Neurodegenerative Diseases Research Network Research Articles

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: the MADE Phase II, three-arm RCT

Background Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies. Trial registration Current Controlled Trials ISRCTN16105064 and EudraCT 2013-000397-30. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 2. See the NIHR Journals Library website for further project information.

Dementia care and research - What a difference a decade makes?

Dementia care currently costs the UK 21 bn pounds a year, and that doesn't include the huge informal costs of family careers and community support networks. Developing services to meet the needs of patients with complex health problems must involve service users. Professor Robinson has addressed what resources are needed to provide a better quality of care, and how these can be successfully delivered to patients and their family. As Newcastle University's Professor of Primary Care and Ageing, and as a working GP in a Newcastle practice, she is keen to ensure that the benefits of the University's excellent research into ageing and the diseases of old age are translated into high quality treatment and care for older people. She leads the Primary Care Group of the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN), a national network of researchers which aims to explore the whole spectrum of dementia care from diagnosis and early detection, through to advanced dementia and end of life care. Another Professor Robinson's ambitions would be to help create a center of excellence at Newcastle University for training GPs, hospital staff, community nurses and others in all aspects of dementia care. In this lecture, Prof Robinson will talk about how her translational research had influenced UK practice over the last 10+ years and at same time bring in her career development in both clinical and academic field.(Presented at the 1982th Meeting, June 25, 2019).

How dementia and neurodegenerative disease clinical research networks have enhanced research delivery in England

In 2005 the Government established a clinical research network in dementia and neurodegenerative diseases to increase and improve research in an area of unmet need. Since its creation, the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN) has facilitated a 300% increase in the number of the National Health Service trusts recruiting people to dementia and neurodegeneration research, a 500% increase in the number of open studies each year, and a 600% increase in the number of people taking part in studies. This article summarizes the increased activity and improvements in performance delivered since 2005; describes some of the people networks through which this has been delivered; and describes how the network is evolving as part of the reorganization of the National Institute for Health Research Clinical Research Network.

Perspectives of carers on medication management in dementia: lessons from collaboratively developing a research proposal.

BackgroundThe need for carers to manage medication-related problems for people with dementia living in the community raises dilemmas, which can be identified by carers and people with dementia as key issues for developing carer-relevant research projects.A research planning Public Patient Involvement (PPI) workshop using adapted focus group methodology was held at the Alzheimer’s Society’s national office, involving carers of people with dementia who were current members of the Alzheimer’s Society Research Network (ASRN) in dialogue with health professionals aimed to identify key issues in relation to medication management in dementia from the carer viewpoint. The group was facilitated by a specialist mental health pharmacist, using a topic guide developed systematically with carers, health professionals and researchers. Audio-recordings and field notes were made at the time and were transcribed and analysed thematically. The participants included nine carers in addition to academics, clinicians, and staff from DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) and the Alzheimer’s Society.FindingsSignificant themes, for carers, which emerged from the workshop were related to: (1) medication usage and administration practicalities, (2) communication barriers and facilitators, (3) bearing and sharing responsibility and (4) weighing up medication risks and benefits. These can form the basis for more in-depth qualitative research involving a broader, more diverse sample.DiscussionThe supported discussion enabled carer voices and perspectives to be expressed and to be linked to the process of identifying problems in medications management as directly experienced by carers. This was used to inform an agenda for research proposals which would be meaningful for carers and people with dementia.

Enabling research in care homes: an evaluation of a national network of research ready care homes

BackgroundIn the UK care homes are one of the main providers of long term care for older people with dementia. Despite the recent increase in care home research, residents with dementia are often excluded from studies. Care home research networks have been recommended by the Ministerial Advisory Group on Dementia Research (MAGDR) as a way of increasing research opportunities for residents with dementia. This paper reports on an evaluation of the feasibility and early impact of an initiative to increase care home participation in research.MethodsA two phase, mixed methods approach was used; phase 1 established a baseline of current and recent studies including the National Institute for Health Research portfolio. To explore the experiences of recruiting care homes and research participation, interviews were conducted with researchers working for the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN) and care home managers. In phase 2, four DeNDRoN area offices recruited care homes to a care home network for their region. The care home networks were separate from the DeNDRoN research network. Diaries were used to document and cost recruitment; DeNDRoN staff were interviewed to understand the barriers, facilitators and impact of the care home networks.ResultsThirty three current or recent studies were identified as involving care homes as care home specific studies or those which included residents. Further details of care home recruitment were obtained on 20 studies by contacting study teams. Care home managers were keen to be involved in research that provided staff support, benefits for residents and with minimal disruption. In phase 2, 141 care homes were recruited to the care home research networks, through corporate engagement and individual invitation. Pre-existing relationships with care homes facilitated recruitment. Sites with minimal experience of working with care homes identified the need for care home training for researchers.ConclusionsPhase 1 review revealed a small but increasing number of studies involving care homes. Phase 2 demonstrated the feasibility of care home research networks, their potential to increase recruitment to research and develop partnerships between health services and care homes, but highlighted the need for care home training for researchers.

