Napryeyenko 2009.

Study characteristics
Methods	A 2‐armed (Ginkgo biloba and placebo), parallel‐group randomised controlled trial with 22 weeks duration of treatment and 12 and 22 weeks duration of follow‐up
Participants	Location: Kyiv, Ukraine Setting: multi‐centre study, outpatient clinics of 16 psychiatric or neurological hospitals Sample size: Number randomised: 200 in Ginkgo biloba group and 200 in placebo group Number completed: 196 in Ginkgo biloba group and 195 in placebo group Participant baseline characteristics: Age (mean (SD) years): 65 (8) in Ginkgo biloba group versus 63 (8) in placebo group Gender (male/female, n): 55/143 in Ginkgo biloba group versus 55/142 in placebo group Other characteristics: all participants had either Alzheimer's disease (AD; n = 214) or vascular dementia (VaD; n = 181). Baseline tinnitus symptom severity in the whole study sample measured on the 11‐point box scale (from 0 indicating absence to 10 indicating extreme severity of the symptom) was 2.1 (SD 2.3) in the Ginkgo biloba group and 2.1 (SD 2.2) in the placebo group. From 400 participants enrolled in the study 204 had tinnitus (101 in the Ginkgo biloba group and 103 in the placebo group). Baseline tinnitus symptom severity for participants with tinnitus was 4.02 in the Ginkgo biloba group and 3.90 in the placebo group. Baseline data for tinnitus characteristics and hearing were not reported. Inclusion criteria: participants were eligible for the study if they were at least 50 years of age and diagnosed with AD (probable AD or possible AD with cerebrovascular disease) or VaD. Diagnoses were established employing the criteria specified by the National Institute for Neurological and Communicative Disorders and Stroke (NINCDS) together with the Alzheimer's Disease and Related Disorders Association (ADRDA) and by the National Institute of Neurological Disorders and Stroke (NINDS) together with the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) as appropriate. A CT or MRI scan, no more than 1 year old, had to be consistent with the inclusion diagnosis. The Test for Early Detection of Dementia with Discrimination from Depression (TE4D) was used as a screening instrument and to verify the presence of cognitive impairment in at least 2 domains. A total cognitive score of no more than 35 was required for inclusion. Patients had to have mild to moderate dementia as evidenced by a total score from 9 to 23 (both inclusive) on the SKT test battery, which roughly corresponds to a range from 14 to 25 on the MMSE or 17 to 35 on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐cog). The Clock‐Drawing Test (CDT) after Sunderland et al was employed as a second screening instrument, the score of which had to be below 6. Patients had to score at least 5 on the 12‐item Neuropsychiatric Inventory (NPI), with at least one item score (other than delusions or hallucinations) being 3 or higher. Severe depression was excluded by requiring a score below 20 on the 17‐item Hamilton Rating Scale for Depression (HAMD). The presence of a caregiver was required who was able and willing to provide information on the patient's behaviour and competence to perform activities of daily living. Exclusion criteria: patients were excluded from the study if they had any other type of dementia or neurological disorder, current or recent major depression or other psychiatric disorder, severe or insufficiently controlled cardiovascular, renal or hepatic disorder, diabetes, anaemia or thyroid dysfunction. Active malignant disease, HIV or lues infection and gastrointestinal diseases with uncertain absorption were not accepted. Treatment with other anti‐dementia drugs, cognitive enhancers, cholinergic, anti‐cholinergic or haemo‐rheologically active drugs, anti‐Parkinson drugs or Ginkgo supplements was prohibited during the study and at least 8 weeks preceding randomisation.
Interventions	Intervention group: EGb 761 dry extract from Ginkgo biloba leaves (35 to 67:1), extraction solvent: acetone 60% (w/w). The extract was adjusted to 22.0% to 27.0% Ginkgo flavonoids, calculated as Ginkgo flavone glycosides, and 5.0% to 7.0% terpene lactones consisting of 2.8% to 3.4% ginkgolides A, B, C and 2.6% to 3.2% bilobalide, with a content of ginkgolic acids below 5 ppm. Daily dose of 240 mg (2 × 120 mg), 22 weeks. Comparator group: placebo, 22 weeks Use of additional interventions: none reported
Outcomes	Primary outcome: the SKT, a 9‐item cognitive test battery with scores ranging from 0 to 27 at 12 and 22 weeks Secondary outcomes: 12‐item Neuropsychiatric Inventory (NPI), which assesses frequency and severity of neuropsychiatric symptoms (composite score range 0 to 144) and caregiver distress caused by such symptoms (score range 0 to 60); the activities‐of‐daily living (ADL) subscale of the Gottfries–Bråne–Steen (GBS) overall geriatric assessment scale; the total score of the GBS (comprised by the intellectual “I”, the emotional “E”, and ADL subscores, but not the behavioural “S” subscore which was not documented to avoid redundancy); the Verbal Fluency Test (animal fluency); the Clock‐Drawing Test and the Hamilton Rating Scale for Depression. Patient self‐ratings of presence and severity of dizziness and tinnitus, symptoms often associated with old age, were documented using 11‐point box scales, 0 representing absence and 10 indicating extreme severity of a symptom. All measures were collected at baseline, 12 and 22 weeks. Safety was assessed by documentation of adverse events at 6, 12, 17 and 22 weeks and physical examination, electrocardiography and laboratory tests at 22 weeks.
Funding sources	The clinical trial was sponsored by Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany
Declarations of interest	No information provided
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Centre‐stratified randomisation (drug–placebo ratio 1:1) in blocks of four was performed by the sponsor's biometrics unit using a validated computer program that linked ascending drug numbers to active drug or placebo, respectively."
Allocation concealment (selection bias)	Low risk	Quote: "The randomisation list was sealed and stored safely at the sponsor's biometrics unit, and block length was not disclosed to investigators."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The multi‐centre trial with two parallel treatment arms was carried out in a double‐blind manner. Drug and placebo tablets were indistinguishable by appearance, packaging and labelling."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Information not reported in the manuscript.
Incomplete outcome data (attrition bias) All outcomes	Low risk	214 of 218 patients with Alzheimer's and 181 of 182 patients with vascular dementia with full data for analysis.
Selective reporting (reporting bias)	High risk	There are 2 reports from this study, one reporting tinnitus score in the whole study population (from 0 ‐ absence of tinnitus to 10 ‐ extreme severity) and one brief report reporting tinnitus scores only in those participants with tinnitus.
Other bias	High risk	No prospective protocol available. No declarations of interest reported. This was a study of effects of Ginkgo biloba on Alzheimer's disease or vascular dementia. Tinnitus was secondary outcome measure.