Table e-1: Inclusion and Exclusion Criteria

Inclusion criteria:

  1. MS by McDonald’s criteria(12), EDSS 0-7.5
  2. Age 18 to 65 years,
  3. A score one or more standard deviations below the mean in one or more of the cognitive tests in the battery
  4. No Ginkgo use in preceding 30 days
  5. Native English speaker

Exclusion criteria:

  1. Substance abuse, psychosis, or significant depression (Beck Depression Inventory II (BDI-II) greater than28)
  2. Any uncontrolled medical problemsuch as unstable angina, stage IV hypertension, cancer undergoing chemotherapy etc.
  3. MS relapse within 30 prior to screening
  4. Abnormalities of coagulation or current use of drugs that affect coagulation except for aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).
  5. Surgery planned for four months after screening.
  6. Epilepsy.
  7. Use of nifedipine, nicardipine, Saint John’s Wort, papaverine, or mono-amino oxidase inhibitors.
  8. Pregnancy
  9. Women not using reliable contraception
  10. Corrected binocular visual acuity worse than 20/50
  11. More than one error on binocular color vision testing
  12. Sustained nystagmus or diplopia on primary gaze
  13. Inability to complete the neuropsychological test battery at screening

Table e-2: Adverse events with higher incidence in the Gingko group

Placebo / Gingko / p∫
Urinary tract infection / 7/59 / 10/61 / NS
Dyspepsia / 0/59 / 3/61 / NS
Flu like symptoms / 2/59 / 3/61 / NS
Back pain / 0/59 / 2/61 / NS
Conjunctivitis infective / 0/59 / 2/61 / NS
Headache / 0/59 / 2/61 / NS
Worsening EDSS / 10/59 / 14/61 / NS

∫Fischer’s exact test

Table e-3: Distribution of baseline Z-scores

Zscore / Gingko / Placebo / Total
Pasat / >= -3 < / 1 (2%) / 0 (0%) / 1 (1%)
>= -2 <-3 / 13 (21%) / 11 (19%) / 24 (20%)
>= -1 <-2 / 30 (49%) / 29 (49%) / 59 (49%)
>= -0.5 <-1 / 11 (18%) / 7 (12%) / 18 (15%)
>= 0 <-0.5 / 6 (10%) / 12 (20%) / 18 (15%)
Stroop / >= -3 < / 6 (10%) / 7 (12%) / 13 (11%)
>= -2 <-3 / 5 (8%) / 7 (12%) / 12 (10%)
>= -1 <-2 / 15 (25%) / 14 (24%) / 29 (24%)
>= -0.5 <-1 / 7 (11%) / 7 (12%) / 14 (12%)
>= 0 <-0.5 / 28 (46%) / 24 (41%) / 52 (43%)
COWAT / >= -2 < / 7 (11%) / 9 (15%) / 16 (13%)
>= -1 <-2 / 28 (46%) / 21 (36%) / 49 (41%)
>= -0.5 <-1 / 7 (11%) / 11 (19%) / 18 (15%)
>= 0 <-0.5 / 19 (31%) / 18 (31%) / 37 (31%)
CVLT-II / >= -3 < / 2 (3%) / 2 (3%) / 4 (3%)
>= -2 <-3 / 6 (10%) / 6 (10%) / 12 (10%)
>= -1 <-2 / 3 (5%) / 5 (8%) / 8 (7%)
>= -0.5 <-1 / 16 (26%) / 13 (22%) / 29 (24%)
>= 0 <-0.5 / 34 (56%) / 33 (56%) / 67 (56%)

Table e-4: Post-hoc subgroup analyzes for the mean z-scores for each neuropsychological test limited to participants scoring less than one SD below the mean on each test.

