'25 at 25': ACORD collaboration for multi-arm multi-stage trials in neurodegenerative diseases
20 Jun 2024
In 2021, the MRC Clinical Trials Unit at UCL founded the national ACORD collaboration in partnership with UCL Queen Square Institute of Neurology and the University of Edinburgh. This ambitious project marked the beginning of a new era for clinical trials in neurodegenerative diseases, offering new hope to people affected by these conditions.
ACORD brings together clinical triallists, neurologists, drug development specialists, charities, and patient representatives with a common goal: to identify new treatments which can slow, stop, or even reverse the progression of neurodegenerative diseases.
The collaboration aims to achieve this by introducing the innovative multi-arm multi-stage (MAMS) clinical trial design to the neurodegenerative diseases field for the first time. Alongside, ACORD will inspire and train the next generation of researchers through the ACORD Fellows Academy.
Neurodegenerative diseases are chronic conditions caused by a loss of structure or function in nerve cells. In the UK alone, more than one million people are living with a neurodegenerative condition, and this is a leading cause of ill health and disability.
There are many different neurodegenerative disorders, but ACORD focuses on four diseases with a major impact: motor neurone disease (MND), progressive multiple sclerosis (MS), Parkinson’s disease, and Alzheimer’s disease.
In recent years, the scientific community have made remarkable progress in understanding the mechanisms that drive neurodegenerative diseases. Researchers are identifying ever more potential treatments, whether new drugs, or repurposed existing drugs which are already licensed to treat other conditions.
However, this is yet to translate into tangible benefits for patients; for decades, there has been little or no improvement. Very few treatments are available that can delay or slow disease progression – and certainly none that can reverse disease.
Testing each candidate treatment is a long and slow process, and many will fail to show an effect on disease progression in the later stages of clinical research. To capitalise on recent scientific advances, we need a new generation of innovative clinical trials.
ACORD is running the first ever large-scale, phase III, MAMS trials in several neurodegenerative diseases. The MAMS design provides a smarter way of testing potential treatments, producing results up to three times more quickly than traditional clinical trials.
MAMS trials test multiple experimental treatments at the same time, all compared to a single control arm. Treatments which show sufficient promise in an interim analysis can seamlessly progress to the next stage, while other treatments are dropped. New treatments can be added to the trial as they become available.
This is much more efficient than running a separate trial for each individual treatment (which is like building a new stadium for each football match). Therefore, MAMS trials can help deliver potentially life-changing treatments for people with neurodegenerative diseases much sooner.
Currently, the ACORD collaboration has two clinical trials open for recruitment, in MND (MND-SMART) and progressive MS (OCTOPUS). A third, in Parkinson’s disease (EJS ACT-PD) will open in 2025 and a trial in Alzheimer’s disease (MASTODON) is currently in development.
MND-SMART
MND-SMART is a MAMS trial testing repurposed drugs for MND. The trial opened in 2020 with three arms: a placebo control arm, memantine (currently used to improve memory in people with Alzheimer’s disease), and trazodone (currently used to treat anxiety and depression). In April 2023, a new arm joined the trial testing amantadine, which is currently used in the treatment of Parkinson’s disease and to reduce fatigue in MS.
In September 2023, memantine and trazodone were removed from the trial early, as an interim analysis showed that they were highly unlikely to be beneficial for people living with MND. The amantadine arm remains open and the team are currently prioritising further drugs for testing, which will join MND-SMART in the future.
MND-SMART is run by the University of Edinburgh and the Euan MacDonald Centre, with support from MND Scotland, the My Name’5 Doddie Foundation and the Motor Neurone Disease Association.
OCTOPUS
The MRC CTU at UCL launched the OCTOPUS trial in 2023. OCTOPUS is testing multiple repurposed treatments for progressive MS, aiming to find out if they can slow the progression of disability.
The trial is currently recruiting participants for three arms: a placebo control arm, R/S alpha lipoic acid (a health supplement) and metformin (currently used to treat type 2 diabetes).
OCTOPUS is funded by the MS Society.
EJS ACT-PD
Parkinson’s disease is the fastest growing neurological condition in the world, and EJS ACT-PD is doing the underpinning preparatory work for a trial to deliver new treatments for people affected by Parkinson’s.
The trial is scheduled to open for recruitment in 2025 and will initially be recruiting to three arms: a placebo control arm, telmisartan and terazosin (both currently used to treat high blood pressure).
EJS ACT-PD is funded by the Edmond J. Safra Foundation and co-led by UCL and the University of Plymouth, in collaboration with the MRC CTU at UCL.
MASTODON-AD
Alzheimer’s disease is the most common cause of dementia. In its first phase, MASTODON-AD will test three repurposed drugs, aiming to find out if they can effectively treat dementia and mild cognitive impairment in people with Alzheimer’s disease.
MASTODON-AD is currently in development (PRE-MASTODON-AD), with researchers working to select which repurposed drugs to test. The team have invited proposals from the Alzheimer’s disease drug development community. An international panel will then assess these suggestions to generate a shortlist, before selecting the three lead drugs to be used at the start of the MAMS trial.
This process is funded by the National Institute of Health and Care Research Efficacy and Mechanism Evaluation programme and supported by Alzheimer’s Research UK.
Fellows Academy
In addition, the ACORD collaboration includes a Fellows Academy, which launched in 2022 to inspire and train the next generation of trialists by providing bespoke mentorship, training and support to early career researchers affiliated with the collaboration’s studies.
There are currently 18 fellows working in a variety of specialisms, including drug discovery programmes, complex trial design methodology and co-production with patients.
The next annual meeting of the ACORD Collaboration and ACORD Fellows Academy will be held in late 2024.
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