagulation or current use of anticoagulants or antiplatelet agents * Elective surgery planned for the study period or the following four weeks * Epilepsy or history of seizures * Use of nifedipine, nicardipine, Saint John's Wort, papaverine, mono amine oxidase inhibitors * Pregnancy or women not using a reliable form of contraception * Corrected binocular visual acuity worse than 20/50 or more than one error on binocular color vision testing with the Ishihara Color Plates or sustained nystagmus or diplopia on primary gaze * Inability to complete the neuropsychological test battery at the screening visit * History of alcohol abuse or illicit drug use in the prior six months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | 12 weeks | Performance at exit adjusted for baseline performance on 4 neuropsychological tests: STROOP(Victoria version):Tests attention&executive function. Outcome is the interference condition condition; time needed to name the colors in which words (which are names of colors) are printed. Words and colors are mismatched. CaliforniaVerbalLearningTest- II: Tests verbal/learning/memory. Outcome number of words (shopping list) remembered after 20 min delay with no cues. PacedAuditorySerialAdditionTest:Tests working memory/sustained attention. Outcome is the number of correct responses to recording giving numbers every 2 sec. Last 2 numbers must be added together before the next number. ControlledOralWordAssociationTest:Tests letter fluency. Outcome number of words produced in one minute for each of 3 letters. Measures reported as Z-scores based on the available population norms for each test; range -infinite +infinite; 0 average; -1=1std below average; +1=1std above average. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | 12 weeks | The Perceived Deficits Questionnaire (PDQ), a standardized questionnaire in which the subject reports on his or her cognitive function; Measure total score Range (0 best - 80 worse) Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ), in which the family member who was most aware of the participant's cognitive deficits reports on the subject's cognitive deficits; measure total score range (0 best - 60 worse) 'and the Community Integration Questionnaire (CIQ) in which the subject reports his or her degree of social integration; range (0 worst - 32 best); measure total score. Sub-scales for these 3 measures were not used for outcome measures only total scores. |
Countries
United States
Participant flow
Recruitment details
Study sites were the Portland VA Medical Center, Portland, Oregon & VA Puget Sound Health Care System, Seattle Washington. Enrollment time span was January 2009 to November 2010.
Pre-assignment details
A total of 172 people were assessed for eligibility and 52 did not meet criteria for randomization. Reasons for exclusion included cognitive scores too high (35), Beck Depression Inventory II scores too high (7), failed color vision test(4), usage of contraindicated medications (2); miscellaneous reasons (4).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo, one capsule orally twice a day for 12 weeks. | 59 |
| Ginkgo Ginkgo (EGb-761), 120-mg tablet of ginkgo twice a day for 12 weeks. | 61 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Ginkgo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants | 61 Participants | 120 Participants |
| Age, Continuous | 53.0 years STANDARD_DEVIATION 9.5 | 51.3 years STANDARD_DEVIATION 8.6 | 52.1 years STANDARD_DEVIATION 9.1 |
| Disease duration, average number of years | 19.3 years STANDARD_DEVIATION 11.8 | 20.9 years STANDARD_DEVIATION 11.8 | 20.1 years STANDARD_DEVIATION 11.8 |
| Expanded Disability Status Scale | 4 units on a scale STANDARD_DEVIATION 2 | 4 units on a scale STANDARD_DEVIATION 2 | 4 units on a scale STANDARD_DEVIATION 2 |
| Race/Ethnicity, Customized Non-white | 0 participants | 6 participants | 6 participants |
| Race/Ethnicity, Customized White | 59 participants | 55 participants | 114 participants |
| Sex: Female, Male Female | 37 Participants | 29 Participants | 66 Participants |
| Sex: Female, Male Male | 22 Participants | 32 Participants | 54 Participants |
| Type of Multiple Sclerosis Primary Progressive MS | 4 Participants | 5 Participants | 9 Participants |
| Type of Multiple Sclerosis Progressive Remitting MS | 1 Participants | 0 Participants | 1 Participants |
| Type of Multiple Sclerosis Relapsing Remitting MS | 35 Participants | 42 Participants | 77 Participants |
| Type of Multiple Sclerosis Secondary Progressive MS | 19 Participants | 14 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 59 | 0 / 61 |
| serious Total, serious adverse events | 0 / 59 | 2 / 61 |
Outcome results
Primary
Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test.
Performance at exit adjusted for baseline performance on 4 neuropsychological tests: STROOP(Victoria version):Tests attention&executive function. Outcome is the interference condition condition; time needed to name the colors in which words (which are names of colors) are printed. Words and colors are mismatched. CaliforniaVerbalLearningTest- II: Tests verbal/learning/memory. Outcome number of words (shopping list) remembered after 20 min delay with no cues. PacedAuditorySerialAdditionTest:Tests working memory/sustained attention. Outcome is the number of correct responses to recording giving numbers every 2 sec. Last 2 numbers must be added together before the next number. ControlledOralWordAssociationTest:Tests letter fluency. Outcome number of words produced in one minute for each of 3 letters. Measures reported as Z-scores based on the available population norms for each test; range -infinite +infinite; 0 average; -1=1std below average; +1=1std above average.
