<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/NCT03766100</url>
  </required_header>
  <id_info>
    <org_study_id>H-18016081</org_study_id>
    <nct_id>NCT03766100</nct_id>
  </id_info>
  <brief_title>Cognitive Behavioural Therapy for Insomnia on Sleep in Rheumatoid Arthritis.</brief_title>
  <official_title>The Efficacy of Cognitive Behavioural Therapy for Insomnia (CBT-I) on Sleep in Patients With Rheumatoid Arthritis: the Randomised, Non-blinded, Parallel-group Sleep-RA Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bente Appel Esbensen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Danish Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Parker Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Glostrup University Hospital, Copenhagen</source>
  <oversight_info>
    <has_dmc>No</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>
      Introduction:&#xD;
&#xD;
      Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease that attacks&#xD;
      peripheral joints and posterior tissues. More than half of patients with RA also have&#xD;
      insomnia, which can modify pain, fatigue, quality of life and comorbidities. Traditional&#xD;
      treatment of insomnia is often based on pharmacological drugs, however cognitive behavioural&#xD;
      therapy for insomnia (CBT-i) have shown effect in insomnia with less side effects. It remains&#xD;
      to determine whether CBT-i can be effective in patients with RA.&#xD;
&#xD;
      The primary objective of this Sleep-RA trial is to assess the efficacy of CBT-i on sleep&#xD;
      efficiency in patients with RA at week seven. Key secondary objectives are to estimate the&#xD;
      clinical efficacy of CBT-i on wake after sleep onset, total sleep time, sleep onset latency,&#xD;
      insomnia, sleep quality, fatigue, RA impact of disease and depressive symptoms at week 26.&#xD;
&#xD;
      Methods &amp; Analysis:&#xD;
&#xD;
      Sleep-RA will be carried out as a randomised controlled trial (RCT) with randomised&#xD;
      assignment and two-group parallel design. Patients with RA and insomnia are randomly&#xD;
      allocated 1:1 to the intervention group or the control group. The intervention group will&#xD;
      once a week for six weeks receive group-based CBT-i, a multi-component intervention of; sleep&#xD;
      education, stimulus control, sleep restriction, cognitive therapy and relaxation. The control&#xD;
      group will continue treatment as usual (insomnia will remain untreated). Follow-up&#xD;
      assessments will be carried out seven and 26 weeks after baseline. The primary outcome is&#xD;
      sleep efficiency measured with polysomnography at week seven. Key secondary outcomes are:&#xD;
      wake after sleep onset, total sleep time, sleep onset latency, insomnia, sleep quality,&#xD;
      fatigue, RA impact of disease and depressive symptoms from baseline to week 26.&#xD;
      Polysomnography, actigraphy and Disease Activity Score 28-Joint Count C reactive protein will&#xD;
      be assessed by medical staff blinded to group allocation. The project manager will assist the&#xD;
      participants with questionnaires and conduct the intervention of CBT-i and will therefore not&#xD;
      be blinded to group allocation. With a sample size of 60 patients the trial will have more&#xD;
      than 85 % power to detect a mean difference between groups of 6 % points in the primary&#xD;
      outcome of sleep efficiency measured at week seven and a reasonable statistical power to&#xD;
      explore the clinical efficacy according to the eight key secondary outcome measures at week&#xD;
      26.&#xD;
&#xD;
      Ethics and dissemination:&#xD;
&#xD;
      Ethics approval has been obtained from The Committee on Health Research Ethics. We plan to&#xD;
      submit a manuscript with the content of this protocol, and at least one scientific manuscript&#xD;
      on the results of the primary and key secondary outcomes to a peer-reviewed journal. Results&#xD;
      will be presented at conferences, community and consumer forums and hospital grand rounds.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction:&#xD;
&#xD;
      More than half of patients with rheumatoid arthritis has concomitant insomnia. Insomnia may&#xD;
      modify pain, fatigue, quality of life and comorbidities which many patients struggle with. To&#xD;
      address this issue, a nurse led sleep outpatient clinic was established in 2015 at the Center&#xD;
      for Rheumatology and Spine Diseases in the Capital Region of Denmark. The aim of this clinic&#xD;
      is to identify the causes and severity of insomnia in patients with inflammatory joint&#xD;
      diseases and to treat it with non-pharmacological initiatives. Eligible patients can be&#xD;
      referred to the clinic by rheumatologists and rheumatology nurses. The current project,&#xD;
      entitled Sleep-RA, is designed to expand the evidence-based opportunities of&#xD;
      non-pharmacological treatment of insomnia within a biopsychosocial perspective among patients&#xD;
      with inflammatory joint diseases. First and foremost, we want to assess the efficacy of&#xD;
      cognitive behavioural therapy for insomnia on sleep efficiency in patients with rheumatoid&#xD;
      arthritis and concomitant insomnia.&#xD;
&#xD;
      Rheumatoid Arthritis:&#xD;
&#xD;
      Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease (IJD) that&#xD;
      affects peripheral joints. The inflammation typically cause tender and swollen joints and&#xD;
      cartilage degradation and bone erosions may occur. RA is diagnosed from medical history,&#xD;
      physical examination, blood samples and imaging. Prevalence worldwide is 0.4-1.3 % and RA&#xD;
      affects women two-three times more frequently than men; onset is most often at 50-60 years of&#xD;
      age. The most commonly used method for monitoring disease activity is the Disease Activity&#xD;
      Score 28 (DAS28-CRP) based on 28 joint count of tender and swollen joints, C-Reactive Protein&#xD;
      (CRP) and 'patient global assessment'. Rheumatological treatment of RA targets reduction of&#xD;
      disease activity and is primarily pharmacological with synthetic disease-modifying&#xD;
      antirheumatic drugs (csDMARDs), in which methotrexate is the first drug of choice. Biological&#xD;
      antirheumatic drugs (bDMARDs) are used in the absence or insufficient effect of csDMARD.&#xD;
&#xD;
      Consequences and symptoms of RA:&#xD;
&#xD;
      Improvements in early diagnosis and medical treatment with antirheumatic drugs, have reduced&#xD;
      the incidence of severe joint destruction. However, RA still causes stiffness and swelling in&#xD;
      the joints. Some consequences of these symptoms and the inflammation itself are: insomnia,&#xD;
