Developing dementia clinical trials in Ireland 

Prof Iracema Leroi and Dr Anne-Marie Miller of Dementia Trials Ireland speak to Catherine Reilly about a productive first year for the network, which is aiming to enhance dementia trials activity nationally

The headline news in dementia research in recent years has been the development of anti-amyloid monoclonal antibodies (mAbs) for early-stage Alzheimer’s disease (AD).

Currently, a marketing authorisation application for lecanemab is being assessed by the European Medicines Agency (EMA). The medication has been granted traditional approval by the US FDA. If licensed by the EMA, lecanemab will be the first mAb approved for early AD in Europe. The drug, developed by Biogen and Eisai, has been shown to moderately slow the rate of cognitive decline in early AD. It works by reducing amyloid plaques that form in the brain, a defining pathophysiological feature of AD.

In July, Eli Lilly presented full results from the phase 3 TRAILBLAZER-ALZ 2 study showing its drug donanemab “significantly slowed” cognitive and functional decline in people with early symptomatic AD. The data were shared at the 2023 Alzheimer’s Association International Conference (AAIC) in Amsterdam and simultaneously published in the Journal of the American Medical Association. Treatment with donanemab significantly reduced amyloid plaque levels regardless of baseline pathological stage of disease, according to the findings.

At present, there are no mAb trials taking place in Ireland. However, Dementia Trials Ireland (DTI), a Health Research Board (HRB) Clinical Trials Network, is working to enhance readiness to conduct dementia-specific trials. It is also assisting the HSE National Dementia Office to prepare for the eventual introduction of mAb agents into Irish clinical practice, which will be a complex undertaking.

Co-Lead of DTI, Prof Iracema Leroi, told the Medical Independent (MI) that some Irish sites had been due to join an international trial for gantenerumab prior to its discontinuation following failed stage 3 clinical trials. The Irish trial would have enrolled cognitively healthy people who had biomarker positivity for AD. Prof Leroi noted that some of the new agents are now being trialled internationally in pre-clinical cohorts to assess their impact on progression of AD pathology and its “downstream effects”.

DTI remains “very open” to involvement in a mAb trial if an opportunity arises, added Prof Leroi, who is Professor of Geriatric Psychiatry at Trinity College Dublin.

Unmet needs

While undoubtedly a breakthrough, the advent of the mAbs is also serving to illuminate the unmet needs of people living with more advanced AD or other subtypes of dementia.

These cohorts are not currently eligible for the new disease-modifying agents (in trials or clinical practice if licenced), and Prof Leroi emphasised that their quality-of-life and wellbeing must be “prioritised”.

She said “there aren’t enough services and supports for those people” who comprise the majority of individuals living with dementia. 

The unmet needs of people with dementia, their carers and advocates, drives to the heart of DTI’s establishment in September 2022. The central aim of DTI, which is supported by the HRB, is to significantly expand the current small level of dementia clinical trials activity in Ireland. Its remit includes developing a national trials infrastructure, attracting and conducting dementia trials nationally, upskilling the healthcare workforce to facilitate delivery of trials, and ensuring its activities are informed by people with lived experience.

DTI’s Senior Network Manager, Dr Anne-Marie Miller (PhD), told MI: “Our raison d’être is creating opportunities for people with dementia, or their carers, to participate in dementia-focused clinical trials. We are very much focused on developing a trial portfolio that is not solely pharma or drug trial-focused, but developing an umbrella or portfolio of trials that represents all types of intervention, pharmacological and non-pharmacological.”

“And we are also very keen to develop a portfolio that represents all stages of the trajectory of memory impairment. So, from the very early or pre-symptomatic stages… right through to latter stages in the dementia trajectory.”

In addition, Dr Miller emphasised that DTI wants to develop a trials portfolio that encompasses as many dementia subtypes as possible.

Currently, DTI has a small portfolio of industry-led drug trials and investigator-led non-pharmacological studies taking place in Ireland. These include the EVOKE trial, which is sponsored by Novo Nordisk. In Ireland, EVOKE is running in St Vincent’s University Hospital, Dublin, St James’s Hospital, Dublin, Tallaght University Hospital, Dublin, and Mercy University Hospital, Cork. This international trial is investigating whether the anti-diabetic drug semaglutide has a positive effect on early AD. Study participants will be followed and assessed for changes in cognitive function for approximately three years.

DTI is developing a priority setting partnership (PSP) with stakeholders to help guide its work over the coming years. Two national scoping exercises are underway in this regard. The first is focusing on trial activity nationally to provide a detailed picture of what is taking place across all settings. The second exercise is looking at site feasibility in order to assess the ‘road-readiness’ of sites/clinical teams to undertake a trial, their current strengths and deficits, and the level of familiarity with the ancillary facets of trial activity, such as regulatory audits, ethics applications, budgeting, and legal and contractual requirements.  “It is trying to build a picture around the capacity nationally,” said Dr Miller.

DTI’s work is being strongly guided by its public and patient involvement (PPI) panel. Both Prof Leroi and Dr Miller described the panel’s impact as a highlight of DTI’s first year. The panel comprises of people from across Ireland with lived experience of dementia, carers, and advocates. They represent an experience of several different subtypes of dementia.

The panel’s contribution to DTI was recently showcased at the 2023 AAIC, which is the world’s largest annual meeting on dementia science. Several panel members participated in the presentation.

Prof Leroi said the panel members are “very active, dedicated people who advise us on various aspects of the network”.

An example is their “invaluable” feedback in shaping industry trial consent forms and information sheets to ensure accessibility for all people and particularly those with cognitive impairment and their families.

