<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03758820</url>
  </required_header>
  <id_info>
    <org_study_id>FACCSEP</org_study_id>
    <nct_id>NCT03758820</nct_id>
  </id_info>
  <brief_title>Behavior Cognitive Therapy on Fatigue Impact in MS Patients</brief_title>
  <official_title>Multicenter Study, Randomized, Parallel Group Controlled, Testing the Effectiveness of a Behavioral Cognitive Therapy (BCT) vs Usual Local Practice on the Fatigue of Patients With Relapsing Remittent Multiple Sclerosis (RRMS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Réseau Sep Idf Ouest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Réseau Sep Idf Ouest</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple sclerosis (MS) is a chronic inflammatory disease that leads to demyelination of the&#xD;
      central nervous system. Fatigue is one of the most frequent and most disabling symptoms of&#xD;
      MS. Up to 86% of individuals with MS experience fatigue at any one time; 65% consider it to&#xD;
      be one of their three most troubling symptoms. Fatigue may limit or prevent participation in&#xD;
      dayly activities and reduce psychological well-being (1, 2). Pharmacological and&#xD;
      non-pharmacological treatments are available for MS-related fatigue, but evidence on&#xD;
      effectiveness is mostly inconclusive or non-existent. The psychological approaches of fatigue&#xD;
      management are interesting. To date, three RCTs using cognitive-behavioral group-based&#xD;
      approaches in MS fatigue management programs have demonstrated their effectiveness (3-6). The&#xD;
      results demonstrated a reduction in fatigue scores and better self-management of the disease&#xD;
      in general. However, if these programs are effective at the time of their application and in&#xD;
      the medium term, the issue of maintaining long-term therapeutic benefits is problematic.&#xD;
&#xD;
      The aim of this research is to assess the effectiveness of the FACETS program (6), on a&#xD;
      population of French patients with RRMS over a 18 month period. This program focuses on the&#xD;
      management of fatigue and is based on a conceptual framework that incorporates elements of&#xD;
      cognitive-behavioral, self-efficacy, self-management and energy effectiveness theories. It&#xD;
      consists of six once-weekly sessions of 90 minutes, with homework activities between the&#xD;
      sessions. It is designed for groups of 6 to 10 people. The investigators propose to add 4&#xD;
      booster sessions to the FACETS program, at week 6, 12, 18 et 36 after the end of the program,&#xD;
      in order to activate and reinforce the cognitive and behavioral processes and enhance the&#xD;
      benefits of FACETS in the longer term.&#xD;
&#xD;
      This trial is randomized controlled comparative comparing a group receiving a FACETS program&#xD;
      with a group receiving only a current local practice. Socio-demographic and medical data are&#xD;
      measured as well as fatigue impact, fatigue severity, anxiety and depression, sleep disorder&#xD;
      and quality of life.&#xD;
&#xD;
      The expected results are a significantly greater decrease in fatigue severity and impact in&#xD;
      the FACETS group than the control group post intervention and this difference will be&#xD;
      maintained at 1 year.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In spite of the fatigue impact is well known in MS, medical care of this symptom is not&#xD;
      usual. Moreover, treatments of fatigue are available, but evidence for effectiveness is&#xD;
      limited. This study will build upon the existing evidence base for the effectiveness of&#xD;
      cognitive behavioral approaches, and particularly the recent FACETS trial published by&#xD;
      co-applicants.&#xD;
&#xD;
      Scientific aim is to assess the effectiveness of the FACETS program plus 4 additional booster&#xD;
      sessions on a population of French patients with RRMS over a 12 months period.&#xD;
&#xD;
      This study will provide evidence on whether the FACETS program plus booster sessions is&#xD;
      effective in helping MS patients with their fatigue. The program is designed to facilitate&#xD;
      use within health services. Thus, if the results from this trial are positive, there is&#xD;
      potential for directly adding to the treatment options available to MS patients who have&#xD;
      troublesome fatigue, and improving the central nervous system affecting approximately 2.5&#xD;
      million people (5). Fatigue is one of the most commonly reported and disabling symptoms of&#xD;
      MS, often occurring daily (6) and with a variable course (7-8). Up to 86% of individuals with&#xD;
      MS experience fatigue at any one time; 65% consider it to be one of their three most&#xD;
      troubling symptoms. Fatigue has been defined as a &quot;subjective lack of physical and/or mental&#xD;
      energy that is perceived by the individual or caregiver to interfere with usual or desired&#xD;
      activities&quot; (9).&#xD;
&#xD;
      Researchers have distinguished between primary and secondary fatigue (10). &quot;Primary&quot; fatigue&#xD;
      relates to aspects of fatigue deemed to be directly related to the disease process such as&#xD;
