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

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Strenghtening the brain; Behavioral: Strengthening the mind

Detailed Description

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:

1. To compare the effectiveness of the investigated interventions in improving cognitive, psychological and work functioning, and in enhancing the brain's functional network.
2. To examine which factors (i.e. baseline cognitive, psychological, work and brain MRI-parameters) are predictive of the response to the investigated interventions.
3. 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.
4. 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.

• Study Type: Interventional
• Enrollment (Estimated): 270
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jip Aarts; Phone Number: +31 71 5275081; Email: j.aarts@fsw.leidenuniv.nl
• Study Contact Backup: Name: Shalina Saddal; Phone Number: +31 20 566 38 01; Email: s.saddal@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam University Medical Centers, location VUmc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Strengthening the brain; 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; 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.
Experimental: Strengthening the mind; 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; 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.
No Intervention: Enhanced usual care; Participants receiving general information about cognitive impairment in MS and following care as usual for four months.

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Genzyme, a Sanofi Company; Universiteit Leiden; Personal Fitness Nederland; MS Vereniging Nederland; Merck BV; MS Sherpa
• Investigators: Principal Investigator: Hanneke E Hulst, Leiden University

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: August 25, 2023
• First Submitted That Met QC Criteria: September 28, 2023
• First Posted (Actual): October 5, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Exercise; Prevention; Cognition; Employment; Health-related Quality of Life
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Neurocognitive Disorders; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Cognition Disorders; Multiple Sclerosis; Sclerosis; Cognitive Dysfunction
• Other Study ID Numbers: NL82007.018.23; NWA.1292.19.064 (Other Grant/Funding Number: Dutch National Research agenda (NWA))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data relating to the main outcomes will be shared in online repository. Coded data will be published in an online scientific archive for the purpose of future research, in line with Open Science practices, and for the verification of findings. These data would not be traceable as they are not linked in any way to personal data. MRI data will be stored in OSF and other platforms that may accommodate the large capacity of the data set.
• IPD Sharing Time Frame: All data will become available after the project has finished. An embargo period of one year will be used. Coded data will be published in an online scientific archive without unlimited time.
• IPD Sharing Access Criteria: Coded data that cannot be traceable to the participant identifying information will be published in an online repository
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No