Nicola Coley

Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial

BACKGROUND Prevention strategies are urgently needed to tackle the growing burden of Alzheimers disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract for the reduction of incidence of Alzheimers disease in elderly adults with memory complaints. METHODS In the randomised, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, we enrolled adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France. We randomly allocated participants in a 1:1 ratio according to a computer-generated sequence to a twice per day dose of 120 mg standardised ginkgo biloba extract (EGb761) or matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed-up for 5 years by primary-care physicians and in expert memory centres. The primary outcome was conversion to probable Alzheimers disease in participants who received at least one dose of study drug or placebo, compared by use of the log-rank test. This study is registered with ClinicalTrials.gov, number NCT00276510. FINDINGS Between March, 2002, and November, 2004, we enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of ginkgo biloba extract and 1414 received at least one dose of placebo. By 5 years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimers disease (1·2 cases per 100 person-years) compared with 73 participants in the placebo group (1·4 cases per 100 person-years; hazard ratio [HR] 0·84, 95% CI 0·60-1·18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups. 76 participants in the ginkgo group died compared with 82 participants in the placebo group (0·94, 0·69-1·28; p=0·68). 65 participants in the ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1·12, 95% CI 0·77-1·63; p=0·57). Incidence of other haemorrhagic or cardiovascular events also did not differ between groups. INTERPRETATION Long-term use of standardised ginkgo biloba extract in this trial did not reduce the risk of progression to Alzheimers disease compared with placebo. FUNDING Ipsen.

Dementia Prevention: Methodological Explanations for Inconsistent Results

The prevention of neurodegenerative dementias, such as Alzheimer disease, is a growing public health concern, because of a lack of effective curative treatment options and a rising global prevalence. Various potential risk or preventive factors have been suggested by epidemiologic research, including modifiable lifestyle factors, such as social contacts, leisure activities, physical exercise, and diet, as well as some preventive pharmacologic strategies, such as hormone replacement therapy, nonsteroidal antiinflammatory drugs, and Ginkgo biloba. Some factors have been targeted by interventions tested in randomized controlled trials, but many of the results are in conflict with observational evidence. The aim of this paper is to review the epidemiologic data linking potential protective factors to dementia or cognitive decline and to discuss the methodological limitations that could explain conflicting results. A thorough review of the literature suggests that, even if there are consistent findings from large observational studies regarding preventive or risk factors for dementia, few randomized controlled trials have been designed specifically to prove the protective effects of interventions based on such factors on dementia incidence. Because of the multifactorial origin of dementia, it appears that multidomain interventions could be a suitable candidate for preventive interventions, but designing such trials remains very challenging for researchers.

Endpoints for trials in Alzheimer's disease: a European task force consensus

Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimers disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimers disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimers disease, and for trials in severe Alzheimers disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.

Biomarkers for Alzheimer's disease therapeutic trials

The development of disease-modifying treatments for Alzheimers disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimers disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimers disease therapy trials and to propose practical recommendations for the planning of future AD trials.

Prevention of sporadic Alzheimer's disease: lessons learned from clinical trials and future directions.

Interventions that have even quite modest effects at the individual level could drastically reduce the future burden of dementia associated with Alzheimers disease at the population level. In the past three decades, both pharmacological and lifestyle interventions have been studied for the prevention of cognitive decline or dementia in randomised controlled trials of individuals mostly aged older than 50-55 years with or without risk factors for Alzheimers disease. Several trials testing the effects of physical activity, cognitive training, or antihypertensive interventions showed some evidence of efficacy on a primary cognitive endpoint. However, most of these trials had short follow-up periods, and further evidence is needed to confirm effectiveness and establish the optimum design or dose of interventions and ideal target populations. Important innovations in ongoing trials include the development of multidomain interventions, and the use of biomarker or genetic inclusion criteria. Challenges include the use of adaptive trial designs, the development of standardised, sensitive outcome measures, and the need for interventions that can be implemented in resource-poor settings.