      lassitude or asthenia (an overwhelming sense of tiredness not directly related to&#xD;
      participation in activity or exercise), &quot;short-circuiting&quot; fatigue (when muscular performance&#xD;
      deteriorates during sustained activity but recovers after a short rest break) and heat&#xD;
      sensitive fatigue (where fatigue is triggered or worsened by heat). &quot;Secondary&quot; fatigue&#xD;
      refers to fatigue that is not unique to MS and is related to factors common to a range of&#xD;
      chronic and disabling conditions (e.g. sleep disturbance, medication side effects, infection,&#xD;
      physical exertion, depression, anxiety, stressful life events, characteristics of the local&#xD;
      environment - such as lighting and temperature within a work setting). The relationship&#xD;
      between these dimensions is complex; various symptoms of MS may act as predisposing factors&#xD;
      for secondary fatigue.&#xD;
&#xD;
      Fatigue may limit or prevent participation in everyday activities, work, leisure and social&#xD;
      pursuits, restrict role fulfilment and reduce psychological well-being (1-2) and is one of&#xD;
      the key precipitants of early retirement (11-12). Its 'invisible' nature may lead to&#xD;
      difficulties in personal and work relationships (13-14).&#xD;
&#xD;
      Although fatigue is one of the major symptoms of MS patients, the pathophysiology of fatigue&#xD;
      is unclear (15) but likely to be multi- factorial (16-17). Findings on the relationships&#xD;
      between fatigue and other clinical variables (such as age, gender, disease duration, and&#xD;
      clinical activity) have been equivocal (18). The neural correlates are poorly components such&#xD;
      as peripheral vs. central fatigue or physical vs. cognitive or mental, which are difficult to&#xD;
      define or operationalize.&#xD;
&#xD;
      Pharmacological and non-pharmacological treatments are available for MS-related fatigue, but&#xD;
      evidence on effectiveness is mostly inconclusive or non-existent (19-20). Non-pharmacological&#xD;
      studies exploring the effectiveness of energy conservation programs for MS-fatigue have&#xD;
      tended to be small and uncontrolled (21-22). Although the important relationships between&#xD;
      physical and psychological aspects of MS-fatigue are recognized, high quality randomized and&#xD;
      controlled trials (RCTs) of psychological interventions are rare (23).&#xD;
&#xD;
      The integration of cognitive-behavioral approaches in fatigue management programs is&#xD;
      interesting. Indeed, their effectiveness has been demonstrated in Chronic Fatigue Syndrome.&#xD;
      To date, three RCTs using cognitive-behavioral group-based approaches in the context of MS&#xD;
      have been conducted (3-4). Cognitive behavioral approaches are potentially more profitable&#xD;
      than the dual interventions, more easily integrated into a framework of routine care, and&#xD;
      they also offer the possibility of peer support. The results of these studies demonstrated a&#xD;
      reduction in fatigue scores and better self-management of the disease in general, resulting&#xD;
      in improvements in quality of life. In their meta-analysis (24) indicate that the results&#xD;
      obtained with CBT or with physical exercises are similar, but when people are anxious or&#xD;
      depressed, which is often the case with MS (25-26), CBT shows better improvement. Knoop &amp; al.&#xD;
      (27) highlighted the importance of cognitive representations on fatigue and the potential&#xD;
      relevance of CBT: they showed that the strongest mediators of fatigue severity were fatigue&#xD;
      avoidance, symptom focusing and the belief that fatigue symptoms are a sign of damage.&#xD;
&#xD;
      Thomas et al., (4) found that modest effects on fatigue severity were largely maintained at&#xD;
      one year (unpublished data). Given that MS typically is diagnosed during the most productive&#xD;
      years of individuals' lives and lasts the life course it is important to give people flexible&#xD;
      tools and strategies to manage fatigue that can be used in the long term. Booster session&#xD;
      might therefore help to 'boost' or enhance the effectiveness of the program in the longer&#xD;
      term Methodology A multicentre parallel arm randomized controlled trial comparing a group&#xD;
      receiving 'enhanced' FACETS plus current usual practice versus a group receiving current&#xD;
      local practice only.&#xD;
&#xD;
      Inclusion criteria: clinically confirmed diagnosis of relapsing remitting MS; Significant&#xD;
      fatigue levels (score at the Modified Fatigue Impact Scale - MFIS &gt; 45); Expanded Disability&#xD;
      Status Scale score &lt; 6; age ≥ 18 years; written informed consent; speak and understand&#xD;
      French; be able to follow the program.&#xD;
&#xD;
      Exclusion criteria: Individuals with cognitive deficits such that they would not be able to&#xD;
      engage and benefit from this group-based program. Indeed, if individuals have significant&#xD;
      cognitive deficits, most of the content of the fatigue management program would not be&#xD;
