The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce: Randomised Controlled Trial (preprint)

Background: Largescale trials of multi-domain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over two years. Methods A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to Mild Cognitive Impairment (MCI) or Subjective Cognitive Decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE-Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term conditions self-management Two facilitators trained and supervised by a clinical psychologist deliver ten, one-hour group video call sessions over 6 months (approximately every fortnight), video-call “tea breaks” (less structured, facilitated social sessions) in intervening weeks, and individual goal-setting phone calls every two weeks. From 6–12 months, participants meet monthly for “tea breaks”, with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer, and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality adjusted life year (QALY), and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. Discussion If effective, the intervention design, involving remote delivery and non-clinical facilitators would facilitate intervention roll-out to older people with memory concerns. Trial registration: ISRCTN17325135. Registration date 27th November 2019. https://doi.org/10.1186/ISRCTN17325135

Statistical and Health Economic Analysis Plan Including COVID-19 Mitigation Strategy for the Physio4FMD Trial (preprint)

Background: Functional motor disorder (FMD) is a common cause of disabling neurological symptoms such as weakness and tremor. We are carrying out a pragmatic, multicentre single blind randomised controlled trial to evaluate effectiveness and cost effectiveness of specialist physiotherapy versus treatment as usual to improve physical functioning at 12 months. Like many other studies, this trial was affected by the COVID-19 pandemic, which interrupted the trial towards the end of planned recruitment. In this paper, we discuss (i) the impact of COVID-19 on the trial; (ii) the impact mitigation strategies implemented; and (iii) the planned statistical and health economic analysis methods and sensitivity analyses aimed at assessing the disrupting influence of COVID-19 on the trial. Methods The planned statistical and health economics analyses for this trial are described, as well as the sensitivity analyses designed to assess the disruption caused by COVID-19. The trial treatment of at least 89 participants (33%) was disrupted due to the pandemic response. To account for this, we have extended the trial to increase the sample size. We have identified four groups based on how participants’ involvement in Physio4FMD was affected; A: 24 were unaffected; B: 131 received their trial-treatment before the start of the COVID-19 pandemic and were followed up during the pandemic; C: 89 were recruited in early 2020 and had not received any randomised treatment before clinical services closed because of COVID-19; D: participants recruited after the trial was restarted in July 2021 (target 90 to 120). The primary analysis will involve groups A, B and D. Regression analysis will be used to assess treatment effectiveness. We will conduct descriptive statistics for each of the groups identified and sensitivity regression analyses with participants from all groups, including group C, separately. Discussion The COVID-19 mitigation strategy and analysis plans are designed to maintain the integrity of the trial while providing meaningful results. By publishing our analysis plans ahead of database lock, analysis and unblinding, we aim to avoid bias due to data-driven analysis. Trial registration : The trial was registered with the ISRCTN register on 27/03/2018, number ISRCTN56136713.

COVID-19 is associated with multiple sclerosis exacerbations that are prevented by disease modifying therapies (preprint)

BackgroundInfections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS. MethodsThe COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms. ResultsFifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection. ConclusionCOVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.