Improving cognition in people with multiple sclerosis: study protocol for a multiarm, randomised, blinded trial of multidomain cognitive rehabilitation using a video-serious game (E-SEP cognition)

Study design and setting

This study is a multicentre, multiarm, blinded, randomised, controlled trial, which includes three assessments points: at baseline (T0), after the 16 therapy sessions weeks (T1), and 6 months after the end of treatment (T2). The outcome assessor and the statistician will be blinded to the group allocation of participants. PwMS who meet the inclusion criteria and provide written informed consent will be assigned to one of the two treatments, the SGT or the SNT. Subjects will be recruited from the patient afferent to outpatient neurological and rehabilitation clinic at six different university hospitals. Patient recruitment started on 8 October 2021, and it is going to finish on 8 April 2025. Each site has at least one blinded and one unblinded research assistant. The blinded measurement assessor (neuropsychologist) will perform all cognitive assessment (baseline, 4-month and 10-month testing). The unblinded research assistant will screen potential participants. If a participant meets the inclusion criteria (see below), the unblinded research assistant is responsible for randomising participants using CleanWeb. As the study design aims to mask the intent of the intervention given to the participants, the unblinded research assistant will be strictly instructed not to discuss participant allocation and participants will likewise be instructed not to reveal details that can indicate their group allocation to the blinded assessor.

The trial protocol has been registered on ClinicalTrials.Gov (NCT04694534) and benefits from a favourable opinion from an ethics committee for the protection of people involved in an interventional clinical trial (RC-P0066-2018-A00411-54).

Selection criteria and recruitment of participants

People affected by MS (according to the 2010 McDonald criteria20) will be included if they meet the following inclusion criteria:

► Men and women, aged 18–65 years old.

► Diagnosis of MS (primary or secondary progressive, relapsing–remitting), without relapses in the preceding 6 weeks.

► Cognitive complaint and Cognitive deficit of at least one of the 3 Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scores (z<-1,5).

Exclusion criteria will be:

► Nervous breakdown (Fast-Beck Depression Inventory>10).

► Other neurological or psychiatric conditions which may affect cognitive functions.

► Severe visual impairment limiting the performance of the cognitive assessments and use of the tablet.

► Other medical conditions which might interfere with the ability to complete the study protocol safely.

During the first appointment, potential participants will be informed about all the study procedures and screened following the inclusion criteria. In the case that they are interested in taking part in the study, the physician will give them a letter explaining the study’s purpose and procedures, time commitments, risks, potential benefits, treatment alternatives, study staff contact information and the consent form. After a few days of reflection, the potential participant will be contacted. If the subject decides to take part in the study, the research staff will give him/her an appointment for instructions in signed the consent form and to explain the baseline outcome measures, conducted by a neuropsychologist. If the subject rejects participation in the study, the research staff remains available for further information. The total number of subjects screened for participation and the number of subjects who decline to participate will be recorded, according to the Consolidated Standards of Reporting Trials guidelines (figure 1).

Request permission

Randomisation and blinding

The selection of eligible patients is made by the medical team, and the randomisation of the selected patient (meeting inclusion criteria) will be carried out by a clinical research associate. Patient will be randomised to one of the two treatment groups through a randomisation approach (1:1 ratio). The randomisation scheme will be generated using the CleanWeb site to prevent selection bias. The neuropsychologist assessor will be blinded concerning the subject’s group allocation. All outcome data and assignment groups will be organised in different data sets to maintain the blinding during data analysis. The privacy of the participants and their medical records will be guaranteed by treating the data according to the ‘European Union Data Protection Directive (95/46/EC 24 October 1995).

Intervention

In each condition, patients will receive medical and paramedical care according to National Health Authority guidelines. In addition, they will receive specific instructions for cognitive rehabilitation, which will take place during the next 4 months following inclusion in the study, 4 sessions of 20 min of effective activity per week. Each cognitive training session is carried out at home, with at least 24 hours between sessions.