      appropriate; People who have had a relapse within the past three months: (a relapse might&#xD;
      result in increased fatigue) People who have started treatment on a disease modifying drug or&#xD;
      anti-depressant in the past 3 months (one of the possible initial side effects of these drugs&#xD;
      is fatigue); People who have psychiatric disorders Sample size: if one uses the results of&#xD;
      the study (30) (matched groups), these authors show that in 59 MS patients treated with&#xD;
      Modafinil, the mean fatigue score on the MFIS is 52.3 (SD/SE = 18.5), whilst in 56 MS&#xD;
      patients treated by placebo the mean fatigue score is 49.2 (SD/SE = 16.6). The investigators&#xD;
      will seek to uncover an absolute difference of 10 points between mean scores. The FACETS&#xD;
      trial found a standardized effect size of 0.35 on their fatigue severity primary outcome,&#xD;
      which would translate to around 6 points on the MFIS. It is anticipated that by using booster&#xD;
      sessions and by running the programme using psychologists, that the anticipated effect size&#xD;
      will be larger (10 points). In order to detect a 10 points absolute difference between the&#xD;
      mean scores (on the MFIS) of the efficaciousness of the cognitive-behavioral intervention,&#xD;
      power to detect an effect size of 8.5 points Participants will be identified and recruited by&#xD;
      the neurologists of the hospitals who take part in the program, when they come for a medical&#xD;
      examination.&#xD;
&#xD;
      Randomization: After giving their informed consent, the patients will be entered onto the&#xD;
      trial database and randomized in a 1:1 ratio to either the fatigue management program and or&#xD;
      current local practice using a computer, generated randomization sequence stratified by site.&#xD;
&#xD;
      Intervention FACETS (4). Focuses on the management of fatigue and is based on a conceptual&#xD;
      framework that incorporates elements of cognitive-behavioral, self-efficacy, self-management&#xD;
      and energy effectiveness theories. It consists of six once-weekly sessions of 90 minutes&#xD;
      (with a break), with homework activities between the sessions. It is designed for groups of 8&#xD;
      to 10 people and will be delivered by two psychologists. The program is standardized:&#xD;
      PowerPoints presentations support each session and a detailed facilitator manual and&#xD;
      companion patient workbook. accompany the program.&#xD;
&#xD;
      The investigators propose to add 4 booster sessions to the FACETS program, at week 6, 12 et&#xD;
      18 et 36 after the end of the program, in order to activate and reinforce the cognitive and&#xD;
      behavioral processes and they hope to enhance the benefits of FACETS in the longer term.&#xD;
&#xD;
      Measures For the FACETs group these will be administered pre, post and 12 months after the&#xD;
      end of the FACETS program and at the same times for those in the control group&#xD;
      Socio-demographic and medical data: age, sex, level of education, marital status, number of&#xD;
      children and professional status; date of diagnosis, disease type, level of disability.&#xD;
&#xD;
      Neuropsychological measures: Paced Auditory Serial Addition Task (PASAT,28) &amp; the&#xD;
      Computerized Speed Cognitive Test (CSCT,29).&#xD;
&#xD;
      Statistical analysis: They will register the trial and endeavor to publish the full trial&#xD;
      protocol prior to its commencement. The primary analysis of effectiveness will use an&#xD;
      &quot;intention-to-treat&quot; approach and focus on comparing MFIS at 12 months post treatment (ie&#xD;
      after the program and all booster sessions are complete) between the two trial arms using&#xD;
      analysis of covariance to take into account MFIS at baseline, and study center. In addition&#xD;
      to these analyses they will conduct further comparative analyses using a mixed model approach&#xD;
      that permits analysis of repeated measures (baseline, post treatment and 12 months&#xD;
      follow-up), takes into account missing data (i.e. model allows participants to contribute to&#xD;
      the model even if they don't have complete data), and takes into account the group-based&#xD;
      nature of the program (cluster effects). A similar approach will be used for other interval&#xD;
      scaled outcome measures, and adapted if the outcome measure is nominal (eg the EDSS)&#xD;
      Hypotheses There will be a significantly greater decrease in fatigue severity and impact in&#xD;
      the FACETS group than the control group post intervention and this difference will be&#xD;
      maintained at 1 year.&#xD;
&#xD;
      There will be a significantly greater improvement in sleepiness and sleep quality, anxiety,&#xD;
      depression, stress, attention and working memory in the FACETS group than the control group&#xD;
      at the end of the program and at 12 months The FACETS group will show a significantly greater&#xD;
      reduction in cortical atrophy, axonal loss and demyelination within white matter tracts of&#xD;
      DMN than those in the control group Ethics The protocol was submitted to the French competent&#xD;
