An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study.

BACKGROUND: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease. METHODS: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. DISCUSSION: This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer's disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03489044 . Registered on April 5, 2018.

Commentary on Reconstituting Fibrinogen Concentrate to Maintain Blinding in a Double-blind, Randomized Trial in an Emergency Setting.

BACKGROUND: The gold standard of trial design is the double-blind, placebo-controlled, randomized trial. Intravenous medication, which needs reconstitution by the attending clinician in an emergency situation, can be challenging to incorporate into a suitably blinded study. DISCUSSION: We have developed a method of blindly reconstituting and administering fibrinogen concentrate (presented as a lyophilized powder), where the placebo is normal saline. Fibrinogen concentrate is increasingly being used early in the treatment of major hemorrhage. Our methodology was designed for a multicenter study investigating the role of fibrinogen concentrate in the treatment of the coagulopathy associated with major obstetric hemorrhage. The method has been verified by a stand-alone pharmaceutical manufacturing unit with an investigational medicinal products license, and to date has successfully been applied 45 times in four study centers. There have been no difficulties in reconstitution and no related adverse events reported. CONCLUSION: We feel our method is simple to perform and maintains blinding throughout, making it potentially suitable for use in other trials conducted in psychologically high-pressure environments. Although fibrinogen concentrate was the focus of our study, it is likely that the method is applicable to other lyophilized medication with limited shelf life (e.g., antibiotics).

Good friends are hard to find? The social networks of people with mental illness 12 years after deinstitutionalisation.

BACKGROUND: While community care is now well established in England, the development and maintenance of social networks of people with long-term mental illness remains a major challenge to services. AIMS: To investigate the size of the social networks of people with long-term mental illness and the types of social support they receive in relation to their age and accommodation. Sample Thirty-nine men and 46 women (mean age: 61 years; range: 38-88). Forty nine (60%) were 65 years or under and 32 (40%) were over 65. METHODS: Participants were interviewed using the Social Network Guide. Comparisons were made using generalised linear modelling. RESULTS: Social networks (median 19; range 2-85) were generally larger than those reported in previous studies. Older residents (over 65 years) had closer ties than younger residents. Congregate types of community settings were relatively devoid of social supports. CONCLUSION: Appropriate activities and social contexts are still needed to facilitate the social networks of people with mental illness, in particular, for those aged under 65 years.

Cognitive stimulation therapy for people with dementia: cost-effectiveness analysis.

BACKGROUND: Psychological therapy groups for people with dementia are widely used, but their cost-effectiveness has not been explored. AIMS: To investigate the cost-effectiveness of an evidence-based cognitive stimulation therapy (CST) programme for people with dementia as part of a randomised controlled trial. METHOD: A total of 91 people with dementia, living in care homes or the community, received a CST group intervention twice weekly for 8 weeks; 70 participants with dementia received treatment as usual. Service use was recorded 8 weeks before and during the 8-week intervention and costs were calculated. A cost-effectiveness analysis was conducted with cognition as the primary outcome, and quality of life as the secondary outcome. Cost-effectiveness acceptability curves were plotted. RESULTS: Cognitive stimulation therapy has benefits for cognition and quality of life in dementia, and costs were not different between the groups. Under reasonable assumptions, there is a high probability that CST is more cost-effective than treatment as usual, with regard to both outcome measures. CONCLUSIONS: Cognitive stimulation therapy for people with dementia has effectiveness advantages over, and may be more cost-effective than, treatment as usual.

Service use and costs of supporting the most socially disabled patients in a hospital reprovision programme. A two-hospital comparison.

BACKGROUND: The UK, in common with other Western countries, has seen a marked reduction in the number of long-stay hospital beds over the past few decades and most asylums have been closed. Whilst hospital closure and discharge programmes differ, a common characteristic is likely to be that those patients who are "difficult-to-place" in the community are amongst the last to be discharged. This paper compares service use and costs of difficult-to-place patients from two UK hospitals (Friern and Warley) and identifies predictors of cost. One of these hospitals (Warley) provided a more intensive programme of rehabilitation. METHOD: The study included 84 patients (Friern 63, Warley 21). Patient characteristics prior to discharge were recorded. Service use was measured and costs calculated for the year following discharge. Comparisons were made between the Warley and Friern groups and cost predictors were identified using multiple regression analysis. RESULTS: Post-discharge accommodation, in-patient and outpatient costs were substantially higher for the Friern group, whilst the Warley group had higher day care costs. The total mean costs were pound 13,432 higher for the Friern group. However, non-accommodation costs were substantially higher for the Warley group. Patients with more social skills had higher non-accommodation costs. Higher total costs were associated with more self-care skills, fewer domestic skills and younger age. Longer length of stay prior to discharge was associated with higher non-accommodation and total costs. CONCLUSIONS: The costs of care following discharge differed substantially between these two groups. This is partly a supply effect given the different strategies for caring for these difficult-to-place patients. In common with other studies, patient characteristics can explain some of the differences in future costs.

Quality and costs of community-based residential supports for people with mental retardation and challenging behavior.

A longitudinal matched-groups design was used to examine the quality and costs of community-based residential supports to people with mental retardation and challenging behavior. Two forms of provision were investigated: noncongregate settings, where the minority of residents had challenging behavior, and congregate settings, where the majority of residents had challenging behavior. Data were collected for 25 people in each setting. We collected information through interviewing service personnel in each type of setting on the costs of service provision, the nature of support provided, and the quality of life of residents. We also conducted observations in each setting. Results suggest that noncongregate residential supports may be more cost effective than congregate residential supports.