We conducted a 2 × 2 factorial, community-based, pragmatic, randomised, double-blind, parallel-group trial in which participants were treated, double-blind with an high-purity extract of Ginkgo biloba (120 mg daily) or placebo for six months (the DIGGER trial: Dementia In General Practice Ginkgo Extract Research). In addition to randomisation to treatment, participants were randomised to intensive or minimal follow-up (see below for details). The factorial design was economical in terms of the numbers of patients required to address the two questions. The trial was approved by South West Multi-Centre Research Ethics Committee (ref:MREC/02/6/35) and was registered with Current Controlled Trials(ISRCTN45577048). The trial was sponsored by London West Mental Health Research and Development Consortium, and funded by the Alzheimer's Society. There was extensive consumer involvement, through the Alzheimer's Society, at all stages.
Participants
We recruited participants in Greater London (UK) and adjacent regions through referrals from general practitioners, old age psychiatrists and other health care professionals; and from direct responses to advertising in Alzheimer Society newsletters, London-based newspapers, and posters in Age Concern centres.
Eligibility was determined with reference to the following:
Inclusion criteria
• Aged 55 years or over
• Presence of a carer able to report on the functioning of the participant
• Informed consent of the participant or in the case of an individual who lacks the capacity to give their consent, their assent and the agreement of their nominated carer
• Sufficient command of English to complete questionnaires
• Clinical diagnosis of dementia (sub-classified using DSM-IV criteria) [8]
• A Mini Mental State Examination (MMSE) [9] score of 12–26 inclusive
• Living in the community
Exclusion criteria
• Use of Ginkgo in two weeks prior to the baseline assessment
• Commencement of cholinesterase inhibiting drugs within 2 months of baseline or during follow-up
• Concomitant warfarin therapy
• Known bleeding abnormalities
Interventions (follow-up)
In order to assess the Hawthorne Effect, participants were randomised to intensive follow-up (with comprehensive assessment visits at baseline and two, four and six months post randomisation) or minimal follow-up (with an abbreviated assessment at baseline and a full assessment at six months). To minimise the chances that any difference was due to medication intake, the minimal follow-up group was sent their study medication by post (Royal Mail) at two-monthly intervals. All visits were domiciliary.
Outcomes
Our primary outcome measures were: i) cognitive functioning, as measured by the ADAS-Cog, a 0–70 point scale with a higher score indicating worse cognition; and ii) quality of life, rated by the participant and their nominated carer, as measured by the QOL-AD, both 13-item scales, scoring between 13 and 52 points with a higher score indicating better quality of life. Both outcome measures are validated tools previously (and in most cases commonly) used in dementia trials. Other measures undertaken at each assessment as part of the therapy component of the trial included a measure of psychopathology, a social behaviour scale, a caregiver burden scale and a blood test for coagulation time. We decided, a priori, not to consider these outcomes in the Hawthorne analysis. Each patient and caregiver assessment took approximately 1.5 to 2 hours. All outcomes were administered by a trained researcher during a home visit. The ADAS-Cog was scored by the researcher; all other measures were scored by the participant or their carer.
Sample size
As we knew of no studies that had attempted such a comparison before, we did not power the study to detect a difference between the follow-up groups. Instead we relied on the sample size calculation for effect of Ginkgo over placebo, which gave a target sample size of 200 participants. This sample size was sufficient to detect a 4-point between-group difference in ADAS-cog with 80% power at 5% significance.
Randomisation procedure and blinding
A 2 × 2 factorial design involving two separate randomisations, resulting in participants being randomised to one of four arms, was employed. Both factors consisted of two levels: medication group (Ginkgo and placebo); and level of follow-up (minimal or intensive). This produced four groups: the Ginkgo group with intensive follow-up, the Ginkgo group with minimal follow-up, the placebo group with intensive follow-up and the placebo group with minimal follow-up. The randomisation codes were generated usingthe computer algorithm RCODE v.4.8 (Schwabe, 2002).
The Ginkgo vs. placebo component of the trial was double-blind, but it was not possible to blind the Hawthorne component of the trial as both researchers and participants needed to know when the next assessment would be.
Statistical methods
The primary analysis was intention to treat (ITT) with available data, by randomisation group. We were interested in the effects of intensity of follow-up; participants who withdrew from the study were not exposed to the "intervention", so analysis with imputed data was not thought appropriate.
In order to take account of the baseline score, when comparing the outcomes between the treatment groups, analysis of co-variance (ANCOVA) was used. Normal distributions were assumed for the ANCOVA analyses and were checked using residuals from the regression models. If data showed substantial deviations from these assumptions, appropriate transformations were applied. Adjusted differences in means (β) are presented with 95% confidence intervals and p values. Chi-square test was used for comparison of proportions. The analysis was conducted using SPSS v.13 (SPSS Corporation, 2004) and STATAv.8.1 (STATA Corporation, 2003).