Don't be Late! Postponing Cognitive Decline and Preventing Early Unemployment in People With Multiple Sclerosis

Study Overview
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Brief Summary
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The goal of this randomized controlled trial is to compare the effectiveness of two innovative interventions aimed at preventing cognitive decline and work-related problems to enhanced usual care in improving quality of life in people with multiple sclerosis. Secondary objectives are: to compare the effectiveness of the investigated interventions in improving cognitive, psychological, and work functioning, and in enhancing the brain's functional network to examine which factors (i.e., baseline cognitive, psychological, work, and brain MRI-parameters) are predictive of the response to the investigated interventions aim to qualitatively reflect on the process and outcome of the investigated interventions considering the perspectives of relevant stakeholders to allow for smooth and successful implementation in clinical practice Participants will follow the intervention for four months, with follow-up measurements at six months after intervention and 12 months after intervention.

Detailed Description
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Background Up to 65% of the people with multiple sclerosis (PwMS) develop cognitive deficits that severely affect daily life functioning and PwMS' quality of life. Moreover, approximately 65% of all patients end up unemployed within five years after diagnosis. Current treatments mostly focus on symptom management and return to work, which may be too late. It is hypothesized that timely interventions will help prevent or delay cognitive decline and work-related problems in PwMS, thereby improving quality of life. Objectives Primary Objective: To compare the effectiveness of the investigated interventions with enhanced usual care in improving quality of life. Secondary Objectives: To compare the effectiveness of the investigated interventions in improving cognitive, psychological and work functioning, and in enhancing the brain's functional network. To examine which factors (i.e. baseline cognitive, psychological, work and brain MRI-parameters) are predictive of the response to the investigated interventions. To qualitatively reflect on the process and outcome of the investigated interventions considering the perspectives of relevant stakeholders to allow for smooth and successful implementation in clinical practice. To compare the cost-effectiveness of the investigated interventions. Material and methods A randomized controlled trial with three arms and three follow-up visits over a total time period of 16 months. During these visits researchers will gather information from questionnaires, neuropsychological examination, MRI and blood sampling. All participants (N= 240) have a confirmed MS diagnosis according to the McDonald 2017 criteria, have subclinical cognitive impairment and are aged between 18 and 67. Participants will be randomly assigned to one of the three arms (N=90 in each arm). Interviews will be conducted with 12-15 participants from both interventions, 10-12 sport coaches, 8-12 work coaches and 10-12 supervisors from the workplace. 'Strengthening the brain' (4 month-program) consists of weekly 30 minutes 1-on-1 exercise and lifestyle coaching in combination with two moments per week unsupervised exercises at home and a home-based online computerized cognitive training. 'Strengthening the mind' (4 month-program) consists of biweekly contact with work coaches who are all diagnosed with MS themselves. 'Enhanced usual care' entails an appointment with a researcher in addition to usual care. Results The primary outcome is change in quality of life as measured with the 36-item Short Form. Several secondary outcomes will be collected: cognitive, psychological, cost-effectiveness, structural- and functional brain, neurological, physiological, and qualitative measures.

Official Title
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Don't be Late! Postponing Cognitive Decline and Preventing Early Unemployment in People With Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Behavioral: Strenghtening the brain
* Behavioral: Strengthening the mind


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed MS diagnosis according to the McDonald 2017 criteria Age between 18 and 67 No changes in disease modifying therapy prior to inclusion (i.e., no changes in last 3 months) - this criterion only applies at inclusion to ensure participants are in a stable situation at the start of the study and for follow-up measures, changes in treatment will be registered but will not result in exclusion from the study no current relapse or steroid treatment in the six weeks prior to study visits presence of mild cognitive deficits (at least one test with a Z-score of -1.0 to -1.99 below norm scores of healthy controls on the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery being able to participate in an exercise intervention (i.e., EDSS < 6.0) fulfilling safety criteria for MRI (no metal inside body, not pregnant, no claustrophobia) Exclusion Criteria: presence of neurological (other than MS) and psychiatric disorders a current or history of drug or alcohol abuse being unable to speak or read Dutch currently on sick leave for a period of 6 weeks or longer currently pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 67 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Strengthening the brain<br>Participants receive 30 minutes of 1-on-1 fitness training, dietary advice, and mental coaching, in addition to twice 20 minutes fitness at home, and 60 minutes of cognitive training each week for four months. | Behavioral: Strenghtening the brain<br>* Lifestyle intervention containing physical exercise, lifestyle coaching, and cognitive training. The programme contains weekly 30 minutes 1-on-1 fitness and lifestyle coaching with two moments of exercise at home for 20 minutes. Online computerized cognitive training will be done for 60 minutes per week.<br>|