Education

DTI has engaged in significant work related to education and training requirements for healthcare professionals in the context of conducting dementia-specific clinical trials. It has organised, for example, a two-day training course for raters delivered by Dr John Harrison, a neuro-psychological trainer from the UK.

“These are our staff to be able to deliver trials and become qualified in the key outcome ratings, because that is a huge challenge for us in dementia trials – getting sufficient numbers of people who are suitably qualified…,” outlined Prof Leroi.

Asked about the current capacity of consultants to become involved in trials, in the context of service demands, Prof Leroi said: “It is always a challenge; in every country, it is a challenge.”

However, she said consultant time was not the principal challenge in respect of staffing a trial.

“I think the challenges come with the size of the team needed to deliver an industry-sponsored dementia trial. Many of our outcomes depend on rating scales, so for every rater, you need a backup rater, and for every unblinded rater, you need a blinded rater. So, you are potentially looking at a team of four-to-six people, who have to find the capacity in their job plans to take on these additional roles.”

Furthermore, they must also be approved by industry, and this requires a high level of training and clinical trial experience.

The rating capacity is “a huge challenge, and that is not unique to Ireland, that is every setting around the world really, because that is the nature of dementia trials”, noted Prof Leroi.

On 8 November, in collaboration with the HRB-Trials Methodology Research Network, DTI will be holding a training webinar on the barriers to successful delivery of a clinical trial. According to Dr Miller: “We are trying to develop capacity and skills and knowledge amongst the clinical workforce in Ireland so that they are cognisant of the requirements for running a trial and successfully delivering a trial. Hopefully, over the course of our time, we can build up the number of people who have that knowledge, and also increase an interest in supporting clinical trials.”

She continued: “We are not solely focused on training doctors, because aside from the clinical experts whether they be neurologists or gerontologists or psychiatrists… you also need research nurses, advanced research nurses, and all the allied health professionals. Depending on the focus of the trial, it could be speech therapists, physiotherapists, audiologists… it is about building awareness and capacity in all those skillsets for us to have a pool of people nationally.”

Speaking on broader challenges, Prof Leroi said Ireland needs to develop a streamlined pathway for study startup if it is to maximise trial opportunities. She expressed hope that DTI can positively use its voice to advocate for improvements on this important issue.

Trial methodology

Trial methodology research is another area of activity for DTI. It is leading on a significant piece of work to develop a core outcome set specifically for Lewy Body Dementia (LBD), which will have international relevance.

LBD is an under-investigated dementia and comparing treatments is complicated by the range of clinical outcomes reported in existing research.

A core outcome set for LBD research can help ensure that data across studies are comparable and that findings can be more easily translated into clinical decision-making. 

“Core outcome sets are absolutely critical across all areas of medicine to ensure everyone is rating exactly the same things so that we can compare the outcomes of trials and do meta-analyses and so on,” stated Prof Leroi.

Dementia research readiness in care homes in Ireland is also being examined. This is occurring as a study within a trial (SWAT) under the SENSE-Cog Care study, which is a cluster randomised trial of hearing and vision support to improve quality-of-life for residents with dementia in long-term care, funded by the HRB-Definitive Intervention and Feasibility Awards scheme.

“In order to do research in nursing homes you have to understand whether the landscape is fertile for research. Therefore, a study within a trial – SWAT – is undertaken to understand what some of the barriers to research may be,” explained Prof Leroi. “That is an important piece of work that will help the field in general understand how we can do research in care homes better. This is critical, because care home residents are some of the most vulnerable members of society and yet we do the least in terms of research in those settings.”

DTI also provides an annual seed fund award to an early career researcher under its HRB funding. The first recipient was Dr Irina Kinchin, Assistant Research Professor at the Centre for Health Policy and Management, Trinity College Dublin.

Dr Kinchin is leading a PSP in the area of LBD research. In collaboration with stakeholders, this work will focus on setting research priorities for LBD in Ireland.

Future

The landscape of dementia treatment is primed for enormous change – and this extends to diagnostics. At the AAIC 2023, for example, a draft proposal for new AD diagnostic criteria was presented to attendees. The proposal, which was a revision of the 2018 National Institute on Aging-Alzheimer’s Association Alzheimer’s research framework, has incorporated plasma biomarkers into updated criteria for biomarker categorisation, disease diagnosis, and staging.

In the context of recent developments, MI asked Prof Leroi if it was a hopeful or uncertain time for dementia treatment. She indicated that it was both.

“It is extremely hopeful,” she said.

“We have moved forward in a way that we haven’t in the last 20 years; particularly that the lecanemab and donanemab trials are strengthening our understanding of the link between reducing amyloid load and clinical improvement – there was a lot of uncertainty about this issue previously.”

However, expectations will have to be managed. mAbs are not yet available in Ireland and if they are licensed, many people will not be eligible for access due to their stage or type of dementia and/or their particular morbidities.

There will also be wider considerations around the costs of new medications and the level of investment and infrastructure required – such as infusion facilitates and MRI access to monitor drug side-effects. Furthermore, there will be training requirements across healthcare to ensure appropriate referral, as well as competence in monitoring and identifying side-effects. Moreover, if plasma biomarkers are introduced into clinical practice, it will need to be decided where these tests will be administered, etc. 

Currently, DTI is supporting the HSE National Dementia Office in determining service readiness for disease-modifying therapies. As part of this support, it has conducted a public survey of over 1,000 people to gain perspectives on the implications of these new agents. It has also undertaken a smaller survey of healthcare professionals. The findings are currently under review, according to Prof Leroi.

“The National Dementia Office is on top of it, and Dr Seán O’Dowd, who is the new Clinical Lead, is managing that well and very aware of all these issues,” added Prof Leroi. “In that regard it is a really exciting time, but we do have work to do, which is better than not having work to do.”