Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system, involving inflammation, demyelination, and neurodegeneration. It is the most common non-traumatic disabling disease affecting young adults. MS is characterized by its heterogeneity and unpredictable course, which make both evaluation and treatment complex. Patients may present with motor, sensory, cognitive, and neuropsychiatric symptoms, all of which have a significant impact on quality of life. With regard to cognition, the impact of cognitive impairment in MS remains underestimated. However, it is observed in approximately 40-65% of patients and may be present at all stages of the disease, including the earliest ones (patients with low levels of disability and Clinically Isolated Syndromes - CIS). Notably, cognitive alterations appear to precede structural abnormalities on magnetic resonance imaging (MRI), representing a potential marker of disease activity. Therefore, early diagnosis and characterization of MS-related cognitive impairment are essential, followed by the implementation of patient-tailored cognitive rehabilitation programs, which have recently been shown to exert long-term effects persisting beyond the treatment period. The project aims to conduct a single-center, randomized, pragmatic, prospective clinical trial with blinded outcome assessment. Its primary objective is to evaluate the efficacy of an innovative sociocognitive rehabilitation program in patients diagnosed with multiple sclerosis. In addition, the study seeks to characterize cognitive phenotypes in MS, investigate the role of cognitive reserve and metacognition in the effectiveness of the intervention, and correlate neuropsychological findings with other disease biomarkers, with the ultimate goal of proposing a predictive model of disease progression.
The REACT-MS project is designed as a Phase IIa, single-center, randomized, pragmatic, and prospective clinical trial with blinded outcome assessment, following the PROBE methodology. Its overarching aim is to evaluate the efficacy of an innovative sociocognitive rehabilitation program in patients with multiple sclerosis (MS). Beyond this primary goal, the study also intends to characterize cognitive phenotypes in MS, investigate the role of cognitive reserve and metacognition in modulating the effectiveness of the intervention, and correlate neuropsychological performance with clinical, neuroimaging, and biochemical biomarkers in order to propose a predictive model of cognitive disease progression. The research team is composed of neurologists and neuropsychologists from the ULS Coimbra and University of Coimbra, with extensive expertise in MS care, clinical neuropsychology, biomarker research, and clinical trial coordination. The principal investigator and co-investigators bring a strong record of clinical studies, competitive funding and international publications. Multiple sclerosis is a chronic, autoimmune, demyelinating disease of the central nervous system characterized by inflammation, neurodegeneration, and an unpredictable clinical course. It is the leading non-traumatic cause of disability in young adults. In addition to motor and sensory symptoms, cognitive impairment affects between 40 and 65 percent of patients and can appear even in the earliest stages of the disease. Often underestimated, these deficits may precede structural abnormalities detectable by magnetic resonance imaging, functioning as early markers of disease activity. Timely diagnosis and the implementation of patient-tailored cognitive rehabilitation programs have shown sustained benefits that extend beyond the intervention period, which underscores the rationale for this study. The study will randomize participants into an intervention arm and a control arm. Only those in the intervention group will undergo a combined program consisting of weekly sociocognitive rehabilitation sessions using the COGWEB platform and an emotional processing intervention called EMOPRINT. Most sessions will be home-based and delivered online, with only one in-person session scheduled every three months to minimize dropout and fatigue. This intervention will last for one year. A comprehensive baseline assessment will be conducted, including clinical and demographic data, disability scoring with the EDSS, magnetic resonance imaging parameters such as lesion load and brain atrophy, and serum biomarkers including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Neuropsychological testing will encompass measures of global cognition, processing speed, memory, language, attention, executive functions, and social cognition. Questionnaires addressing fatigue, mood, quality of life, and cognitive reserve will also be included, and several instruments will be adapted to assess metacognition. Participants will be reassessed at 12 and 24 months to enable longitudinal monitoring of cognitive and clinical outcomes. Data will be collected through both direct clinical assessment and electronic health records. Each participant will be assigned a unique identifier to ensure confidentiality, and data will be managed using an electronic case report form (eCRF) implemented on the REDCap platform. Secure data storage, anonymization procedures, and standardized operational protocols will be applied in strict compliance with the General Data Protection Regulation (GDPR), national legislation, and the principles of the Declaration of Helsinki. Data will be archived for five years, while scientific results may be shared in peer-reviewed publications and open-access databases with full protection of participant privacy. The study aims to recruit 130 patients, with 65 participants per arm. Statistical analyses will include both descriptive and inferential methods using SPSS and R. The trial has been planned over a period of 36 months, comprising two months of preparation, one month