      pain, fatigue, reduced physical function, depression and reduced quality of life. About 60-80&#xD;
      % of patients with RA report insomnia compared to 10-30 % in the general population. Patients&#xD;
      with RA indicate sleep as one of the most important variables evaluating their medical&#xD;
      treatment with antirheumatic drugs, which indicates the impact sleep can have on physical and&#xD;
      mental well-being. Pain is also a very common symptom of RA and is associated with fatigue,&#xD;
      depressive symptoms, insomnia and inability to work and to cope with social and domestic&#xD;
      activities. Furthermore, fatigue is experienced almost universally by individuals with RA&#xD;
      while severe fatigue occurs in approximately 50 % of cases. The strongest independent&#xD;
      predictors of fatigue are pain, insomnia, depression and physical function. Fatigue is&#xD;
      perceived to have a significant impact on physical and social functioning and health care&#xD;
      utilization and is a predictor of work dysfunction and overall health status. Pain and&#xD;
      fatigue are very important to patient wellbeing and can make the management of other RA&#xD;
      symptoms more challenging.&#xD;
&#xD;
      Sleep:&#xD;
&#xD;
      Common definitions of &quot;good&quot; and &quot;bad&quot; sleep in a healthy population are characterised by&#xD;
      subjective satisfaction, appropriate timing, adequate duration, high efficiency, and&#xD;
      sustained alertness during waking hours. Thus, &quot;sleep health&quot; is seen as a multidimensional&#xD;
      pattern of sleep-wakefulness adapted to individual, social, and environmental demands, which&#xD;
      promotes physical and mental well-being. These elements are essential to good sleep. To&#xD;
      establish a clear meaning of &quot;sleep health&quot;, Buysse (2014) has introduced a conceptual model.&#xD;
      Five dimensions of sleep were identified as relevant including: sleep duration, sleep&#xD;
      continuity or efficiency, timing, alertness/sleepiness, and satisfaction/quality (subjective&#xD;
      assessment of good or poor sleep). Within the research field of sleep, studies have mainly&#xD;
      focused on negative directions and consequences of sleep and there have been few studies&#xD;
      specifically examining the potential benefits of good sleep.&#xD;
&#xD;
      As previously identified, patients with RA suffer from a wide range of disease related&#xD;
      consequences and symptoms and most of them can be associated with insomnia. According to&#xD;
      observational studies sleep quality is associated with pain, fatigue, quality of life,&#xD;
      depression, and disease activity among patients with RA. Insomnia can become long-lasting&#xD;
      when the precipitating factor e.g. being diagnosed with a chronic disease as RA to some&#xD;
      extend is replaced by perpetuating cognitive and behavioural factors.&#xD;
&#xD;
      Sleep disturbances and cognitive behavioural therapy for insomnia:&#xD;
&#xD;
      The gold standard for identifying insomnia in clinical and research settings is&#xD;
      polysomnography (PSG), an objective multi-parametric test. The questionnaires Pittsburgh&#xD;
      Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) are the most used and validated&#xD;
      questionnaires in assessing patient reported sleep. PSQI has been validated for patients with&#xD;
      RA and measures sleep quality and disturbances over the previous month; it differentiates&#xD;
      between &quot;good&quot; and &quot;poor&quot; sleepers. Specifically targeting insomnia, the content of ISI&#xD;
      corresponds in part to the Diagnostic and Statistical Manual 4th Edition (DSM-IV) diagnostic&#xD;
      criteria for insomnia. Actigraphy (small wrist band) is the most valid method to assess&#xD;
      sleep/wake behaviour over time (days or weeks).&#xD;
&#xD;
      Insomnia is characterized by difficulty falling asleep or staying asleep as intended and&#xD;
      insomnia often leads to inappropriate sleep habits and dysfunctional thoughts related to&#xD;
      sleep. Nevertheless, treatment of insomnia is often based on hypnotic drugs that can cause&#xD;
      side effects such as tolerance and addiction. In contrast to treatment with hypnotic drugs,&#xD;
      cognitive behavioural therapy for insomnia (CBT-i) has demonstrated long-term effects on&#xD;
      sleep. So far CBT-i has mostly been tested on people with insomnia and patients with cancer&#xD;
      or mental illness with concomitant insomnia. It is a multi-component intervention that aims&#xD;
      at teaching patients about health-related significance of sleep and factors that affect it,&#xD;
      supporting patients in regulating their sleep habits and dealing with sleep related concerns.&#xD;
      CBT-i combines various components: I) stimulus control (e.g. associating the bed and bedroom&#xD;
      with sleep), II) sleep restriction (e.g. increasing the homeostatic drive to sleep by&#xD;
      reducing time in bed), III) cognitive therapy (i.e. addressing maladaptive beliefs about&#xD;
      sleep and reducing arousal and anxiety about sleep and the consequences of not sleeping), IV)&#xD;
      sleep hygiene (i.e. establishing behavioural routines to promote restorative sleep) and V)&#xD;
      relaxation.&#xD;
&#xD;
      In a recent study in a primary care setting CBT-I conducted as two hours group-based sessions&#xD;
      once a week for six weeks with three to eleven participants had significant effect on&#xD;
      insomnia. Further, group-based interventions of CBT-i with four to six participants can help&#xD;
      break the feeling of isolation.&#xD;
&#xD;
      Rationale:&#xD;
&#xD;
      Even though the prevalence of insomnia is high in patients with RA there have been published&#xD;
      results from only very few randomised controlled trials (RCT) in this area. The intervention&#xD;
      in most of these studies is based on treatment with hypnotic drugs or other pharmaceutical&#xD;
      treatments. Only two studies have been identified as investigating sleep as primary outcome&#xD;
      with a non-pharmacological approach, both with physical exercise as intervention. To our&#xD;
      knowledge no RCT has yet investigated the effect of CBT-i on insomnia in patients with RA or&#xD;
      other (IJD). However, the effect of CBT-i is larger and longer lasting than the effect of&#xD;
      pharmaceutical treatments, presumably because patients learn skills they can use to manage&#xD;
      sleep at later times. At the Copenhagen Centre for Arthritis Research (COPECARE) the efficacy&#xD;
      of high-intensity interval training on sleep in patients with RA has recently been&#xD;