Ginkgo / Placebo / Ginkgo-Placebo*∫
N / Test / Baseline / Exit / N / Baseline / Exit / Exit / p
Subgroup / Mean±SD / Mean±SD / Mean±SD / Mean±SD / Mean(95%CI)
COWAT Z-score <=-1 / 35 / 30
COWAT / -1.5±0.4 / 0.4±-1.2 / -1.2±0.7 / -1.2±0.7 / 0.0(-0.4,0.3) / NS
CVLT-II / -0.7±1.1 / 1.1±-0.4 / -0.4±1.2 / -0.4±1.2 / 0.4(-0.2,0.9) / NS
PASAT / -1.5±0.9 / 0.9±-1.5 / -1.5±0.8 / -1.5±0.8 / -0.3(-0.7,0.1) / NS
Stroop / -1.2±1.6 / 1.6±-1.2 / -1.2±2.0 / -1.2±2.0 / -0.6(-1.3,0.2) / NS
COWAT Z-score <=-2 / 7 / 9
COWAT / -2.2±0.1 / 0.1±-1.9 / -1.9±0.9 / -1.9±0.9 / 0.1(-1.0,1.1) / NS
CVLT-II / -1.1±1.4 / 1.4±-0.6 / -0.6±0.9 / -0.6±0.9 / -0.1(-1.3,1.1) / NS
PASAT / -1.4±0.7 / 0.7±-1.8 / -1.8±0.7 / -1.8±0.7 / 0.0(-0.5,0.4) / NS
Stroop / -1.3±0.9 / 0.9±-1.8 / -1.8±2.1 / -1.8±2.1 / -0.3(-2.6,2.0) / NS
CVLT-II Z-score <=-1 / 11 / 13
COWAT / -0.7±1.2 / 1.2±-0.6 / -0.6±1.2 / -0.6±1.2 / 0.3(-0.3,1.0) / NS
CVLT-II / -2.3±0.8 / 0.8±-1.9 / -1.9±0.7 / -1.9±0.7 / 0.5(-0.5,1.5) / NS
PASAT / -1.8±0.7 / 0.7±-1.7 / -1.7±1.0 / -1.7±1.0 / 0.2(-0.6,1.0) / NS
Stroop / -2.2±1.9 / 1.9±-1.7 / -1.7±2.7 / -1.7±2.7 / 0.7(-0.5,1.9) / NS
CVLT-II Z-score <=-2 / 5 / COWAT / -1.1±1.0 / 1.0±-0.9 / 3 / -0.9±1.2 / -0.9±1.2 / -2.9(.,.) / NS
CVLT-II / -2.9±0.7 / 0.7±-1.9 / -1.9±1.0 / -1.9±1.0 / -3.8(.,.) / NS
PASAT / -1.9±0.8 / 0.8±-1.5 / -1.5±1.2 / -1.5±1.2 / -3.4(.,.) / NS
Stroop / -2.2±2.3 / 2.3±-1.8 / -1.8±3.7 / -1.8±3.7 / -4.8(.,.) / NS
PASAT Z-score <=-1 / 44 / 40
COWAT / -0.8±1.1 / 1.1±-0.6 / -0.6±1.1 / -0.6±1.1 / 0.1(-0.2,0.4) / NS
CVLT-II / -0.4±1.4 / 1.4±-0.3 / -0.3±1.3 / -0.3±1.3 / 0.2(-0.2,0.6) / NS
PASAT / -1.8±0.6 / 0.6±-1.6 / -1.6±0.8 / -1.6±0.8 / -0.1(-0.4,0.2) / NS
Stroop / -0.9±1.7 / 1.7±-0.7 / -0.7±1.8 / -0.7±1.8 / -0.4(-0.9,0.1) / NS
PASAT Z-score <=-2 / 13 / 9
COWAT / -1.4±0.7 / 0.7±-1.0 / -1.0±0.9 / -1.0±0.9 / -0.1(-0.8,0.5) / NS
CVLT-II / -1.1±1.1 / 1.1±-0.6 / -0.6±1.4 / -0.6±1.4 / 0.4(-0.6,1.5) / NS
PASAT / -2.6±0.4 / 0.4±-2.2 / -2.2±0.6 / -2.2±0.6 / 0.0(-0.7,0.8) / NS
Stroop / -1.7±1.7 / 1.7±-1.7 / -1.7±2.4 / -1.7±2.4 / -1.4(-3.1,0.3) / NS
Stroop Z-score <=-1 / 26 / 28
COWAT / -1.1±0.9 / 0.9±-0.8 / -0.8±1.0 / -0.8±1.0 / 0.1(-0.2,0.5) / NS
CVLT-II / -1.0±1.2 / 1.2±-0.6 / -0.6±1.3 / -0.6±1.3 / 0.1(-0.4,0.6) / NS
PASAT / -1.5±0.9 / 0.9±-1.5 / -1.5±0.9 / -1.5±0.9 / -0.3(-0.7,0.0) / NS
Stroop / -2.4±1.4 / 1.4±-1.5 / -1.5±2.0 / -1.5±2.0 / -0.3(-0.9,0.3) / NS
Stroop Z-score-2 / 11 / 14
COWAT / -1.1±1.0 / 1.0±-0.8 / -0.8±0.9 / -0.8±0.9 / 0.4(-0.3,1.0) / NS
CVLT-II / -1.0±1.0 / 1.0±-0.9 / -0.9±1.3 / -0.9±1.3 / 0.3(-0.7,1.2) / NS
PASAT / -1.5±1.0 / 1.0±-1.4 / -1.4±0.9 / -1.4±0.9 / -0.2(-0.6,0.2) / NS
Stroop / -3.6±1.3 / 1.3±-2.8 / -2.8±2.3 / -2.8±2.3 / -0.8(-1.9,0.4) / NS

*Least square means adjusted for baseline performance; larger values indicate better performance.