for ethical approvals, three months for project implementation, twelve months for recruitment, six months for data analysis, and six months for reporting and publication. Ethical oversight will be provided by the Research Ethics Committee of ULS Coimbra, and the study will adhere to ICH-GCP standards and the Declaration of Helsinki. The project incorporates contingency planning to address recruitment challenges, including referral collaborations with other hospitals in the central region of Portugal. Adherence is not expected to be a major limitation given the home-based structure of the intervention, which minimizes burden and facilitates patient compliance. The main innovation of REACT-MS lies in the implementation of a combined sociocognitive and emotional rehabilitation program, delivered largely online and adapted to the needs of MS patients. This dual approach aims to enhance cognitive performance and facial emotion recognition while reducing fatigue-related barriers to participation. Moreover, the study integrates clinical, neuroimaging, and biochemical biomarkers into a predictive framework that could inform individualized prognostic modeling of cognitive outcomes. The expected impact is significant at both clinical and scientific levels. By shifting from a dichotomous classification of preserved versus impaired cognition to the definition of cognitive phenotypes, the project may contribute to more personalized rehabilitation strategies. The integration of cognitive reserve and metacognition is anticipated to explain individual variability in rehabilitation outcomes, as these concepts have been associated with improved coping mechanisms and resilience of brain networks in the context of MS. Ultimately, the project has the potential to establish new predictive markers of disease progression, to inform clinical practice, and to set the stage for future multicenter trials, while offering MS patients sustainable and effective rehabilitation approaches that improve long-term quality of life.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
130
Participants in the study group will subjected weekly sessions of sociocognitive rehabilitation using the COGWEB platform, combined with an emotional processing intervention, aimed at enhancing cognitive abilities and facial expression recognition. Most sessions will be conducted online in a home-based setting, with only one in-person session required every three months in a hospital environment. The dual intervention will be administered over a 12-month period.
Local Health Unit of Coimbra
Coimbra, Coimbra District, Portugal
Unidade Local de Saude de Coimbra
Coimbra, Coimbra District, Portugal
Montreal Cognitive Assessment - MoCA (neuropsychological test)
Cognitive screening; Score 0-30 (0- worst outcome; 30- best outcome)
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Ekman's Faces Test - EFT (neuropsychological test)
Social cognition and metacognition; Score 0-35 (0- worst outcome; 35- best outcome)
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Reading the Mind in the Eyes Test - RMET (neuropsychological test)
Social cognition and metacognition; Score 0-36 (0- worst outcome; 36- best outcome)
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Symbol Digit Modalities Test - SDMT (part of BICAMS-Brief International cognitive Assessment Multiple Sclerosis neuropsychological test)
Processing speed measures and metacognition; Score 0-110 adjusted for age and education (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
California Verbal Learning Test - CVLT-II (part of BICAMS-Brief International cognitive Assessment Multiple Sclerosis neuropsychological test)
Verbal learning, memory and metacognition; Score 0-80 adjusted for age (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Brief Visuospatial Memory Test - BVMT-R (part of BICAMS-Brief International cognitive Assessment Multiple Sclerosis neuropsychological test)
Visual learning, memory and metacognition; Score 0-36 adjusted for age (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Paced Auditory Serial Addition Test - PASAT (part of BRBN-T: Brief repeatable battery of neuropsychological tests)
Processing speed measures and metacognition; Score Score 0-60 adjusted for age, gender and education (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5)
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Selective Reminding Test - SRT (part of BRBN-T: Brief repeatable battery of neuropsychological tests)
Verbal learning, memory and metacognition; Score 0-70 adjusted for age, gender (0-male; 1-female) and education (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
10/36 Spatial Recall Test - SPART (part of BRBN-T: Brief repeatable battery of neuropsychological tests)
Visual learning, memory and metacognition; Score 0-30 adjusted for age, gender and education (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Word List Generation Test - WLG (part of BRBN-T: Brief repeatable battery of neuropsychological tests)
Language measures and metacognition; Score 0-67 adjusted for gender and education (score enables an intermediate T-score allowing for classification- Presence of Impairment \< 34.5).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Boston Naming Test - BNT (neuropsychological test)
Language measures: Score 0-30, calculated based on the number of items correctly named spontaneously.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
d2 Test of Attention (neuropsychological test)
Measures processing speed, rule compliance, and quality of performance, allowing for an estimation of individual attention, according to several metrics. There is no specified cut-off.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Irregular Word Reading Test - TeLPI (neuropsychological test)
Premorbid intelligence, ability to read irregularly spelled words ; there is no specified cut-off.