Effectiveness of a specific care plan in patients with Alzheimer’s disease: cluster randomised trial (PLASA study)

Objective To test the effectiveness of a comprehensive specific care plan in decreasing the rate of functional decline in patients with mild to moderate Alzheimer’s disease compared with usual care in memory clinics. Design Cluster randomised trial. Setting 50 memory clinics in France. Participants Patients with Alzheimer’s disease (mini-mental state examination score 12-26). 1131 patients were included: 574 from 26 clinics in the intervention group, and 557 from 24 clinics in the usual care (control) group. Memory clinics were the unit of randomisation. Intervention The intervention included a comprehensive standardised twice yearly consultation for patients and their caregivers, with standardised guidelines for the management of problems identified during the assessment. Main outcome measures The primary outcome measure was change on the Alzheimer’s Disease Cooperative Study-activities of daily living scale assessed at 12 and 24 months. Secondary outcome measures were the rate of admission to institutional care and mortality. Results At two years the assessment was completed by 58.4% (n=335) of patients in the intervention group and 61.6% (n=343) in the control group. The rate of functional decline at two years did not differ between the groups. The annual rate of change on the Alzheimer’s Disease Cooperative Study-activities of daily living was estimated at −5.73 (95% confidence interval −6.89 to −4.57) in the intervention group and −5.96 (−7.05 to −4.86) in the control group (P=0.78). Conclusion A comprehensive specific care plan in memory clinics had no additional positive effect on functional decline in patients with mild to moderate Alzheimer’s disease. Future research should aim to determine the effects of more direct involvement of general practitioners. Trial registration ClinicalTrials.gov NCT00480220.

Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials

Clinical measures continue to be used as primary endpoints for disease‐modifying trials for Alzheimers disease (AD). Currently, two co‐primary endpoints must be specified, which measure cognitive and functional impairments. Generally, the Alzheimers Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) is one of the co‐primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co‐primary approach.

GuidAge Study: A 5-Year Double Blind, Randomised Trial of EGb 761 for the Prevention of Alzheimers Disease in Elderly Subjects with Memory Complaints. I. Rationale, Design and Baseline Data

Primary and secondary prevention strategies for Alzheimers disease (AD) are urgently needed. We have initiated a five-year prospective prevention study involving patients spontaneously reporting memory complaints. The primary objective is to determine the effect of treatment with EGb 76 on the rate of conversion from memory complaints to AD using survival analysis. Ambulatory patients aged at least 70 years who spontaneously reported a memory complaint during a GP or memory centre consultation were eligible for inclusion. Patients with major objective memory impairment or clinically relevant symptoms of anxiety and depression were excluded. Subjects were randomised to receive either EGb 761 120mg bid or matching placebo. Participants undergo an annual visit at a memory centre, where a series of neuropsychological tests are administered to assess cognitive function (Grober and Buschke, Trail-Making and controlled oral word association tests) and cognitive status (MMS and CDR). Functional status is evaluated with the Instrumental Activities of Daily Living questionnaire. The primary outcome is the transition to a diagnosis of AD (DSM-IV and NINCDS-ADRDA criteria), determined at the annual memory centre visit. A total of 4066 patients were screened for participation, of whom 2854 fulfilled the eligibility criteria and were entered into the study. Their mean age was 76.8+/-4.4 years and 66.7% were female. The mean MMSE score was 27.8+/-1.7 and 55.5% presented a CDR score of 0.5. This study will enable us to evaluate the efficacy of EGb761 in the prevention of AD, and to assess the usefulness of various baseline characteristics as predictors of conversion to AD in this population.

Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials

We used the database of the Alzheimers Disease Neuroimaging Initiative (ADNI) to explore the psychometric properties of the Clinical Dementia Rating Sum of Boxes (CDR‐SB) to consider its utility as an outcome measure for clinical trials in early and mild, as well as later, stages of Alzheimers disease (AD).

Long-term progression of Alzheimer's disease in patients under antidementia drugs

Patients with Alzheimers disease (AD), even in the presence of symptomatic relief from medical intervention, face a persistent worsening of cognitive decline and performance in activities of daily living. Data regarding the long‐term disease progression outside of therapeutic trials are lacking. We examined the effects of standard of care for AD patients on the prognosis of the disease in a real‐life study over a 4‐year period.