      authorities and a declaration was made to the CNIL.&#xD;
&#xD;
      Patients allocated to the control group (current local practice) will be offered the FACETS&#xD;
      program after the 12 months follow-up.&#xD;
&#xD;
      Finally, all information collected will be strictly confidential. Identification numbers of&#xD;
      participants will be noted on the questionnaires which will not contain any names or details&#xD;
      to identify the participants. Only members of the research team will be allowed to access the&#xD;
      trial data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 31, 2017</start_date>
  <completion_date type="Actual">October 15, 2020</completion_date>
  <primary_completion_date type="Actual">October 15, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>parallel group assignment</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>randomization of patients</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change assessment from Baseline measure of Fatigue Impact to month 6, 12 and 18</measure>
    <time_frame>After 6 weeks and 6,12 and 18 months</time_frame>
    <description>Fatigue impact evaluated by MFIS autoquestionnaire MFIS : Modified Fatigue Impact Scale, 5 response option (0 to 4), score of between 0 (better) and 84 (worse) : A score &gt; 45 means the patient is affected by fatigue.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Anxiety and depression</measure>
    <time_frame>After 12 months</time_frame>
    <description>Anxiety and depression evaluated by HADS autoquestionnaire HADS : Hospital Anxiety and Depression Scale, five-point rating scale (0 to 4), score of between 0 (better) and 42 (worse).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Fatigue severity</measure>
    <time_frame>After 6 weeks and 6 and 12 months</time_frame>
    <description>Fatigue severity evaluated by FSS autoquestionnaire FSS : Fatigue Severity Scale, seven-point rating scale (1 to 7), score &gt;3 = fatigue severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Quality of sleep: Pittsburgh Sleep Quality scale</measure>
    <time_frame>After 12 months</time_frame>
    <description>Quality of sleep evaluated by Pittsburgh scale. IQSP 1.0 : Pittsburgh Sleep Quality scale, four-point rating scale (0 to 3), score of between 0 (better) and 21 (worse) : score &gt;5 = sleep disorder.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Quality of sleep: Epworth Sleepiness Scale</measure>
    <time_frame>After 12 months</time_frame>
    <description>Quality of sleep evaluated by Epsworth scale. Epworth Sleepiness Scale : four-point rating scale (0 to 3), score of between 0 (better) and 24 (worse) : score &gt;9 = risk of pathological somnolence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Cognitive disorders</measure>
    <time_frame>After 12 months</time_frame>
    <description>Cognitive disorders evaluated by PASAT. PASAT : Paced Auditory Serial Addition Test de Gronwall. Score of between 0 (worse) and 60 (better).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Cognitive disorders</measure>
    <time_frame>After 12 months</time_frame>
    <description>Cognitive disorders evaluated by CSCT. CSCT : Computerized speed cognitive test. The score is the number of correct answer provided in 90 seconds. At the end of each test, the patient's score is automatically interpreted according to the normative values for his age, level of education and sex. If a patient's score is less than 1.5 SD of normal values, it is likely that this patient has a TTI slowing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Quality of life: MSIS-29</measure>
    <time_frame>After 6,12 and 18 months</time_frame>
    <description>Quality of life evaluated by MSIS-29. MSIS-29 : The Multiple Sclerosis Impact Scale. 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. 5 response options (1 to 5). Each of the two scales are scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates greater impact of disease on daily function (worse health).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Quality of life: EQ5D-3L</measure>
    <time_frame>After 6,12 and 18 months</time_frame>
    <description>Quality of life evaluated by EQ5D-3L. EQ5D-3L European Quality of Life. Five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of Medical care consumption and professional impact</measure>
    <time_frame>After 6,12 and 18 months</time_frame>
    <description>Medical care consumption evaluated by the number of visits to the physician, treatment and hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change assessment from Baseline of professional impact</measure>
    <time_frame>After 6,12 and 18 months</time_frame>
    <description>professional impact evaluated by the number of work stoppage</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">105</enrollment>
  <condition>Relapsing Remitting Multiple Sclerosis</condition>
  <condition>Fatigue</condition>
  <condition>Cognitive Therapy</condition>
  <arm_group>
    <arm_group_label>BCT group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention : Behavorial Cognitive Therapy (BCT) will be delivered by two psychologists at six once-weekly sessions of 90 minutes (with homework activities between the sessions) + 4 booster sessions at week 6, 12, 18 and 36 after the end of the programme.&#xD;