New horizons in the pathogenesis, assessment and management of movement disorders

In this review, we shall outline recent advances in our understanding of the movement disorders which geriatricians encounter in their clinical practice. Many of these diseases are no longer simply considered disorders of movement: carefully conducted longitudinal studies have shown that concomitant cognitive dysfunction, neuropsychiatric disturbance and behavioural issues are frequent and exert a heavy burden on the individual and their carers. Great progress has been made in understanding the molecular and cellular processes that drive the pathological changes in these conditions, as have advances in neuroimaging and preclinical drug discovery programmes. Unfortunately, this is yet to translate into disease-modifying therapies for these progressive disorders. Advances have been also made in non-pharmacological interventions such as tailored physiotherapy and speech therapy programmes. The important contribution of palliative care has been recognised and increasingly incorporated into the multidisciplinary approach. The UK is at the forefront of research into these conditions and geriatricians are well placed to contribute to research through recruiting patients to observational studies or therapeutic trials, particularly with the support of agencies such as the National Institute for Health Research-Dementias & Neurodegenerative Diseases Research Network (NIHR-DeNDRoN).

Contribution of research networks to a clinical trial of antidepressants in people with dementia

Background.The Mental Health Research Network and Dementia and Neurodegenerative Diseases Research Network were established in the UK to increase research capacity and activity; the former in mental health generally, and the latter specifically in neurodegenerative disorders including dementia. Little evidence exists on the impact of these networks on research in mental health of older people.AimsTo examine research network support to a multi-centre randomised controlled trial of antidepressants in people with depression superimposed on dementia.MethodQualitative questionnaires were completed by principal investigators, trial-funded research workers and clinical study officers (CSOs) of the research networks.ResultsResearch network contribution was much valued by principal investigators and the nine research teams. CSOs boosted the recruitment campaign in a challenging environment and enhanced assessment processes. Some problems with consistency and staff turnover were raised.ConclusionResearch network input can make an appreciable difference to the process and outcome of a multi-centre clinical trial.

Supporting clinical research in the NHS in England: the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network.

Clinical research is best done when aligned with clinical care - that is, when the patient can be identified, recruited and, in many instances, researched in parallel with the delivery of clinical service. However, to achieve this effectively requires identification of the additional cost to the National Health Service clinical support services and the development of an appropriately skilled workforce. The National Institute for Health Research (NIHR) Cancer Research Network demonstrated the value of dedicated research support in terms of the number of patients recruited into clinical trials. Building on this model, the NIHR in England funded the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). DeNDRoN is now in its sixth year and has established a geographically widespread network of research support staff and research leadership managed by a central coordinating centre. Success can already be measured by a significant increase in the number of patients entering studies and the speed with which both commercial and noncommercial studies are completed. There are also early indications that the network will result in improved patient outcomes.

The impact of patient and public involvement in the work of the Dementias & Neurodegenerative Diseases Research Network (DeNDRoN): case studies

(i) To describe patient and public involvement (PPI) in a network promoting research in dementia and neurodegenerative diseases, in terms of activity at the different stages of the research cycle and within the different levels of the research network. (ii) To use case studies to try and answer the question: what benefits (if any) does PPI in research bring to the research process? PPI in health research is a central part of government policy, but the evidence base underpinning it needs strengthening. PPI allows exploration of feasibility, acceptability and relevance of hypotheses, assists in the precise definition of research questions and increases accrual to studies. However, the measurement of outcomes is methodologically difficult, because the impact of lay researchers may occur through team interactions and be difficult to untangle from the efforts of professional researchers. Opportunities for PPI in rapidly progressive diseases may be limited, and involvement of people with marked cognitive impairment is particularly challenging. (i) Description of PPI within the DeNDRoN network. (ii) Case studies of three research projects which asked for extra help from centrally organized PPI. PPI in research projects on the DeNDRoN portfolio may function at different levels, occurring at project, local research network and national level. Case studies of three research projects show different roles for PPI in research and different functions for centrally organized PPI, including contribution to remedial action in studies that are not recruiting to target, solving problems because of the complexity and sensitivity of the research topic, and linking researchers to PPI resources. The case studies suggest that centrally organized PPI can have 'diagnostic' and remedial functions in studies that are struggling to recruit and serve as reinforcement for study-level PPI in the complex and sensitive research topics that are typical in neurodegenerative diseases research. PPI may be actively sought by researchers, but the infrastructure of PPI is not yet so widespread in the research community that lay researchers are easy to find; a centrally organized PPI resource can assist in this situation.

