Neuropsychological evaluation and rehabilitation in multiple sclerosis – definitive randomised controlled trial (RCT) and implementation study

Approved 07/11/2023, North West – Greater Manchester West Research Ethics Committee (3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, United Kingdom; +44 207 104 8278; gmwest.rec@hra.nhs.uk), ref: 23/NW/0272

Self-reported psychological impact of MS on everyday life, measured using the Psychological Subscale of the Multiple Sclerosis Impact Scale (MSIS-Psych; Hobart et al., 2001) at baseline, 3, 6 and 12 months post randomisation. The primary endpoint is at 3 months post-randomisation.

Outcomes for secondary objectives 1a and 1b:
1.1. Participant scores from cognitive screening measures (completed at a single time-point at screening) including an online, self-administered: Symbol Substitution Task (SST), and Word Colour Task (WCT).
1.2. Demographic, clinical features and screening usage information (e.g., time taken to complete the screening, type of device used to complete screening, setting the screening completed at, number of patients who required reminders and extra support, etc.) will be collected as part of cognitive screening (at a single-time point at screening).

Outcomes for secondary objective 1c:
1.3. Clinical data collected as part of usual care: Patient scores from the three measures from the Multiple Sclerosis Quality of Life Inventory for self-reported cognitive problems, fatigue and mental health (Ritvo et al., 1997), measured during screening as part of usual care.

Outcomes for secondary objectives 2a and 2b:
The following secondary outcome measures will be used to capture information about the patient at baseline and to assess outcomes at 3, 6 and 12 months after randomisation:
2.1. Self-reported (subjective) cognitive impairment as measured using the Perceived Deficits Questionnaire – 20-items (PDQ-20) (Sullivan et al., 1990).
2.2. Objective cognitive impairment as measured using the Symbol Substitution Task (SST). Participants’ Part 1 SST scores will be used as baseline, and SST will be repeated at 3-, 6- and 12-month follow-ups.
2.3. Quality of life as measured using the Multiple Sclerosis Impact Scale (MSIS-29; Hobart et al., 2001) and EQ-5D-5L (Herdman et al., 2011).
2.4. Mood as measured using the Patient Health Questionnaire 9-items (PHQ-9; Kroenke et al., 2001); Generalized Anxiety Disorder-7 (GAD-7; Spitzer et al., 2006).
2.5. Function as measured using the Nottingham Extended Activities of Daily Living Scale (Nicholl et al., 2002).
2.6. Self-efficacy as measured using the Multiple Sclerosis Self-efficacy Scale (Rigby et al., 2003).
2.7. Fatigue as measured using the Modified Fatigue Impact Scale-5 item version (MFIS-5; Fisk et al., 1994; D’Souza, 2016).
2.8. Work-related issues as measured using the Multiple Sclerosis Work Difficulties Questionnaire short form (Honan et al., 2014) and a bespoke single item question asking to what extent work has been impacted by cognitive problems. For participants who are in education, a bespoke single item question will be asked to measure to what extent education has been impacted by cognitive problems.
2.9. Medication adherence as measured using a bespoke single-item question asking to what extent medication adherence has been impacted by cognitive problems.
2.10. Cost-effectiveness as measured by the:
2.10.1. Service-use questionnaire, based on a measure used in other MS trials (Lincoln et al., 2020) adapted for use in the NEuRoMS project and refined in WP3 feasibility study.
2.10.2. EQ-5D-5L (Herdman et al., 2011).
2.10.3. MSIS-8D (using MSIS-29) to derive utilities.
2.10.4. ICECAP-A (ICEpop CAPability measure for Adults; (Al-Janabi, N Flynn, & Coast, 2012)) measure of capability and wellbeing for health economic evaluation.
Please note: MSIS-29 and EQ-5D-5L will be collected only once per time point, but will be used for two purposes: 1) for clinical evaluation, and 2) for cost-effectiveness evaluation.
2.11. Goal attainment, measured using the Goal Attainment Scale at 3, 6 and 12 months after randomisation for goals set at baseline.

Outcomes for secondary objectives 3a, 3b, 3c and 3d:
Process evaluation is assessed throughout the screening pathway and intervention delivery and Part 3 data collection period by:
3.1. The qualitative data collected through interviews with patients, healthcare professionals and intervention providers, audio-/video-recordings of intervention sessions and session record forms, and notes from monthly teleconferences/videoconferences with study site teams and supervision sessions with intervention providers on: a) Experiences of cognitive screening and management pathway and the intervention, b) Factors facilitating or hindering engagement with the pathway and the intervention, c) Resources and mechanisms considered important in delivering key outcomes, d) Experiences of how the pathway and the intervention were delivered/received and they are working, e) Any unintended consequences/outcomes of the pathway and the intervention, f) Acceptability of the intervention, g) Content of usual care, h) Intervention providers’ readiness to deliver the NEuRoMS rehabilitation intervention following training.
3.2. The level of satisfaction with the pathway and intervention, measured using the NEuRoMS pathway satisfaction questionnaire at Part 3 interview.
3.3. Intervention record forms completed by intervention providers for each intervention session to describe the number of intervention sessions, frequency, and duration.

Outcomes for secondary objective 3e:
Fidelity of the intervention, measured throughout intervention delivery, as assessed by:
3.4. The content of intervention sessions and quality of intervention delivery, through intervention record forms, audio-/video-recordings of intervention sessions, and case notes of interventions
3.5. Contextual and process issues related to intervention delivery, assessed by a review of case notes, intervention record forms, audio-/video-recordings of intervention sessions, and through monthly supervision sessions with the NEuRoMS therapists and the Part 3 and Part 4 interviews with intervention providers.

Outcomes for secondary objectives 4a, 4b, 4c and 4d
4.1. Process of implementation measured by the qualitative data collected through interviews with patients, HCPs, intervention providers and service commissioners (or similar), observations, and notes from monthly teleconferences/videoconferences with study site teams and supervision sessions with intervention providers on: a) Facilitators and barriers to implementation of the pathway and the intervention, and b) Views and experiences of how the intervention is understood and implemented in differing contexts (in terms of service configuration, socioeconomic context, etc.).