Improving clinical trial design

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This is blog number 18 in our ‘Symposium Blogathon’ – counting down to the 32^nd International Symposium on ALS/MND. Numbers in bold green type correspond to the code in the abstract book. Click on the number to be redirected to the full abstract (the page may take a minute to load).

As we learn more and more about MND, and move ever closer to precision medicine, a revolution in clinical trial design has begun. Clinical trials are an essential part of drug development and, fuelled by a desire to compare multiple treatments in different sub-groups of patients with related conditions, and to minimise the time between clinical trials, innovatively designed platform trials have begun throughout the UK and the rest of the world.

Traditional clinical trials tend to follow the same format – participants are randomly split into either a group that will receive a single trial drug or a placebo group which will receive a ‘dummy’ drug and, if we’re lucky, we end up with a ‘one-drug-fits-most’ treatment option.

One of the major hurdles for people with MND who want to take part in a clinical trial is meeting the inclusion criteria. Traditionally, clinical trials will only recruit participants who, for example, are within a few months of symptom onset/diagnosis, However, follow-up studies in some clinical trials have found that the trial drug worked better at later stages of the disease, meaning that people who were further progressed may have benefitted from being included in the trial from the beginning. Researchers are now looking at ways to split broader groups of participants into sub-groups so that more people can be included in trials.

Platform trials can find beneficial treatments with fewer patients in less time and with greater probability of success than a traditional clinical trial. In an era of personalised medicine, platform trials provide the innovation needed to efficiently evaluate modern treatments and speed up the process of finding a cure for MND.

Drug development in MND poses multiple challenges. Not only is the biology of MND complex, biomarkers that can track the effectiveness of new drugs are yet to be identified. Lengthy clinical studies are needed to demonstrate effectiveness and there is significant competition for clinical trial participants. These challenges require innovative solutions if drug development efforts for MND are to be successful. In his talk, ‘Innovative trial design considerations for ALS proof of concept and beyond’ (C20), Dr Roubenoff talks about developing an integrated approach to the development of new drugs, and how building relationships with MND patient groups and clinical consortia will ensure patient-centric clinical trial designs and study efficiency.

The HEALEY ALS Platform Trial was scheduled to launch in March 2020 with three novel investigational products and a fourth scheduled to start six months later. The trial uses a common Master Protocol at over 50 sites across the USA. In March 2020, the Covid-19 pandemic caused widespread research and societal restrictions that have continued for well over a year.

Rapidly implemented adjustments were made to make the HEALEY ALS Platform Trial ‘COVID-resilient’ and enable the trial to initiate and sustain enrolment safely and effectively. Because the Platform Trial is conducted under a centralised infrastructure, protocol changes could be carried out very quickly. Modifications meant that monitoring could be completed remotely and in July 2020 the trial enrolled its first participant.

The HEALEY ALS Platform Trial has demonstrated robust enrolment rates and high data quality despite widespread restrictions caused by the pandemic. These results were achieved through a focused set of protocol changes, as well as close communication with trial sites and the patient community. Lessons from the Covid-19 pandemic can be carried forward to increase access, operational feasibility and quality of clinical trials for MND long term (CLT-09).

MND-SMART is a multi-site clinical trial being carried out in the UK that is seeking to identify disease modifying drugs for people with MND. Historically, MND trials have been plagued by recruitment and retainment difficulties leading to insufficiently representative samples, terminated trials or invalid conclusions.

The team running the trial in Scotland investigated patient-specific factors that affect recruitment and retention, specifically for MND-SMART, hypothesising that these may include neuropsychiatric symptoms, cognitive impairment, behavioural change, disease phenotype, quality of life and physical functioning, and will have a significant impact on the decision to participate and remain in MND-SMART.

One hundred and fifty-eight people with MND consented to participate (recruited from the Scottish MND Register), completing either paper, online or telephone questionnaires. Ten individuals died prior to completion. Additional behavioural questionnaires were completed by caregivers in 73% of respondents. 40% of respondents are enrolled in MND-SMART, with more expected to join as sites across Scotland are opened.

This is the first study to prospectively explore the reasons why people with MND join, and remain in, a clinical trial. After 12 months, the team will assess how many people in this study were recruited into the trial and how many remain involved (CLT-18).

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