| Experimental: Strengthening the mind<br>Partiicpants receive biweekly 1-on-1 coaching by a trained work-coach who has MS to identify challenges at work and implement solutions. It is completed when satisfactory solutions have been implemented for all challenges or after four months. | Behavioral: Strengthening the mind<br>* Work-focused intervention combining the capability approach and the participatory approach. Together with a work-coach who has been diagnosed with MS themselves, participants will assess important work values, discover challenges participants are facing, think of solutions for these challenges, develop a plan of action and implement these solutions.<br>|
| No Intervention: Enhanced usual care<br>Participants receiving general information about cognitive impairment in MS and following care as usual for four months. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life | Quality of life assessed using the 36-item Short Form. Item-scores are summed and transformed into a total score that ranges 0-100. Higher score corresponds with better quality of life. | Baseline, Month 4, Month 10, and Month 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Information processing speed | Information processing speed is assessed using the Symbol Digit Modalities Test (SMDT). The total responses made in 90 seconds is administered. Higher amount of correct responses equals better information processing speed. | Baseline, Month 4, Month 10, and Month 16 | 
| Information processing speed | Information processing speed is assessed using the Paced Auditory Serial Addition Test (PASAT). The total correct answers given, out of 60, is administered. Higher amount of correct responses equals better information processing speed. | Baseline, Month 4, Month 10, and Month 16 | 
| Verbal fluency | Verbal fluency is assessed using the Dutch adaptation of the Controlled Oral Word Association Test; Dutch Letter Fluency Test. Total number of correct words will be administered. Higher score corresponds with better verbal fluency. | Baseline, Month 4, Month 10, and Month 16 | 
| Spatial Processing | Spatial Processing is assessed using the Judgement of Line Orientation. Total correct responses, with maximum 30, will be administered. Higher score corresponds with better spatial processing. | Baseline, Month 4, Month 10, and Month 16 | 
| Verbal New Learning and Memory | New Learning and Memory is assessed using the California Verbal Learning Test, second edition (CVLT-II). Direct recall on the CVLT-II will be administered using number of correctly remembered items over learning trials 1-5. Delayed recall on CVLT-II will be administered using number of correctly remembered items 20 minutes after learning trail 5. Maximum scores for direct recall, delayed recall, and recognition are set at 80, 16, and 44, respectively. Higher score equals better verbal learning and memory. | Baseline, Month 4, Month 10, and Month 16 | 
| Visual New Learning and Memory | New Learning and Memory is assessed using the Brief Visuospatial Memory Test-Revised (BVMT-R). Direct recall on BVMT-R will be administered using number of correctly remembered items over learning trials 1-3. Delayed recall on BVMT-R will be administered using number of correctly remembered items 25 minutes after learning trail 3. Maximum scores for direct recall, delayed recall, and recognition are set at 36, 12, and 12, respectively. Higher score equals better visual learning and memory. | Baseline, Month 4, Month 10, and Month 16 | 
| Executive Function | Executive Function is assessed using the Delis-Kaplan Executive Function System. Total correct sorts will be administered, with a maximum of 16 sorts. A higher score suggests better executive functioning. | Baseline, Month 4, Month 10, and Month 16 | 
| Self-Reported Cognitive Functioning | Self-Reported Cognitive Functioning is assessed using the Multiple Sclerosis Neuropsychological Screening Questionnaire. Maximum score of 70 can be reached, with a score of 27 or higher indicating presence of neuropsychological problems. | Baseline, Month 4, Month 10, and Month 16 | 
| Work Participation and Productivity | Work Participation and Productivity is assessed using the Work Productivity and Activity Impairment Questionnaire: General Health, which administers the effect of health-problems on ability to work. Scores are calculated as percentages, with higher numbers indicating greater impairment and less productivity. | Baseline, Month 4, Month 10, and Month 16 | 
| Work Difficulties | Work Difficulties are assessed using the Multiple Sclerosis Work Difficulties Questionnaire. The questionnaire consists of 23 items, which can be grouped into three subscales: psychological/cognitive barriers, physical barriers, and external barriers. The maximum score of each subscale is 100, with higher scores indicating higher perceived difficulties. Total score consists of an average of the three subscale scores. | Baseline, Month 4, Month 10, and Month 16 | 
