Multiple sclerosis (MS) is a chronic inflammatory disease that leads to demyelination of the central nervous system. Fatigue is one of the most frequent and most disabling symptoms of MS. Up to 86% of individuals with MS experience fatigue at any one time; 65% consider it to be one of their three most troubling symptoms. Fatigue may limit or prevent participation in dayly activities and reduce psychological well-being (1, 2). Pharmacological and non-pharmacological treatments are available for MS-related fatigue, but evidence on effectiveness is mostly inconclusive or non-existent. The psychological approaches of fatigue management are interesting. To date, three RCTs using cognitive-behavioral group-based approaches in MS fatigue management programs have demonstrated their effectiveness (3-6). The results demonstrated a reduction in fatigue scores and better self-management of the disease in general. However, if these programs are effective at the time of their application and in the medium term, the issue of maintaining long-term therapeutic benefits is problematic.

The aim of this research is to assess the effectiveness of the FACETS program (6), on a population of French patients with RRMS over a 18 month period. This program focuses on the management of fatigue and is based on a conceptual framework that incorporates elements of cognitive-behavioral, self-efficacy, self-management and energy effectiveness theories. It consists of six once-weekly sessions of 90 minutes, with homework activities between the sessions. It is designed for groups of 6 to 10 people. The investigators propose to add 4 booster sessions to the FACETS program, at week 6, 12, 18 et 36 after the end of the program, in order to activate and reinforce the cognitive and behavioral processes and enhance the benefits of FACETS in the longer term.

This trial is randomized controlled comparative comparing a group receiving a FACETS program with a group receiving only a current local practice. Socio-demographic and medical data are measured as well as fatigue impact, fatigue severity, anxiety and depression, sleep disorder and quality of life.

The expected results are a significantly greater decrease in fatigue severity and impact in the FACETS group than the control group post intervention and this difference will be maintained at 1 year.

In spite of the fatigue impact is well known in MS, medical care of this symptom is not usual. Moreover, treatments of fatigue are available, but evidence for effectiveness is limited. This study will build upon the existing evidence base for the effectiveness of cognitive behavioral approaches, and particularly the recent FACETS trial published by co-applicants.

Scientific aim is to assess the effectiveness of the FACETS program plus 4 additional booster sessions on a population of French patients with RRMS over a 12 months period.

This study will provide evidence on whether the FACETS program plus booster sessions is effective in helping MS patients with their fatigue. The program is designed to facilitate use within health services. Thus, if the results from this trial are positive, there is potential for directly adding to the treatment options available to MS patients who have troublesome fatigue, and improving the central nervous system affecting approximately 2.5 million people (5). Fatigue is one of the most commonly reported and disabling symptoms of MS, often occurring daily (6) and with a variable course (7-8). Up to 86% of individuals with MS experience fatigue at any one time; 65% consider it to be one of their three most troubling symptoms. Fatigue has been defined as a "subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities" (9).

Researchers have distinguished between primary and secondary fatigue (10). "Primary" fatigue relates to aspects of fatigue deemed to be directly related to the disease process such as lassitude or asthenia (an overwhelming sense of tiredness not directly related to participation in activity or exercise), "short-circuiting" fatigue (when muscular performance deteriorates during sustained activity but recovers after a short rest break) and heat sensitive fatigue (where fatigue is triggered or worsened by heat). "Secondary" fatigue refers to fatigue that is not unique to MS and is related to factors common to a range of chronic and disabling conditions (e.g. sleep disturbance, medication side effects, infection, physical exertion, depression, anxiety, stressful life events, characteristics of the local environment - such as lighting and temperature within a work setting). The relationship between these dimensions is complex; various symptoms of MS may act as predisposing factors for secondary fatigue.

Fatigue may limit or prevent participation in everyday activities, work, leisure and social pursuits, restrict role fulfilment and reduce psychological well-being (1-2) and is one of the key precipitants of early retirement (11-12). Its 'invisible' nature may lead to difficulties in personal and work relationships (13-14).

Although fatigue is one of the major symptoms of MS patients, the pathophysiology of fatigue is unclear (15) but likely to be multi- factorial (16-17). Findings on the relationships between fatigue and other clinical variables (such as age, gender, disease duration, and clinical activity) have been equivocal (18). The neural correlates are poorly components such as peripheral vs. central fatigue or physical vs. cognitive or mental, which are difficult to define or operationalize.

Pharmacological and non-pharmacological treatments are available for MS-related fatigue, but evidence on effectiveness is mostly inconclusive or non-existent (19-20). Non-pharmacological studies exploring the effectiveness of energy conservation programs for MS-fatigue have tended to be small and uncontrolled (21-22). Although the important relationships between physical and psychological aspects of MS-fatigue are recognized, high quality randomized and controlled trials (RCTs) of psychological interventions are rare (23).

The integration of cognitive-behavioral approaches in fatigue management programs is interesting. Indeed, their effectiveness has been demonstrated in Chronic Fatigue Syndrome. To date, three RCTs using cognitive-behavioral group-based approaches in the context of MS have been conducted (3-4). Cognitive behavioral approaches are potentially more profitable than the dual interventions, more easily integrated into a framework of routine care, and they also offer the possibility of peer support. The results of these studies demonstrated a reduction in fatigue scores and better self-management of the disease in general, resulting in improvements in quality of life. In their meta-analysis (24) indicate that the results obtained with CBT or with physical exercises are similar, but when people are anxious or depressed, which is often the case with MS (25-26), CBT shows better improvement. Knoop & al. (27) highlighted the importance of cognitive representations on fatigue and the potential relevance of CBT: they showed that the strongest mediators of fatigue severity were fatigue avoidance, symptom focusing and the belief that fatigue symptoms are a sign of damage.