Time frame: 12 weeks
Population: Data of all 120 participants was analyzed. For subjects with missing exit values (1 placebo, 2 ginkgo) the baseline measures were carried forward in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ginkgo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | PASAT | -1.4 z-scores | Standard Deviation 0.8 |
| Ginkgo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | Stroop Interference | -0.9 z-scores | Standard Deviation 1.6 |
| Ginkgo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | COWAT | -0.9 z-scores | Standard Deviation 1 |
| Ginkgo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | CVLT-II delayed free recall | -0.5 z-scores | Standard Deviation 1.2 |
| Ginkgo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | Stroop Interference | -0.8 z-scores | Standard Deviation 1.8 |
| Ginkgo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | COWAT | -0.7 z-scores | Standard Deviation 1 |
| Ginkgo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | CVLT-II delayed free recall | -0.4 z-scores | Standard Deviation 1.2 |
| Ginkgo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | PASAT | -1.3 z-scores | Standard Deviation 0.9 |
| Placebo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | COWAT | -1.0 z-scores | Standard Deviation 1 |
| Placebo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | Stroop Interference | 01.0 z-scores | Standard Deviation 1.4 |
| Placebo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | CVLT-II delayed free recall | -0.5 z-scores | Standard Deviation 1.2 |
| Placebo Baseline | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | PASAT | -1.2 z-scores | Standard Deviation 0.9 |
| Placebo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | CVLT-II delayed free recall | -0.4 z-scores | Standard Deviation 1.2 |
| Placebo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | Stroop Interference | -0.3 z-scores | Standard Deviation 1.1 |
| Placebo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | PASAT | -1.0 z-scores | Standard Deviation 1.1 |
| Placebo Exit | Primary Outcome is Performance on the Interference Condition of the Stroop, the Long Delay Free Recall Portion of the California Verbal Learning Test II, the 2 Second Paced Auditory Serial Addition Test and the Controlled Oral Word Association Test. | COWAT | -0.8 z-scores | Standard Deviation 1 |
Comparison: PASAT Exit Z-score least square means difference adjusted for baseline. Positive values indicate a beneficial effect from treatment with Ginkgo.p-value: 0.195% CI: [-0.5, 0.1]ANCOVA
Comparison: Stroop Exit Z-score least square means difference adjusted for baseline.Positive values indicate a beneficial effect from treatment with Ginkgo.p-value: 0.00795% CI: [-0.9, -0.1]ANCOVA
Comparison: COWAT Exit Z-score least square means difference adjusted for baseline. Positive values indicate a beneficial effect from treatment with Ginkgo.p-value: 0.595% CI: [-0.2, 0.3]ANCOVA
Comparison: CVLT-II Delayed Recall Exit Z-score least square means difference adjusted for baseline. Positive values indicate a beneficial effect from treatment with Ginkgo.p-value: 0.595% CI: [-0.3, 0.3]ANCOVA
Comparison: MANCOVA for all four cognitive tests at exit adjusting for baseline. Individual ANOVAs were to follow if the multivariate test was significant.p-value: 0.19MANCOVA
Secondary
Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration.
The Perceived Deficits Questionnaire (PDQ), a standardized questionnaire in which the subject reports on his or her cognitive function; Measure total score Range (0 best - 80 worse) Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ), in which the family member who was most aware of the participant's cognitive deficits reports on the subject's cognitive deficits; measure total score range (0 best - 60 worse) 'and the Community Integration Questionnaire (CIQ) in which the subject reports his or her degree of social integration; range (0 worst - 32 best); measure total score. Sub-scales for these 3 measures were not used for outcome measures only total scores.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ginkgo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | PDQ: Perceived deficits Questionnaire | 37.2 units on a scale | Standard Deviation 11.5 |
| Ginkgo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | CIQ:Community Integration Questionnaire | 23.0 units on a scale | Standard Deviation 3.7 |
| Ginkgo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | MSNQ: MS Neuropsychological ScreeningQuestionnaire | 25.2 units on a scale | Standard Deviation 11.1 |
| Ginkgo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | PDQ: Perceived deficits Questionnaire | 31.7 units on a scale | Standard Deviation 11.1 |
| Ginkgo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | CIQ:Community Integration Questionnaire | 23.1 units on a scale | Standard Deviation 4.4 |
| Ginkgo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | MSNQ: MS Neuropsychological ScreeningQuestionnaire | 24.5 units on a scale | Standard Deviation 11.1 |
| Placebo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | MSNQ: MS Neuropsychological ScreeningQuestionnaire | 27.8 units on a scale | Standard Deviation 12.5 |
| Placebo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | PDQ: Perceived deficits Questionnaire | 38.2 units on a scale | Standard Deviation 13.8 |
| Placebo Baseline | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | CIQ:Community Integration Questionnaire | 23.0 units on a scale | Standard Deviation 4.5 |
| Placebo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | PDQ: Perceived deficits Questionnaire | 33.4 units on a scale | Standard Deviation 15.7 |
| Placebo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | CIQ:Community Integration Questionnaire | 22.9 units on a scale | Standard Deviation 4.4 |
| Placebo Exit | Secondary Outcome: Measures of Self-report as Well as Family Reports of Subject's Cognitive Deficits and Assessment of Social Integration. | MSNQ: MS Neuropsychological ScreeningQuestionnaire | 27.0 units on a scale | Standard Deviation 11.1 |
Comparison: Perceived Deficits Questionnairep-value: 0.495% CI: [-5.7, 4.7]ANCOVA
Comparison: Multiple Sclerosis Neuropsychological Questionnairep-value: 0.795% CI: [-3.2, 4.8]ANCOVA
Comparison: Community Integration Questionnairep-value: 0.495% CI: [-1.3, 0.8]ANCOVA