Patient-reported outcome measures as final and interim outcome measures in novel progressive multiple sclerosis trials

Neurodegenerative diseases are a group of chronic, slowly progressive, disabling and traditionally untreatable conditions, with examples such as progressive multiple sclerosis (PMS), Alzheimer’s disease (dementia), motor neuron disease, Parkinson disease. These diseases affect many people and place huge emotional, physical, and financial burdens on patients, families, and healthcare services. Focusing on the case of PMS, this represents the neurodegenerative-dominant subtype of multiple sclerosis (MS). While MS is classically an auto-immune condition in which the body accidentally attacks the protective coating (myelin) around nerves in the brain and spinal cord, we now know that the progressive, neurodegenerative component is present in all stages of the condition and account for the majority of disability accumulation over time. Despite the clear clinical need and decades of research using traditional clinical trial designs, there are still very few treatments that can slow or stop disability progression in PMS. One major problem is that conventional trials take a very long time – often more than 10 years – and are extremely expensive.

Newer trial designs could make progress much faster. Multi-arm multi-stage (MAMS) trials can test several drugs at once and use early-stage results to decide whether a drug is promising enough to continue in the trial or should be dropped and resources focused on more promising drugs. This saves time, money, and participant effort. These designs have already brought multiple new treatments and changes to standard practice in cancer and infectious disease research. Decentralised trials can be run remotely, reducing the need for people to travel to clinics, making participation easier and more inclusive, especially for people who are more disabled or who live far from specialist centres.

For both of these trial types, reliable and practical ways of measuring treatment benefit are essential. The standard measure used in PMS trials is the Expanded Disability Status Scale Plus (EDSS-Plus), which assesses disability, mobility and hand function. However, this needs in-person clinical assessments and long follow-up periods to show whether a treatment is working. The use of advanced medical scans called “magnetic-resonance imaging (MRI)” brain scans allow us to see the brain in great details. In PMS specifically, they can be used to track brain shrinkage, which is able to detect earlier changes, predict disability, and show responses to treatment. However, they are costly, difficult for some participants to undergo, and available only at specialist centres. There is growing interest in patient-reported outcome measures (PROs), which are questionnaires in which patients describe their own experience of their condition. Some PROs are specifically designed for MS, such as the MS Impact Scale 29 (MSIS-29) and MS Walking Scale 12 (MSWS-12), while others are disease generic, such as the Short-Form 36 (SF-36) and ABILHAND questionnaires. Although they have clear value, it’s not yet known how best to use them in clinical trials. Previous work by our research team suggests that PROs might be able to reflect changes in disability measured by EDSS-Plus, making them potentially useful for both MAMS and decentralised trials.

To explore this further, we will use detailed data from the ORATORIO, EXPAND, INFORMS and ASCEND trials. The drugs tested in ORATORIO (drug: ocrelizumab) and EXPAND (drug: siponimod) found a clinical benefit for PMS progression and had collected relevant PROs (ORATORIO: SF-36, EXPAND: the MSIS-29 and MSWS-12). ASCEND (drug: natalizumab) showed evidence of benefit in arm and hand function, though not overall measures of disability progression, and collected the MSIS-29, MSWS-12, and ABILHAND questionnaires. While in INFORMS (drug: fingolimod) did not demonstrate a benefit on disability progression, it will allow for meaningful assessment of the relationship between outcomes, and to test our methods in a trial that did not show a benefit on clinical change. Our goal is to test whether the treatment effects seen in clinical outcomes and MRI scans are also detectable in PROM scores. We will also investigate whether combining PROs, clinical measures, and MRI data can better detect early signs that a treatment is working – which would be especially valuable for MAMS trials.