Thomas et al., (4) found that modest effects on fatigue severity were largely maintained at one year (unpublished data). Given that MS typically is diagnosed during the most productive years of individuals' lives and lasts the life course it is important to give people flexible tools and strategies to manage fatigue that can be used in the long term. Booster session might therefore help to 'boost' or enhance the effectiveness of the program in the longer term Methodology A multicentre parallel arm randomized controlled trial comparing a group receiving 'enhanced' FACETS plus current usual practice versus a group receiving current local practice only.

Inclusion criteria: clinically confirmed diagnosis of relapsing remitting MS; Significant fatigue levels (score at the Modified Fatigue Impact Scale - MFIS > 45); Expanded Disability Status Scale score < 6; age ≥ 18 years; written informed consent; speak and understand French; be able to follow the program.

Exclusion criteria: Individuals with cognitive deficits such that they would not be able to engage and benefit from this group-based program. Indeed, if individuals have significant cognitive deficits, most of the content of the fatigue management program would not be appropriate; People who have had a relapse within the past three months: (a relapse might result in increased fatigue) People who have started treatment on a disease modifying drug or anti-depressant in the past 3 months (one of the possible initial side effects of these drugs is fatigue); People who have psychiatric disorders Sample size: if one uses the results of the study (30) (matched groups), these authors show that in 59 MS patients treated with Modafinil, the mean fatigue score on the MFIS is 52.3 (SD/SE = 18.5), whilst in 56 MS patients treated by placebo the mean fatigue score is 49.2 (SD/SE = 16.6). The investigators will seek to uncover an absolute difference of 10 points between mean scores. The FACETS trial found a standardized effect size of 0.35 on their fatigue severity primary outcome, which would translate to around 6 points on the MFIS. It is anticipated that by using booster sessions and by running the programme using psychologists, that the anticipated effect size will be larger (10 points). In order to detect a 10 points absolute difference between the mean scores (on the MFIS) of the efficaciousness of the cognitive-behavioral intervention, power to detect an effect size of 8.5 points Participants will be identified and recruited by the neurologists of the hospitals who take part in the program, when they come for a medical examination.

Randomization: After giving their informed consent, the patients will be entered onto the trial database and randomized in a 1:1 ratio to either the fatigue management program and or current local practice using a computer, generated randomization sequence stratified by site.

Intervention FACETS (4). Focuses on the management of fatigue and is based on a conceptual framework that incorporates elements of cognitive-behavioral, self-efficacy, self-management and energy effectiveness theories. It consists of six once-weekly sessions of 90 minutes (with a break), with homework activities between the sessions. It is designed for groups of 8 to 10 people and will be delivered by two psychologists. The program is standardized: PowerPoints presentations support each session and a detailed facilitator manual and companion patient workbook. accompany the program.

The investigators propose to add 4 booster sessions to the FACETS program, at week 6, 12 et 18 et 36 after the end of the program, in order to activate and reinforce the cognitive and behavioral processes and they hope to enhance the benefits of FACETS in the longer term.

Measures For the FACETs group these will be administered pre, post and 12 months after the end of the FACETS program and at the same times for those in the control group Socio-demographic and medical data: age, sex, level of education, marital status, number of children and professional status; date of diagnosis, disease type, level of disability.

Neuropsychological measures: Paced Auditory Serial Addition Task (PASAT,28) & the Computerized Speed Cognitive Test (CSCT,29).

Statistical analysis: They will register the trial and endeavor to publish the full trial protocol prior to its commencement. The primary analysis of effectiveness will use an "intention-to-treat" approach and focus on comparing MFIS at 12 months post treatment (ie after the program and all booster sessions are complete) between the two trial arms using analysis of covariance to take into account MFIS at baseline, and study center. In addition to these analyses they will conduct further comparative analyses using a mixed model approach that permits analysis of repeated measures (baseline, post treatment and 12 months follow-up), takes into account missing data (i.e. model allows participants to contribute to the model even if they don't have complete data), and takes into account the group-based nature of the program (cluster effects). A similar approach will be used for other interval scaled outcome measures, and adapted if the outcome measure is nominal (eg the EDSS) Hypotheses There will be a significantly greater decrease in fatigue severity and impact in the FACETS group than the control group post intervention and this difference will be maintained at 1 year.

There will be a significantly greater improvement in sleepiness and sleep quality, anxiety, depression, stress, attention and working memory in the FACETS group than the control group at the end of the program and at 12 months The FACETS group will show a significantly greater reduction in cortical atrophy, axonal loss and demyelination within white matter tracts of DMN than those in the control group Ethics The protocol was submitted to the French competent authorities and a declaration was made to the CNIL.

Patients allocated to the control group (current local practice) will be offered the FACETS program after the 12 months follow-up.

Finally, all information collected will be strictly confidential. Identification numbers of participants will be noted on the questionnaires which will not contain any names or details to identify the participants. Only members of the research team will be allowed to access the trial data.

Inclusion Criteria:

• RRMS
• EDSS ≤ 5,5
• MFIS score > 45
• Outpatient treatment
• Enable to follow the BCT sessions
• French understanding
• More than 18 years old
• Inform consent signature
• Membership in a social protection

Exclusion criteria

• Cognitive disorders avoiding patient participation
• Relapse within last 3 months before baseline
• Onset of DMT within 3 months
• Onset of antidepressive treatment within 3 months
• Onset of treatment for fatigue within 3 months
• Psychiatric disorders

randomization of patients