Serious Game Therapy

The SGT is a home-based videogame developed by a multidisciplinary team, including neuropsychologists and a physical medicine physician, and programmed by the company ‘3 Prime’ between 2018 and 2020. The SGT, accessible via a secure dedicated, was realised using a touch screen, from a first-person perspective. The SGT is a serious ecological game based on a virtual vacation island (Cognition Island), in which subjects are invited to interact with different parts of the scenario and perform specific tasks. All actions performed by subjects in the SGT are recorded and measured during the completion of different tasks, involving different cognitive functions, divided into four worlds, with a specific goal, involving specific cognitive functions: (1) world 1: planning, (2) world 2: episodic memory, (3) visuospatial processes and (4) divided attention. Each of these worlds comprises different tasks involving different cognitive processes: episodic memory, working memory, mental flexibility, inhibition, IPS and visuospatial processes. All scenarios are paced in terms of increasing difficulty and have the same structure:

► The beginning of each game session is preceded by a phase of presentation of one or two specific cognitive function(s), their characteristics, their operation and the consequences of their dysfunction, to improve metacognition and understanding of cognitive functioning.

►A main objective in the game, involving different cognitive functions.

► Additional activities, involving a main cognitive function.

For example, in the second world, entitled ‘Boat trip’, the patient organises a trip out to sea. This scenario is preceded by a presentation of cognitive functions: episodic memory and inhibition. During this scenario, the patient is required to obtain a boating license (involving episodic memory), carry out driving tests (episodic memory and sustained attention), purchase the equipment needed for the trip (planning, multitasking) and then carry out the boat trip. During the boat trip, the patient explores different islands, involving different working memory tasks.

The passage from one stage to another is done when the patient has obtained a percentage of success for each activity, according to the level of difficulty of the task. Each specific task contains four difficulty levels. During the first exploration of a world, the patient begins each activity at level 1. When this first level is validated, the patient moves on to the next level. During a level, less than 50% performance rate leads to a drop back down to the lower level (or is maintained at level 1). With a performance between 50% and 75%, the patient is maintained at the current level. Above 75%, the patient goes on to the next level. And so on until the last level. For each activity, the patient also has the possibility of modulating the level of difficulty of the task him or herself to allow the implementation of adapted strategies. To improve metacognitive abilities, advice (pop-ups) will be offered to the patient, during all activities and in difficult situations. The unlocking of the bonus worlds is underpinned by the repetition of the mini-games and the realisation of the activities within the scenarios. This repetition is encouraged by earning rewards when performing the activities. For each task performed, the patient receives feedback on the level of his or her performance. If performance levels fluctuate from one session to the next, patients are offered explanations on the variables that may explain these fluctuations, to improve their understanding of cognitive functioning. The overall structure of the serious game is shown in figure 2. Screenshots of the game are provided in online supplemental data 2.

Request permission

Standardised neuropsychological rehabilitation

The standardised cognitive remediation procedure consists of different paper-and-pencil cognitive activities involving cognitive functions weakened in PwMS (such as learning and attentional abilities). Patients are provided with cognitive stimulation booklets. Each of these booklets features different activities such as sudoku, memory games, word games and explorations games, with a real cognitive challenge but without the motivational and playful characteristics of the serious game.

Concomitant care and recommendations

All the subjects will be advised not to undertake other cognitive rehabilitation until the end of the assessment period.

Intervention fidelity and monitoring of adverse events

Any unpredictable adverse events will be recorded in the patient’s registry and the electronic study database. Their management will agree with the related hospital policies, with a referral for appropriate medical follow-up.

Outcome assessment and data collection

In each medical centre, all the clinical evaluations will be performed by the same blinded assessor at the three timepoint evaluations: (T0) baseline, before the first intervention; (T1) end of treatment, after the 16 weeks of therapy sessions; (T2) follow-up, 6 months after the end of treatment. Demographical, clinical and neuropsychological assessment will be delivered by a physician and a neuropsychologist adequately trained in evaluation procedures. A summary of the study plan is reported in table 1.