      investigated in a pilot/feasibility RCT, data are under review. High-intensity interval&#xD;
      training may not appeal to all patients with RA or patients with other IJD. With an intention&#xD;
      to offer different non-pharmacological treatments for insomnia in rheumatology outpatient&#xD;
      clinics, it is meaningful to assess the efficacy of CBT-i.&#xD;
&#xD;
      CBT-i is often carried out by health professionals with training and experience in&#xD;
      psychology. As these professionals rarely are integrated in daily clinical hospital practice,&#xD;
      it is difficult to standardize psychologist-led CBT-i in outpatient treatment of insomnia.&#xD;
      The clinical effectiveness of group-based CBT-i led by nurses is evidenced in RCTs in&#xD;
      European general practice settings.&#xD;
&#xD;
      Previous group-based psychological behavioural interventions, including CBT, have been&#xD;
      effective for pain, fatigue, physical function, psychological well-being, social activities&#xD;
      and coping resources among patients with RA and CBT-i have had a positive effect on sleep in&#xD;
      people with cancer and mental illness.&#xD;
&#xD;
      Aim and objectives:&#xD;
&#xD;
      The aim of Sleep-RA is to assess the efficacy and safety of CBT-i in patients with RA and&#xD;
      concomitant insomnia.&#xD;
&#xD;
      Primary objective: To compare the effect of CBT-i relative to a control group on sleep&#xD;
      efficiency at week seven in patients with RA and concomitant insomnia.&#xD;
&#xD;
      Key secondary objectives: To compare the effect of CBT-i, relative to a control group, on&#xD;
      changes in wake after sleep onset, total sleep time, sleep onset latency, insomnia, sleep&#xD;
      quality, fatigue, RA impact of disease and depressive symptoms from baseline to week 26 in&#xD;
      patients with RA and concomitant insomnia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 17, 2018</start_date>
  <completion_date type="Actual">March 8, 2021</completion_date>
  <primary_completion_date type="Actual">March 8, 2021</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Application of PSG equipment prior to monitoring sleep efficiency and subsequent analysis of results will be conducted by neurophysiology assistants at the Danish Center for Sleep Medicine (DCSM) blinded to participants' allocation. Examination of participants' joints related to the secondary outcome of disease activity will be conducted by a project nurse specialized in rheumatology blinded to participants' allocation. Blood samples related to RA and disease activity will be taken and analysed by a medical laboratory technologist blinded to participants' allocation. Patient Reported Outcome Measures (PROMs) will be collected via questionnaires on tablets handed out by the project manager, who will also conduct the intervention of CBT-I, and therefore not able to be blinded to allocation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Polysomnography (PSG): Sleep efficiency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Polysomnography (PSG): Wake after sleep onset.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Polysomnography (PSG): Total sleep time.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Polysomnography (PSG): Sleep onset latency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insomnia Severity Index (ISI): Insomnia.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>ISI measures self-reported insomnia severity the last two weeks. ISI is a seven-item questionnaire and each item is rated using a five-point Likert scale ranging from 0 (not at all) to 4 (very much), for a total score ranging from 0 (no insomnia) to 28 (clinical insomnia).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep quality.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>BRAF-MDQ measures self-reported RA-related fatigue for the previous seven days. It consists of 20 items with four responses (&quot;not at all&quot;, &quot;a bit&quot;, &quot;part&quot;, &quot;much&quot;). Items are combined to create 5 scores, high is worse: Total fatigue score 0-70 Items 1-20 summed, Physical (severity) subscale 0-22 Items 1-4 summed, Living with fatigue subscale 0-21 Items 5-11 summed, Cognitive fatigue subscale 0-15 Items 12-16 summed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>RAID measures self-reported impact of RA on daily life the last seven days. RAID consist of seven items, each item rated using af numerical rating scale (NRS 0-10), high is worse covering pain, physical function, fatigue, sleep, physical well-being, mental well-being and coping. RAID final value = (pain NRS value (range 0-10) x 0.21) + (function NRS value (range 0-10) x 0.16) + (fatigue NRS value (range 0-10) x 0.15) + (physical well-being NRS value (range 0-10) x 0.12) + (sleep NRS value (range 0-10) x 0.12) + (emotional well-being NRS value (range 0-10) x 0.12) + (coping NRS value (range 0-10) x 0.12).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>HADS-D measures self-reported depressive symptoms as psychological morbidity the last seven days. Seven items are rated on a four-point scale and scored from 0-3 with total scores therefore ranging from 0-21. Scores between 0 and 7 represent 'no case', 8 to 10 indicate 'possible case', 11-15 'moderate case' and '15-21' suggest a 'probable severe case of depression'.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Actigraphy: Sleep efficiency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Wake after sleep onset.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Total sleep time.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Sleep onset latency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Total sleep time.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>DAS28-CRP measures disease activity; an objective, reproducible and comparable assessment of the RA activity. A DAS28-CRP greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.</description>
  </other_outcome>
  <other_outcome>
    <measure>28-Joint Count: Tender joints.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>28-Joint Count measures tender joints by physical examination, reported as yes or no.</description>
  </other_outcome>
  <other_outcome>
    <measure>28-Joint Count: Swollen joints.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>28-Joint Count measures swollen joints by physical examination, reported as yes or no.</description>
  </other_outcome>
  <other_outcome>
    <measure>C-reactive protein level (CRP): Acute-phase reactant value.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>C-reactive protein level is a blood sample measuring Acute-phase reactant value. Higher value indicate inflammation.</description>
  </other_outcome>
  <other_outcome>