It was designed for groups of 8 to 10 people. The programme is standardised: PowerPoints presentations support each session and a detailed facilitator manual and companion patient workbook. accompany the programme.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Usual local practice</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Behavorial Cognitive Therapy (BCT)</intervention_name>
    <description>Check-in : review of the homewok Talk : Presentation of the aim of the session Group Activity : Relaxation and Execises Refreshment break Homework : exercises to practice at home and explanation about the forms to fill in.&#xD;
Passout : session handbook and supports for exercises.</description>
    <arm_group_label>BCT group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  RRMS&#xD;
&#xD;
          -  EDSS ≤ 5,5&#xD;
&#xD;
          -  MFIS score &gt; 45&#xD;
&#xD;
          -  Outpatient treatment&#xD;
&#xD;
          -  Enable to follow the BCT sessions&#xD;
&#xD;
          -  French understanding&#xD;
&#xD;
          -  More than 18 years old&#xD;
&#xD;
          -  Inform consent signature&#xD;
&#xD;
          -  Membership in a social protection&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Cognitive disorders avoiding patient participation&#xD;
&#xD;
          -  Relapse within last 3 months before baseline&#xD;
&#xD;
          -  Onset of DMT within 3 months&#xD;
&#xD;
          -  Onset of antidepressive treatment within 3 months&#xD;
&#xD;
          -  Onset of treatment for fatigue within 3 months&#xD;
&#xD;
          -  Psychiatric disorders&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Olivier HEINZLEF, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Réseau Sep Idf Ouest</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Poissy St Germain Hospital</name>
      <address>
        <city>Poissy</city>
        <zip>78300</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
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    <citation>Flensner G, Landtblom AM, Soderhamn O, Ek AC. Work capacity and health-related quality of life among individuals with multiple sclerosis reduced by fatigue: a cross-sectional study. BMC Public Health. 2013 Mar 15;13:224. doi: 10.1186/1471-2458-13-224.</citation>
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    <PMID>8621999</PMID>
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    <citation>Schwid SR, Covington M, Segal BM, Goodman AD. Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev. 2002 Mar-Apr;39(2):211-24.</citation>
    <PMID>12051465</PMID>
  </results_reference>
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    <citation>Racke MK, Hawker K, Frohman EM. Fatigue in multiple sclerosis: is the picture getting simpler or more complex? Arch Neurol. 2004 Feb;61(2):176-7. doi: 10.1001/archneur.61.2.176. No abstract available.</citation>
    <PMID>14967763</PMID>
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    <PMID>20070277</PMID>
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    <PMID>25112509</PMID>
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    <citation>Knoop H, van Kessel K, Moss-Morris R. Which cognitions and behaviours mediate the positive effect of cognitive behavioural therapy on fatigue in patients with multiple sclerosis? Psychol Med. 2012 Jan;42(1):205-13. doi: 10.1017/S0033291711000924. Epub 2011 Jun 15.</citation>
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    <citation>Ruet A, Deloire MS, Charre-Morin J, Hamel D, Brochet B. A new computerised cognitive test for the detection of information processing speed impairment in multiple sclerosis. Mult Scler. 2013 Oct;19(12):1665-72. doi: 10.1177/1352458513480251. Epub 2013 Mar 4.</citation>
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    <citation>Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, Moreau T, Pelletier J, Lubetzki C, Clanet M; French Modafinil Study Group. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005 Apr 12;64(7):1139-43. doi: 10.1212/01.WNL.0000158272.27070.6A.</citation>
    <PMID>15824337</PMID>
  </results_reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>October 19, 2017</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 29, 2018</study_first_posted>
  <last_update_submitted>March 15, 2021</last_update_submitted>
  <last_update_submitted_qc>March 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Relapsing-Remitting</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Fatigue</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03758820
org study id: FACCSEP
nct id: NCT03758820
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: parallel group assignment
primary purpose: Supportive Care
masking: Single (Participant)
masking description: randomization of patients
measure: Change assessment from Baseline measure of Fatigue Impact to month 6, 12 and 18
time frame: After 6 weeks and 6,12 and 18 months
description: Fatigue impact evaluated by MFIS autoquestionnaire MFIS : Modified Fatigue Impact Scale, 5 response option (0 to 4), score of between 0 (better) and 84 (worse) : A score > 45 means the patient is affected by fatigue.