The following clinical and demographic data will be collected by an interview preceding the experiment: age, sex, years of education, laterality, medical history, MS subtype, disease duration, date of the last relapse and current disease-modifying treatment. Physical disability will be assessed using Expanded Disability Status Scale (EDSS).21

Primary outcome measures

The primary outcomes were the measures from the BICAMS.22 Due to its excellent psychometric properties, the BICAMS has been introduced as an international consensus instrument to screen cognitive status in PwMS23 and this battery has been standardised for the French population.24 The BICAMS includes three cognitive measures: The California Verbal Learning Test,25 the Brief Visuo-spatial Memory Test26 and the SDMT27 (table 2). Details on description and measures of each test are reported in the additional document (online supplemental data 1).

Psychological assessment

Cognitive assessment is completed by psychological assessment, notably Subjective cognitive decline by the McNair & Kahn scale,28 depression by the Fast-Screen Beck Depression Inventory (BDI-FS),29 anxiety by State Trait Anxiety Inventory (STAI-Y)30 and fatigue by a Visual Analog Scale (VAS) of Fatigue (table 2). Details on the description of each psychological assessment are reported in the additional document (online supplemental data 1).

Data management

Data analysis will be performed according to the research hypothesis mentioned, using the SPSS V.25.0 (SPSS).

Sample size and power

The main objective of this study is to compare the effectiveness of rehabilitation in the two groups. First, the evolution of each BICAMS score between inclusion and the two measurement points will be compared between the two groups using a mixed model. Second, the groups will be compared specifically at each measurement time using an Analysis of Covariance (ANCOVA). The calculation of the number of subjects was based on the ANCOVAs which will be carried out for the three BICAMS tests. A maximum of six tests will be performed; thus, a multiple comparison correction will be used. The number of patients needed for the study has been calculated so that each test has sufficient power, considering the multiplicity correction that will be used. To be relevant, the difference between the two groups must be greater than the minimum clinically important difference (MCID), estimated from the SD and the intraclass correlation coefficient of normative data.22 23 An ANCOVA being carried out, we can estimate the number of subjects necessary by knowing the correlation between the score after and before the intervention Indeed, the number of subjects required in an ANCOVA is (1−r²)n, where n is the number of subjects required when using a Student’s t-test and r the correlation between the variable of interest and the covariate. We estimated it by the intraclass correlation coefficient. By taking all these elements into account, in order to be able to detect a difference between the two groups of at least the MCID in one of the BICAMS tests with a power of 90% and an alpha risk of 5%, and considering 20% lost to follow-up, 75 patients must be included per group, that is, a total of 150 patients.

Statistical analyses

Descriptive statistics (mean and 95% CI) will be reported before treatment, after treatment and at the 6-month follow-up for all the selected variables: the means and SD will be the numbers and frequencies for the qualitative variables.

The comparability of the two groups will be checked for the quantitative data by the Student’s t-test in the event of normality or the Mann-Whitney-Wilcoxon test otherwise; for discreet data by the Mann-Whitney-Wilcoxon test; for qualitative data by the χ² test or Fisher’s exact test in the event of insufficient numbers.

Analysis of the primary outcome measures: the evolution curves of the difference of the BICAMS tests for each group will be compared by implementing a mixed linear model integrating the group and time as fixed effects. The patients will be integrated in random order to consider the correlation between the data due to the repeated nature of the measurements. The regression application conditions will be checked graphically on the residuals (normality and homoscedasticity). A log transformation may be applied if these conditions are not verified. The significance of the group will be sought as well as that of the Treatment × Time interaction. Moreover, a repeated-measures analysis of variance (within-group factor: Time; between-group factor: Treatment) will be conducted to detect main effects for treatment and time for all the available outcomes. To calculate the effect size of both treatments, we will use Cohen’s d. Significance will be recognised for p<0.05.

Intention to treat

Every attempt will be made to avoid missing data through a careful check of self-reported measures, such as self-administered questionnaires. An intention-to-treat analysis was carried out on all outcome measures. Missing data will be treated using the last observation carried forward approach.

Data monitoring and interim analysis

The trial includes a data monitoring committee. An update on trial progress will be shared with the Research office every 6 months. The research group will discuss any subsequent modifications and communicate to the funding agency and Ethics Committee.

Patient and public involvement

The research question in this study starts from years of experience in rehabilitation of PwMS and previous research studies on the use of computerised cognitive training in MS.