    <measure>Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>VAS global patient measures patient's self-reported global assessment of disease activity with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Physician's global assessment of the patient's current disease activity (VAS global physician): physician's global assessment of the patient's current disease activity.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>VAS global physician measures physician's self-reported global assessment of the patient's current disease activity, an overall assessment of how the patient's arthritis is doing with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>BRAF-NRS measures self-reported fatigue (severity, coping and effect) the last seven days with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Visual Analogue Scale (VAS pain): Pain.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>VAS pain measures self-reported current level of RA related pain (VAS 0-100), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>MD-HAQ measures self-reported physical function the last seven days and contains 10 items covering: dressing, rising, eating, walking, hygiene, reach, grip and everyday activities. Mean of the score = HAQ-score (0,0-3,0), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Short Form [36] Health Survey (SF-36): Health related quality of life.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>SF-36 measures self-reported health related physical and metal quality of life. SF-36 consists of eight scaled scores, which are the weighted sums of the items in their section. Each scale is transformed into a 0-100 scale. The lower the score the more disability.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polysomnography (PSG): Sleep efficiency.</measure>
    <time_frame>Assessed at week 26.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polysomnography (PSG): Wake after sleep onset.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polysomnography (PSG): Total sleep time.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </other_outcome>
  <other_outcome>
    <measure>Polysomnography (PSG): Sleep onset latency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.</description>
  </other_outcome>
  <other_outcome>
    <measure>Insomnia Severity Index (ISI): Insomnia.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>ISI measures self-reported insomnia severity the last two weeks. ISI is a seven-item questionnaire and each item is rated using a five-point Likert scale ranging from 0 (not at all) to 4 (very much), for a total score ranging from 0 (no insomnia) to 28 (clinical insomnia).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep quality.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>BRAF-MDQ measures self-reported RA-related fatigue for the previous seven days. It consists of 20 items with four responses (&quot;not at all&quot;, &quot;a bit&quot;, &quot;part&quot;, &quot;much&quot;). Items are combined to create 5 scores, high is worse: Total fatigue score 0-70 Items 1-20 summed, Physical (severity) subscale 0-22 Items 1-4 summed, Living with fatigue subscale 0-21 Items 5-11 summed, Cognitive fatigue subscale 0-15 Items 12-16 summed.</description>
  </other_outcome>
  <other_outcome>
    <measure>Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>RAID measures self-reported impact of RA on daily life the last seven days. RAID consist of seven items, each item rated using af numerical rating scale (NRS 0-10), high is worse covering pain, physical function, fatigue, sleep, physical well-being, mental well-being and coping. RAID final value = (pain NRS value (range 0-10) x 0.21) + (function NRS value (range 0-10) x 0.16) + (fatigue NRS value (range 0-10) x 0.15) + (physical well-being NRS value (range 0-10) x 0.12) + (sleep NRS value (range 0-10) x 0.12) + (emotional well-being NRS value (range 0-10) x 0.12) + (coping NRS value (range 0-10) x 0.12).</description>
  </other_outcome>
  <other_outcome>
    <measure>The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>HADS-D measures self-reported depressive symptoms as psychological morbidity the last seven days. Seven items are rated on a four-point scale and scored from 0-3 with total scores therefore ranging from 0-21. Scores between 0 and 7 represent 'no case', 8 to 10 indicate 'possible case', 11-15 'moderate case' and '15-21' suggest a 'probable severe case of depression'.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Sleep efficiency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Wake after sleep onset.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Total sleep time.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Actigraphy: Sleep onset latency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Total sleep time.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score &lt; 5) and bad sleep (PSQI global sum score &gt; 5).</description>
  </other_outcome>
  <other_outcome>
    <measure>Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>DAS28-CRP measures disease activity; an objective, reproducible and comparable assessment of the RA activity. A DAS28-CRP greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.</description>
  </other_outcome>
  <other_outcome>
    <measure>28-Joint Count: Tender joints.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>28-Joint Count measures tender joints by physical examination, reported as yes or no.</description>
  </other_outcome>
  <other_outcome>
    <measure>28-Joint Count: Swollen joints.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>28-Joint Count measures swollen joints by physical examination, reported as yes or no.</description>
  </other_outcome>
  <other_outcome>
    <measure>C-reactive protein level (CRP): Acute-phase reactant value.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>C-reactive protein level is a blood sample measuring Acute-phase reactant value. Higher value indicate inflammation.</description>
  </other_outcome>
  <other_outcome>
    <measure>Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>VAS global patient measures patient's self-reported global assessment of disease activity with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Physician's global assessment of the patient's current disease activity (VAS global physician): physician's global assessment of the patient's current disease activity.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>VAS global physician measures physician's self-reported global assessment of the patient's current disease activity, an overall assessment of how the patient's arthritis is doing with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>BRAF-NRS measures self-reported fatigue (severity, coping and effect) the last seven days with numerical rating scale (NRS 0-10), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Visual Analogue Scale (VAS pain): Pain.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>VAS pain measures self-reported current level of RA related pain (VAS 0-100), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>MD-HAQ measures self-reported physical function the last seven days and contains 10 items covering: dressing, rising, eating, walking, hygiene, reach, grip and everyday activities. Mean of the score = HAQ-score (0,0-3,0), high is worse.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Short Form [36] Health Survey (SF-36): Health related quality of life.</measure>
