부산대학교 도서관

BACKGROUND: Motor neuron disease (MND), often referred to by its most common subtype amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressive neurodegenerative disorder for which there is no cure. Average life expectancy from diagnosis is 2 to 3 years and the majority of individuals experience disabling limb weakness and bulbar symptoms, ultimately succumbing from respiratory failure. Established in 1989, the Scottish Motor Neuron Disease Register was the first population-based register for MND in the world. In 2015 the register was re-launched as the electronic platform Clinical Audit Research and Evaluation of MND (CARE-MND) and records all cases of MND in Scotland. This register will be used to support recruitment, and provide additional clinical data, for the studies in this thesis. Despite over 75 trials being completed in the past decade, only one disease modifying treatment with limited efficacy is licensed in the United Kingdom. However, the landscape of trials in MND is rapidly changing. Multi-arm, multi-stage adaptive trials such as MND-SMART (Motor Neuron Disease Systematic Multi-Arm Randomised Adaptive Trial) encapsulate this new direction. Many of the issues associated with the failure of historical trials have been addressed in MND-SMART; a definitive statistical design with large numbers of participants and long duration follow up assessing functioning (ALS-FRS(R) and survival as co-primary outcome measures, ability to discontinue ineffective drugs at interim analysis points due to futility, ability to seamlessly add new treatment arms, wide inclusion criteria, remote assessment, liquid medications and reduced chance of being assigned to the placebo condition. With many previous barriers to participation acknowledged we then have a unique opportunity to prospectively explore the characteristics of individuals who self-select to participate in a trial. It is also now widely understood that MND does not exclusively affect the motor system, and non-motor symptoms that occur secondary from, or in addition to, motor degeneration are part of the disease. These symptoms also require new treatments and should be addressed when evaluating candidate drugs' therapeutic mechanisms. Progression of functionally impairing MND symptoms has been traditionally evaluated, in clinical care and as a primary outcome of trials, using the ALSFRS(R) (ALS Functional Rating Scale Revised), a questionnaire-based assessment, usually administered face to face in clinic, which has limited sensitivity to detect smaller changes in functional ability. Technology-based outcome measures are increasingly being evaluated across neurological disorders as an alternative, sensitive and objective assessment of progression, and may also offer new directions in MND research. AIMS: To evaluate holistic assessments that may be of utility in contemporary trials of motor neuron disease (MND), including non-motor outcome measures and digital assessment tools, and explore person-specific reasons that determine participation in an innovative new clinical trial for MND. OBJECTIVES: Through systematic reviews we evaluated previous use of non-motor outcome measures in MND trials, and an experimental study using a participant-completed questionnaire provided a participant perspective on the occurrence and importance of these symptoms. To explore person-specific reasons for participation in a clinical trial, a second experimental study was conducted involving participant and caregiver questionnaires and clinical data, the responses from which were then evaluated against trial participation data. A final systematic review provided a background on previous use of digital devices to evaluate motor progression in MND, which informed a final experimental study evaluating the acceptability of wearable accelerometers to a group of people with MND. RESEARCH QUESTIONS AND HYPOTHESES: 1.Non-motor symptoms have been historically under evaluated in MND trials, but people with MND report them as frequently occurring and consider these symptoms as important to include in future trial design. 2.Person-specific factors, such as neuropsychiatric symptoms, cognitive impairment, demographics, phenotype, quality of life, apathy and physical functioning, are associated with an individual with MND's decision to engage with a clinical trial. 3.The use of technology to evaluate motor progression in MND is in the early stages of development and validation, but with new studies continuing to emerge as technology becomes more common in health research. 4.People with MND find using technology to monitor motor decline to be an acceptable method of data collection, with wearable sensors offering a feasible alternative to traditional questionnaire-based assessment. METHODS: In order to answer the above research questions, the thesis is structured as follows: 1)Systematic Review 1: A rigorous unbiased systematic literature review to establish the frequency of neuropsychiatric, cognitive and behavioural assessments in the last 25 years of MND trials. 2)Systematic Review 2: A rigorous unbiased systematic literature review considering a broader range of non-motor symptoms. 3)Experimental Study 1: A questionnaire-based study evaluating non-motor symptoms and investigating the frequency, severity, impact, and importance of these symptoms to people with MND for inclusion in trials. 4)Experimental Study 2: A standardised questionnaire-based study with associated relevant clinical data to evaluate the characteristics of a cohort of people with MND, followed up over a year later to establish participation and retention in MND-SMART, an innovative new UK wide clinical trial for MND. 5)Systematic Review 3: A rigorous unbiased systematic review to evaluate digital technologies used to evaluate motor progression in MND. The results of this review were used to inform the design of the final study of this PhD thesis: 6)Experimental Study 3: A study evaluating the acceptability of a wearable accelerometers in remote longitudinal videoconferencing based motor assessments including 24-hour wear periods, in a cohort of people with MND. RESULTS: Neuropsychiatric, cognitive, behavioural and other non-motor symptoms have been under evaluated in the last 25 years of MND trial design. In Experimental Study 1, all but one of the 120 participants experienced at least one non-motor symptom, with pain and fatigue most frequently identified (76%). 80% of participants considered non-motor symptoms to be important to include in trial design, independent of the number of symptoms that they reported themselves. Results from Experimental Study 2, identified that older age and the presence of apathy were associated with lower likelihood of trial participation and retention. Despite this, the cohort were overall highly motivated to engage with MND-SMART, with 50% of participants being randomised to the trial by the one-year data collection time-point. Systematic Review 3 identified 20 studies, involving 1,275 people with MND and using 26 types of digital technologies. All studies showed initial feasibility, but well-powered longitudinal studies were needed. Only 25% of studies in this review evaluated the acceptability of these devices to people with MND. In Experimental Study 3, 10 participants completed the full 12-week protocol of motor tasks and 24-hour wear periods, with wear-time increasing as the study progressed. 80% found wearing the devices to be a positive experience, and although 30% experienced technical issues all participants remained excited about the potential benefits of using technology to assess MND. CONCLUSIONS: Findings from this thesis can be used to inform the design of future trials; particularly recruitment and retention strategies. Engaging older adults, supporting participants with apathy-related behavioural change and continuing to explore how to support people with MND to become involved in a clinical trials if they wish to do so, are essential directions for future research in this area. To deliver participant-centric clinical trials in MND it is important to expand the concept of impairment, and treatment, to include non-motor symptoms. Previous trials have not adequately explored the potential secondary benefits or side effects of investigative medicinal products on the broad range of symptoms that can be present in MND. Non-motor symptoms are present, frequently occurring and impactful to people with MND, who are supportive of evaluating the holistic impact of a candidate drug in clinical trials. Results from this thesis confirm that the way in which trial outcomes are measured is changing. Technology to monitor health, track progression and evaluate motor symptoms offer promising new directions for MND research. These devices are often more sensitive than traditional questionnaire-based assessments, and their capacity to detect smaller changes in function may mean that they are ideal to evaluate trial outcomes. Further, larger, well-powered studies are needed to establish the responsiveness and suitability of different devices, but participants found wrist and ankle worn accelerometers to be an acceptable method of measuring motor symptoms remotely over 24-hour wear periods.