measure: Change assessment from Baseline of Anxiety and depression
time frame: After 12 months
description: Anxiety and depression evaluated by HADS autoquestionnaire HADS : Hospital Anxiety and Depression Scale, five-point rating scale (0 to 4), score of between 0 (better) and 42 (worse).
measure: Change assessment from Baseline of Fatigue severity
time frame: After 6 weeks and 6 and 12 months
description: Fatigue severity evaluated by FSS autoquestionnaire FSS : Fatigue Severity Scale, seven-point rating scale (1 to 7), score >3 = fatigue severity
measure: Change assessment from Baseline of Quality of sleep: Pittsburgh Sleep Quality scale
time frame: After 12 months
description: Quality of sleep evaluated by Pittsburgh scale. IQSP 1.0 : Pittsburgh Sleep Quality scale, four-point rating scale (0 to 3), score of between 0 (better) and 21 (worse) : score >5 = sleep disorder.
measure: Change assessment from Baseline of Quality of sleep: Epworth Sleepiness Scale
time frame: After 12 months
description: Quality of sleep evaluated by Epsworth scale. Epworth Sleepiness Scale : four-point rating scale (0 to 3), score of between 0 (better) and 24 (worse) : score >9 = risk of pathological somnolence
measure: Change assessment from Baseline of Cognitive disorders
time frame: After 12 months
description: Cognitive disorders evaluated by PASAT. PASAT : Paced Auditory Serial Addition Test de Gronwall. Score of between 0 (worse) and 60 (better).
measure: Change assessment from Baseline of Cognitive disorders
time frame: After 12 months
description: Cognitive disorders evaluated by CSCT. CSCT : Computerized speed cognitive test. The score is the number of correct answer provided in 90 seconds. At the end of each test, the patient's score is automatically interpreted according to the normative values for his age, level of education and sex. If a patient's score is less than 1.5 SD of normal values, it is likely that this patient has a TTI slowing.
measure: Change assessment from Baseline of Quality of life: MSIS-29
time frame: After 6,12 and 18 months
description: Quality of life evaluated by MSIS-29. MSIS-29 : The Multiple Sclerosis Impact Scale. 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. 5 response options (1 to 5). Each of the two scales are scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates greater impact of disease on daily function (worse health).
measure: Change assessment from Baseline of Quality of life: EQ5D-3L
time frame: After 6,12 and 18 months
description: Quality of life evaluated by EQ5D-3L. EQ5D-3L European Quality of Life. Five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
measure: Change assessment from Baseline of Medical care consumption and professional impact
time frame: After 6,12 and 18 months
description: Medical care consumption evaluated by the number of visits to the physician, treatment and hospitalization
measure: Change assessment from Baseline of professional impact
time frame: After 6,12 and 18 months
description: professional impact evaluated by the number of work stoppage
arm group label: BCT group
arm group type: Experimental
description: Intervention : Behavorial Cognitive Therapy (BCT) will be delivered by two psychologists at six once-weekly sessions of 90 minutes (with homework activities between the sessions) + 4 booster sessions at week 6, 12, 18 and 36 after the end of the programme.
It was designed for groups of 8 to 10 people. The programme is standardised: PowerPoints presentations support each session and a detailed facilitator manual and companion patient workbook. accompany the programme.
arm group label: Control group
arm group type: No Intervention
description: Usual local practice
intervention type: Behavioral
intervention name: Behavorial Cognitive Therapy (BCT)
description: Check-in : review of the homewok Talk : Presentation of the aim of the session Group Activity : Relaxation and Execises Refreshment break Homework : exercises to practice at home and explanation about the forms to fill in.
Passout : session handbook and supports for exercises.
arm group label: BCT group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Olivier HEINZLEF, MD
role: Principal Investigator
affiliation: Réseau Sep Idf Ouest
facility: 
country: France
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responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Sclerosis
mesh term: Fatigue
sharing ipd: No