    <time_frame>Assessed at week 7.</time_frame>
    <description>SF-36 measures self-reported health related physical and metal quality of life. SF-36 consists of eight scaled scores, which are the weighted sums of the items in their section. Each scale is transformed into a 0-100 scale. The lower the score the more disability.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">62</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <condition>Insomnia</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cognitive Behavioural Therapy for Insomnia (CBT-i).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Insomnia is untreated.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Cognitive behavioural therapy (CBT-i)</intervention_name>
    <description>CBT-i aims to alter behaviours that sustain or add to insomnia and correct cognitions that drive these behaviours. The behavioural components of CBT-i are stimulus control (SC) and Sleep Restriction Therapy (SRT). SC works through the extinction of a conditioned arousal that emerges when bed and bedroom have become associated with wakefulness. With SRT time in bed is reduced to build up sleep pressure. When wakefulness is decreased, time in bed is gradually increased until optimal sleep is attained. With the cognitive component, insomnia is treated by identifying and changing unhelpful or inaccurate thinking regarding sleep and distressing emotional responses to insomnia. The last component of CBT-i aims to reduce hyperarousal with relaxation techniques, scheduled worry time, creating a time to unwind, and employing cognitive therapy strategies.</description>
    <arm_group_label>Intervention group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosed with RA according to American College of Rheumatology/European League&#xD;
             Against Rheumatism criteria 2010&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  Patients with low-to-moderate disease activity (DAS28-CRP ≤ 5.1)&#xD;
&#xD;
          -  Sleep score ≥ 2 (DANBIO)&#xD;
&#xD;
          -  Insomnia severity Index (ISI) ≥ 11&#xD;
&#xD;
          -  Unchanged medical treatment with anti-rheumatics &gt; 3 months&#xD;
&#xD;
          -  No indication for change of medical treatment with anti-rheumatic drugs the next three&#xD;
             months&#xD;
&#xD;
          -  Understand and read Danish.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Glucocorticoid administration (i.m., i.a., i.v.) &lt; four weeks&#xD;
&#xD;
          -  Oral glucocorticoid administration &gt; 5 mg/day&#xD;
&#xD;
          -  Change in oral glucocorticoid dose &lt; three month&#xD;
&#xD;
          -  Prior or current contact with rheumatic sleep outpatient clinic&#xD;
&#xD;
          -  Night work during the intervention&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Current alcohol or drug use disorder&#xD;
&#xD;
          -  Patient related circumstances (physical or mental) that impede the ability to give&#xD;
             informed consent or adhere to the trial programme.&#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>Bente Appel Esbensen</last_name>
    <role>Principal Investigator</role>
    <affiliation>Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases</name>
      <address>
        <city>Glostrup</city>
        <zip>2600</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <link>
    <url>https://www.rigshospitalet.dk/english/departments/centre-of-head-and-orthopaedics/centre-for-rheumatology-and-spine-diseases/copecare/Pages/default.aspx</url>
    <description>Copenhagen Center for Arthritis Research (COPECARE)</description>
  </link>
  <reference>
    <citation>Abad VC, Sarinas PS, Guilleminault C. Sleep and rheumatologic disorders. Sleep Med Rev. 2008 Jun;12(3):211-28. doi: 10.1016/j.smrv.2007.09.001.</citation>
    <PMID>18486034</PMID>
  </reference>
  <reference>
    <citation>Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018 Oct 2;320(13):1360-1372. doi: 10.1001/jama.2018.13103.</citation>
    <PMID>30285183</PMID>
  </reference>
  <reference>
    <citation>Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA. 2001 Apr 11;285(14):1856-64. doi: 10.1001/jama.285.14.1856.</citation>
    <PMID>11308399</PMID>
  </reference>
  <reference>
    <citation>Davidson JR, Dawson S, Krsmanovic A. Effectiveness of Group Cognitive Behavioral Therapy for Insomnia (CBT-I) in a Primary Care Setting. Behav Sleep Med. 2019 Mar-Apr;17(2):191-201. doi: 10.1080/15402002.2017.1318753. Epub 2017 May 2.</citation>
    <PMID>28463015</PMID>
  </reference>
  <reference>
    <citation>Smith MT, Finan PH, Buenaver LF, Robinson M, Haque U, Quain A, McInrue E, Han D, Leoutsakis J, Haythornthwaite JA. Cognitive-behavioral therapy for insomnia in knee osteoarthritis: a randomized, double-blind, active placebo-controlled clinical trial. Arthritis Rheumatol. 2015 May;67(5):1221-33. doi: 10.1002/art.39048.</citation>
    <PMID>25623343</PMID>
  </reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>April 15, 2021</last_update_submitted>
  <last_update_submitted_qc>April 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Glostrup University Hospital, Copenhagen</investigator_affiliation>
    <investigator_full_name>Bente Appel Esbensen</investigator_full_name>
    <investigator_title>Researcher Manager, Associate professor</investigator_title>
  </responsible_party>
  <keyword>Rheumatoid Arthritis</keyword>
  <keyword>Insomnia</keyword>
  <keyword>Sleep</keyword>
  <keyword>Cognitive Behavioural Therapy for Insomnia</keyword>
  <keyword>CBT-I</keyword>
  <keyword>Non-pharmacological treatment</keyword>
  <keyword>Polysomnography</keyword>
  <keyword>Actigraphy</keyword>
  <keyword>Patient reported outcomes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
    <mesh_term>Sleep Initiation and Maintenance Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Full dataset to replicate the main analysis will be available from the corresponding author on reasonable request.</ipd_description>
  </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/NCT03766100
org study id: H-18016081
nct id: NCT03766100
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Introduction:

      Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease that attacks
      peripheral joints and posterior tissues. More than half of patients with RA also have
      insomnia, which can modify pain, fatigue, quality of life and comorbidities. Traditional
      treatment of insomnia is often based on pharmacological drugs, however cognitive behavioural
      therapy for insomnia (CBT-i) have shown effect in insomnia with less side effects. It remains
      to determine whether CBT-i can be effective in patients with RA.

      The primary objective of this Sleep-RA trial is to assess the efficacy of CBT-i on sleep
      efficiency in patients with RA at week seven. Key secondary objectives are to estimate the
      clinical efficacy of CBT-i on wake after sleep onset, total sleep time, sleep onset latency,
      insomnia, sleep quality, fatigue, RA impact of disease and depressive symptoms at week 26.

      Methods & Analysis:

      Sleep-RA will be carried out as a randomised controlled trial (RCT) with randomised
      assignment and two-group parallel design. Patients with RA and insomnia are randomly
      allocated 1:1 to the intervention group or the control group. The intervention group will
      once a week for six weeks receive group-based CBT-i, a multi-component intervention of; sleep
      education, stimulus control, sleep restriction, cognitive therapy and relaxation. The control
      group will continue treatment as usual (insomnia will remain untreated). Follow-up
      assessments will be carried out seven and 26 weeks after baseline. The primary outcome is
      sleep efficiency measured with polysomnography at week seven. Key secondary outcomes are:
      wake after sleep onset, total sleep time, sleep onset latency, insomnia, sleep quality,
      fatigue, RA impact of disease and depressive symptoms from baseline to week 26.
      Polysomnography, actigraphy and Disease Activity Score 28-Joint Count C reactive protein will
      be assessed by medical staff blinded to group allocation. The project manager will assist the
      participants with questionnaires and conduct the intervention of CBT-i and will therefore not
      be blinded to group allocation. With a sample size of 60 patients the trial will have more
      than 85 % power to detect a mean difference between groups of 6 % points in the primary
      outcome of sleep efficiency measured at week seven and a reasonable statistical power to
      explore the clinical efficacy according to the eight key secondary outcome measures at week
      26.