NICE: Managing conflict

Some of the strengths of NICE (the National Institute for Health and Clinical Excellence) are that it ‘sees guidelines as guidelines, not as rules set in stone’, adopts ‘flexible approaches’, and does not ‘expect its pronouncements to be accepted without questioning’ (JRSM 2007;100:442-3).1 It thrives on argument, as the recent papers in the October 2007 issue of the JRSM demonstrate, and grows stronger through debate and controversy. This is hardly surprising, given that it has the task of promoting cost-effective use of resources whilst also encouraging innovation, improving quality and reducing variation in practice, in response to the need to deal with clinical and budgetary uncertainties about therapies (JRSM 2007;100:453-60).2 It stands, therefore, at the controversial intersection of quality, innovation, access and cost, with a remit to operate in a transparent and inclusive way, using cost effectiveness to inform decisions about treatments, without considering their affordability.3 As an organization it is designed to manage conflicts of opinion, not avoid them, and it is becoming increasingly capable of doing so. NICE was established to correct inequalities and inefficiencies in health care, including unacceptable variations in the uptake of technologies of proven value, failure to provide patients with optimum care for the treatment of common diseases and the too-ready adoption of therapies with no proven clinical benefit.4 It is, therefore, an openly political body. NICE operates a form of deliberative democracy which engages clinicians, researchers, industry, economists and public organizations in an iterative process of decision making. This deliberative democracy has proved beneficial to clinicians, patients and the pharmaceutical industry. For example, the decisions made by NICE about neuropsychiatric agents like the atypical antipsychotics and the cholinesterase inhibitors have lifted restrictions on their funding and facilitated their wider use. Likewise, openness to patient opinion seems to encourage NICE to accept therapies where the evidence base is relatively weak or the cost effectiveness analysis unfavourable.5 While some decisions by NICE lead to high-profile media criticisms supported by parts of the industry and some patient groups, NICE is for politicians a comparatively safe haven from which decisions can be defended in public by those with expertise. It is therefore no stranger in the British NHS but a continuation of attempts to keep clinical decisions away from politicians, even though they sometimes cannot resist becoming embroiled. Among NICE's political weaknesses are the unrealistic signals that it can send about affordability to politicians and the public and its absence from debates about prioritization.6 The decisions over which services or therapies will be displaced by new treatments approved by NICE are made at local level, whilst cost-effectiveness judgements are made nationally. There is a risk is that therapies may be displaced that are more cost effective than those being introduced, which means that a methodology is now needed to decide how best to disinvest from relatively ineffective but well-established treatments.7 Such arguments about the applicability and implementation of NICE guidelines are, as Gupta and Warner point out, currently central to both clinical governance and commissioning at local level, and have different implications for social services,8 social care,9 nursing10 and general practice.11 Although ‘only in research’ decisions are often seen as rejections12 designed to evade appeals and pressure from lobby groups, their purpose is to generate the additional evidence to allow confident decisions to be made. Influencing the research agenda is not just a good intention, but now has operational expression in research networks designed to facilitate large trials, and in funding streams that supplement industry-funded studies. In the field of dementia, the Dementia & Neurodegenerative Diseases Research Network (DeNDRoN) supports clinical trials and the National Institute of Health Research has recently funded three five-year programmes of projects focusing on non-pharmacological interventions. We are approaching an integrated system of research and development, informed by NICE's assessments. NICE is certainly ‘here to stay’ (JRSM 2007;100:439)13 partly because it is an organization with very significant intellectual resources at its disposal that is capable of rapid learning. More importantly, it is able to set the agenda for the development of new treatments as well as to evaluate their cost effectiveness, and before long is likely to look beyond the specific therapy under review to the wider system of health services provision. We should look forward to this.

Is neuroscience nursing adding value to care?

The Dementias and Neurodegenerative Diseases Research Network (DeNDRoN) supports a fresh approach to clinical research: its aim is to place NHS expertise and resources at the centre of a quality research infrastructure, improving both the speed of research and the integration of best practice into patient care. Its core aims include timeliness of trial set-up, support for recruitment and the provision of a trained workforce to facilitate the conduct of quality research.