∫Positive values indicate a beneficial effect from Ginkgo.

Table e-5: Post-hoc subgroup analyzes: Z-scores on the neuropsychological tests sub-grouped by type of MS

Ginkgo / Placebo / Ginkgo-Placebo*∫
N / Test / Baseline / Exit / N / Baseline / Exit / Exit
Type of MS / Mean±SD / Mean±SD / Mean±SD / Mean±SD / Mean(95%CI)
PPMS / 5 / COWAT / -1.2±0.5 / -1.2±0.6 / 4 / -1.4±1.3 / -1.6±1.0 / -0.4 (-0.9,1.7)**
5 / CVLT-II / -0.6±0.9 / -0.8±0.8 / 4 / -1.1±0.5 / -0.9±0.9 / -0.1 (-1.2,1.3) **
5 / PASAT / -2.1±1.0 / -1.7±0.6 / 4 / -1.2±0.5 / -0.8±0.6 / -0.9(-1.8,0.1) **
5 / Stroop / -1.8±1.7 / -1.0±1.6 / 4 / -0.8±1.5 / -0.8±1.4 / -0.2(-2.6,2.1) **
RRMS / 42 / COWAT / -0.8±1.0 / -0.6±1.0 / 35 / -0.9±0.8 / -0.7±0.9 / 0.1 (-0.2,0.5)
42 / CVLT-II / -0.5±1.2 / -0.5±1.2 / 35 / -0.3±1.3 / -0.1±1.2 / -0.2 (-0.6,0.2)
42 / PASAT / -1.3±0.7 / -1.4±0.8 / 35 / -1.0±0.9 / -0.9±1.1 / -0.2 (-0.6,0.1)
42 / Stroop / -0.7±1.5 / -0.7±1.7 / 35 / -0.8±1.4 / -0.1±0.9 / -0.6 (-1.2,0.0)
SPMS / 14 / COWAT / -1.0±1.2 / -1.0±1.2 / 19 / -0.9±1.2 / -0.8±1.2 / -0.2 (-0.7,0.2)
14 / CVLT-II / -0.6±1.3 / -0.2±1.4 / 19 / -0.7±0.9 / -0.8±1.0 / 0.5 (-0.3,1.2)
14 / PASAT / -1.5±0.9 / -1.2±1.1 / 19 / -1.4±1.0 / -1.1±1.2 / 0.0 (-0.5,0.5)
14 / Stroop / -1.3±1.8 / -0.9±2.4 / 19 / -1.4±1.3 / -0.6±1.3 / -0.5 (-1.4,0.3)

*Least square means adjusted for baseline performance; larger values indicate better performance.

∫Positive values indicate a beneficial effect from Ginkgo.*For PPMS subgroup no baseline adjustment was used due to small sample size.

Table e-6: Secondary and exploratory outcomes

Ginkgo
N=59 / Placebo
N=61 / Ginkgo-placebo*∫
Baseline
Mean±SD / Exit
Mean±SD / Baseline
Mean±SD / Exit
Mean±SD / Exit
Mean (95%CI)
FSS / 47.6±12.8 / 47.0±13.1 / 51.3±9.2 / 45.5±14.1 / -0.1 (-7.2,7.2)
MFIS / 46.9±15.5 / 43.2±13.7 / 50.3±13.5 / 42.9±16.1 / -3.1 (-9.6,3.4)
PDQ / 37.2±11.5 / 31.7±11.1 / 38.2±13.8 / 33.4±15.7 / -0.5 (-5.7,4.7)
CIQ / 23.0±3.7 / 23.1±4.4 / 23.0±4.5 / 22.9±4.4 / -0.2(-1.3,0.8)
MSNQ / 25.2±11.1 / 24.5±11.1 / 27.8±12.5 / 27.0±11.1 / 0.8(-3.2,4.8)
BDI-II / 9.0±7.2 / 6.8±7.0 / 10.7±6.2 / 8.1±7.4 / 0.3(-2.0,2,7)

*Least square means adjusted for baseline performance; larger values indicate better performance.

∫Positive values indicate a beneficial effect from Ginkgo.