Time frame: At baseline.
Stroop Test (neuropsychological test)
Measures cognitive flexibility, processing speed, and executive function; Score varies according to speed and accuracy abilities. There is no specified cut-off.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Modified Fatigue Impact Scale - MFIS (PROM: Patient Reported Outcome Measure)
Fatigue; Score 0-84 (Significant fatigue \>= 38)
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Cognitive Reserve Index Questionnaire - CRIq
Cognitive reserve: Score 0-24, the higher the score, the higher the cognitive reserve. There is no specified cut-off.
Time frame: At baseline
Hospital Anxiety and Depression Scale - HADS (PROM: Patient Reported Outcome Measure)
Anxiety and depression; Score 0-21, normal (0-7); low risk (8-10); moderate risk (11-14); high risk (15-21).
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
World Health Organization Quality of Life short-form - WHOQOL-Bref (PROM: Patient Reported Outcome Measure)
Quality of life; evaluates four main domains: physical health, psychological health, social relationships and family/finantial environment ; Scoring requires averaging the items within each domain to calculate raw scores, which are then linearly transformed to a 0-100 scale. Higher scores denote a higher perceived quality of life.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Neurofilament Light chain (NfL): pg/mL
Quantification of biochemical central markers in serum; Healthy individuals frequently present \< 10 pg/mL (according to age); expected levels for patients in relapse: \> 10 pg/mL.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Glial Fibrillary Acidic Protein (GFAP): pg/mL
Quantification of biochemical central markers in serum. Levels are influenced by age, sex, and BMI. Currently lacking literature cut-off values for MS patients.
Time frame: At baseline, follow-up 12 months, 18 months and follow-up 24 months
Clinical Trials Unit do Centro Académico Clínico de Coimbra CTU CTU-CACC
CONTACT
Clinical Trials Unit - Coimbra Academic Clinical Center CTU CTU-CACC
CONTACT
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Number of T2 lesions in brain MRI
Number of new brain lesions (nº).
Time frame: At baseline, follow-up 12 months and follow-up 24 months
Status of MRI T2 lesions
Presence of Gd-enhancing lesions: Active/not active.
Time frame: At baseline, 12 months and 24 months.
MRI lesion load (mm3)
Measures the total volume of hyperintense (bright) spots on T2 or FLAIR MRI sequences.
Time frame: At baseline, 12 months, 18 months and 24 months.
MRI- affected brain region (cerebellum)
Existence of brain lesions in cerebellum: yes/no.
Time frame: At baseline, 12 months and 24 months.
MRI- affected brain region (spinal cord)
Existence of brain lesions in the spinal cord: yes/no.
Time frame: At baseline, 12 months and 24 months.
MRI- affected brain region (cortical/juxtacortical)
Existence of brain lesions in the cortical/juxtacortical regions: yes/no.
Time frame: At baseline, 12 months and 24 months.
MRI- affected brain region (brainstem)
Existence of brain lesions in the brainstem: yes/no.
Time frame: At baseline, 12 months and 24 months.