| Capability to carry out Work Activities | Capability to carry out Work Activities is assessed using the Capability Set for Work Questionnaire. This questionnaire evaluates for seven valued work aspects whether, A) it is important to the worker, B) their work offers sufficient opportunities to do it, and C) it can be achieved, on a 5-point Likert scale. | Baseline, Month 4, Month 10, and Month 16 | 
| Quality of Working Life | Quality of Working Life is assessed using the Quality of Working Life Questionnaire for Cancer Survivors. The questionnaire consists of five subscales: meaning of work, perception of the work situation, atmosphere in the work environment, understandings and recognition in the organisation, and problems due to health situation. The overall score and sum scores of the subscales are calculated with a standardised score 0-100. Higher score corresponds with better quality of working life. | Baseline, Month 4, Month 10, and Month 16 | 
| Grey Matter Volume of the Brain | Grey Matter Volume will be determined using FSL-SIENAX, after lesion filling on the 3DTI. | Baseline, Month 4, and Month 16 | 
| White Matter Volume of the Brain | White Matter Volume will be determined using FSL-SIENAX, after lesion filling on the 3DTI. | Baseline, Month 4, and Month 16 | 
| Total Brain Volume | Total Brain Volume will be determined using FSL-SIENAX, after lesion filling on the 3DTI. | Baseline, Month 4, and Month 16 | 
| Volumes of Deep Grey Matter Structures | Volumes of Deep Grey Matter Structures will be determined using FIRST. | Baseline, Month 4, and Month 16 | 
| Cortical Thickness | Cortical Thickness will be determined using Freesurfer. | Baseline, Month 4, and Month 16 | 
| White Matter Integrity | White Matter Integrity will be determined using Diffusion Tensor Imaging | Baseline, Month 4, and Month 16 | 
| Functional Connectivity | Functional Connectivity will be determined using Resting-State fMRI | Baseline, Month 4, and Month 16 | 
| Regional Functional Activation | Regional Functional Activation will be determined using Task-Based fMRI | Baseline, Month 4, and Month 16 | 
| Fatigue | Fatigue will be assessed using the Checklist Individual Strength. The questionnaire consists of 20 items, scored on a 7-point Likert scale. Fatigue is a subscale of the questionnaire, and is scored by adding the scores of the items, where a higher score corresponds with more fatigue. | Baseline, Month 4, Month 10, and Month 16 | 
| Mood and Anxiety | Mood and Anxiety will be assessed using the Hospital Anxiety and Depression Scale. The questionnaire consists of 14 items on a 4-point Likert scale. The range of scores is 0-21 where a higher score equals more complaints of anxiety and depression. | Baseline, Month 4, Month 10, and Month 16 | 
| Resilience | Resilience will be assessed using the Connor Davidson Resilience Scale. Total score ranges 0-100, with higher scores reflecting greater resilience. | Baseline, Month 4, Month 10, and Month 16 | 
| Perceived Level of Stress | Perceived Level of Stress will be assessed using the Perceived Stress Scale. Total score ranges 0-40, with higher scores indicating higher perceived stress. | Baseline, Month 4, Month 10, and Month 16 | 
| Social Mindfulness | Social Mindfulness will be assessed using the SoMi paradigm by van Doesum et al. (2013). Choices that are made are scores as mindful (1) or unmindful (0). Final score will be computed by averaging the scores over all decisions, resulting in a number between 0 (unmindful) and 1 (mindful). | Baseline, Month 4, Month 10, and Month 16 | 
| Social Participation | Social Participation will be assessed using the PROMIS 'Ability to Participate in Social Roles and Activities' item bank. The questionnaire consists of eight items that can be scored on a 5-point Likert scale. Higher scores indicate better ability to participate in social roles and activities. | Baseline, Month 4, Month 10, and Month 16 | 
| MS-related disability | MS-related disability will be assessed using the Expanded Disability Status Scale. This scale ranges from 0.0 to 10.0, where a higher score indicates worse disability. | Baseline, Month 4, Month 10, and Month 16 | 
| Balance | Balance will be assessed using the Mini-BESTest. The test contains 14 items where a total score of 28 points can be achieved, where a score <19 induces an increased risk of falling. | Baseline, Month 4, and Month 16 | 
| Walking Speed | Walking Speed will be assessed using the Timed 25-Foot Walk. | Baseline, Month 4, and Month 16 | 
| Endurance | Endurance will be assessed using the Shuttle Walk Test according to the protocol of Singh et al. (1992). | Baseline, Month 4, and Month 16 | 
| Grip Strength | Grip Strength will be assessed using a JAMAR hand-held dynamometer. | Baseline, Month 4, and Month 16 | 
| Upper Limb Dexterity | Upper Limb Dexterity will be assessed using the 9-Hole Peg Test and the Purdue Pegboard Test. | Baseline, Month 4, and Month 16 | 
| Lost Productivity Costs | Lost Productivity Costs will be assessed using the iMTA Productivity Cost Questionnaire. The questionnaire consists of three modules measuring absenteeism, presenteeism, and productivity loss from unpaid work. | Baseline, Month 4, Month 10, and Month 16 | 
| Societal Costs including Healthcare, Patient, and family | Societal Costs will be assessed using the iMTA Medical Consumption Questionnaire. | Baseline, Month 4, Month 10, and Month 16 | 
| Quality Adjusted Life Years | Quality Adjusted Life Years will be assessed using the EuroQol five-dimensional Questionnaire. The questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Higher scores indicate more problems considering the dimensions. | Baseline, Month 4, Month 10, and Month 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Cognition, Exercise, Employment, Prevention, Health-related Quality of Life