      Ethics and dissemination:

      Ethics approval has been obtained from The Committee on Health Research Ethics. We plan to
      submit a manuscript with the content of this protocol, and at least one scientific manuscript
      on the results of the primary and key secondary outcomes to a peer-reviewed journal. Results
      will be presented at conferences, community and consumer forums and hospital grand rounds.
Introduction:

      More than half of patients with rheumatoid arthritis has concomitant insomnia. Insomnia may
      modify pain, fatigue, quality of life and comorbidities which many patients struggle with. To
      address this issue, a nurse led sleep outpatient clinic was established in 2015 at the Center
      for Rheumatology and Spine Diseases in the Capital Region of Denmark. The aim of this clinic
      is to identify the causes and severity of insomnia in patients with inflammatory joint
      diseases and to treat it with non-pharmacological initiatives. Eligible patients can be
      referred to the clinic by rheumatologists and rheumatology nurses. The current project,
      entitled Sleep-RA, is designed to expand the evidence-based opportunities of
      non-pharmacological treatment of insomnia within a biopsychosocial perspective among patients
      with inflammatory joint diseases. First and foremost, we want to assess the efficacy of
      cognitive behavioural therapy for insomnia on sleep efficiency in patients with rheumatoid
      arthritis and concomitant insomnia.

      Rheumatoid Arthritis:

      Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease (IJD) that
      affects peripheral joints. The inflammation typically cause tender and swollen joints and
      cartilage degradation and bone erosions may occur. RA is diagnosed from medical history,
      physical examination, blood samples and imaging. Prevalence worldwide is 0.4-1.3 % and RA
      affects women two-three times more frequently than men; onset is most often at 50-60 years of
      age. The most commonly used method for monitoring disease activity is the Disease Activity
      Score 28 (DAS28-CRP) based on 28 joint count of tender and swollen joints, C-Reactive Protein
      (CRP) and 'patient global assessment'. Rheumatological treatment of RA targets reduction of
      disease activity and is primarily pharmacological with synthetic disease-modifying
      antirheumatic drugs (csDMARDs), in which methotrexate is the first drug of choice. Biological
      antirheumatic drugs (bDMARDs) are used in the absence or insufficient effect of csDMARD.

      Consequences and symptoms of RA:

      Improvements in early diagnosis and medical treatment with antirheumatic drugs, have reduced
      the incidence of severe joint destruction. However, RA still causes stiffness and swelling in
      the joints. Some consequences of these symptoms and the inflammation itself are: insomnia,
      pain, fatigue, reduced physical function, depression and reduced quality of life. About 60-80
      % of patients with RA report insomnia compared to 10-30 % in the general population. Patients
      with RA indicate sleep as one of the most important variables evaluating their medical
      treatment with antirheumatic drugs, which indicates the impact sleep can have on physical and
      mental well-being. Pain is also a very common symptom of RA and is associated with fatigue,
      depressive symptoms, insomnia and inability to work and to cope with social and domestic
      activities. Furthermore, fatigue is experienced almost universally by individuals with RA
      while severe fatigue occurs in approximately 50 % of cases. The strongest independent
      predictors of fatigue are pain, insomnia, depression and physical function. Fatigue is
      perceived to have a significant impact on physical and social functioning and health care
      utilization and is a predictor of work dysfunction and overall health status. Pain and
      fatigue are very important to patient wellbeing and can make the management of other RA
      symptoms more challenging.

      Sleep:

      Common definitions of "good" and "bad" sleep in a healthy population are characterised by
      subjective satisfaction, appropriate timing, adequate duration, high efficiency, and
      sustained alertness during waking hours. Thus, "sleep health" is seen as a multidimensional
      pattern of sleep-wakefulness adapted to individual, social, and environmental demands, which
      promotes physical and mental well-being. These elements are essential to good sleep. To
      establish a clear meaning of "sleep health", Buysse (2014) has introduced a conceptual model.
      Five dimensions of sleep were identified as relevant including: sleep duration, sleep
      continuity or efficiency, timing, alertness/sleepiness, and satisfaction/quality (subjective
      assessment of good or poor sleep). Within the research field of sleep, studies have mainly
      focused on negative directions and consequences of sleep and there have been few studies
      specifically examining the potential benefits of good sleep.

