Trial of Ginkgo as a Treatment for Cognitive Problems in Multiple Sclerosis

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.

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