      As previously identified, patients with RA suffer from a wide range of disease related
      consequences and symptoms and most of them can be associated with insomnia. According to
      observational studies sleep quality is associated with pain, fatigue, quality of life,
      depression, and disease activity among patients with RA. Insomnia can become long-lasting
      when the precipitating factor e.g. being diagnosed with a chronic disease as RA to some
      extend is replaced by perpetuating cognitive and behavioural factors.

      Sleep disturbances and cognitive behavioural therapy for insomnia:

      The gold standard for identifying insomnia in clinical and research settings is
      polysomnography (PSG), an objective multi-parametric test. The questionnaires Pittsburgh
      Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) are the most used and validated
      questionnaires in assessing patient reported sleep. PSQI has been validated for patients with
      RA and measures sleep quality and disturbances over the previous month; it differentiates
      between "good" and "poor" sleepers. Specifically targeting insomnia, the content of ISI
      corresponds in part to the Diagnostic and Statistical Manual 4th Edition (DSM-IV) diagnostic
      criteria for insomnia. Actigraphy (small wrist band) is the most valid method to assess
      sleep/wake behaviour over time (days or weeks).

      Insomnia is characterized by difficulty falling asleep or staying asleep as intended and
      insomnia often leads to inappropriate sleep habits and dysfunctional thoughts related to
      sleep. Nevertheless, treatment of insomnia is often based on hypnotic drugs that can cause
      side effects such as tolerance and addiction. In contrast to treatment with hypnotic drugs,
      cognitive behavioural therapy for insomnia (CBT-i) has demonstrated long-term effects on
      sleep. So far CBT-i has mostly been tested on people with insomnia and patients with cancer
      or mental illness with concomitant insomnia. It is a multi-component intervention that aims
      at teaching patients about health-related significance of sleep and factors that affect it,
      supporting patients in regulating their sleep habits and dealing with sleep related concerns.
      CBT-i combines various components: I) stimulus control (e.g. associating the bed and bedroom
      with sleep), II) sleep restriction (e.g. increasing the homeostatic drive to sleep by
      reducing time in bed), III) cognitive therapy (i.e. addressing maladaptive beliefs about
      sleep and reducing arousal and anxiety about sleep and the consequences of not sleeping), IV)
      sleep hygiene (i.e. establishing behavioural routines to promote restorative sleep) and V)
      relaxation.

      In a recent study in a primary care setting CBT-I conducted as two hours group-based sessions
      once a week for six weeks with three to eleven participants had significant effect on
      insomnia. Further, group-based interventions of CBT-i with four to six participants can help
      break the feeling of isolation.

      Rationale:

      Even though the prevalence of insomnia is high in patients with RA there have been published
      results from only very few randomised controlled trials (RCT) in this area. The intervention
      in most of these studies is based on treatment with hypnotic drugs or other pharmaceutical
      treatments. Only two studies have been identified as investigating sleep as primary outcome
      with a non-pharmacological approach, both with physical exercise as intervention. To our
      knowledge no RCT has yet investigated the effect of CBT-i on insomnia in patients with RA or
      other (IJD). However, the effect of CBT-i is larger and longer lasting than the effect of
      pharmaceutical treatments, presumably because patients learn skills they can use to manage
      sleep at later times. At the Copenhagen Centre for Arthritis Research (COPECARE) the efficacy
      of high-intensity interval training on sleep in patients with RA has recently been
      investigated in a pilot/feasibility RCT, data are under review. High-intensity interval
      training may not appeal to all patients with RA or patients with other IJD. With an intention
      to offer different non-pharmacological treatments for insomnia in rheumatology outpatient
      clinics, it is meaningful to assess the efficacy of CBT-i.

      CBT-i is often carried out by health professionals with training and experience in
      psychology. As these professionals rarely are integrated in daily clinical hospital practice,
      it is difficult to standardize psychologist-led CBT-i in outpatient treatment of insomnia.
      The clinical effectiveness of group-based CBT-i led by nurses is evidenced in RCTs in
      European general practice settings.

      Previous group-based psychological behavioural interventions, including CBT, have been
      effective for pain, fatigue, physical function, psychological well-being, social activities
      and coping resources among patients with RA and CBT-i have had a positive effect on sleep in
      people with cancer and mental illness.

      Aim and objectives:

      The aim of Sleep-RA is to assess the efficacy and safety of CBT-i in patients with RA and
      concomitant insomnia.

      Primary objective: To compare the effect of CBT-i relative to a control group on sleep
      efficiency at week seven in patients with RA and concomitant insomnia.

      Key secondary objectives: To compare the effect of CBT-i, relative to a control group, on
      changes in wake after sleep onset, total sleep time, sleep onset latency, insomnia, sleep
      quality, fatigue, RA impact of disease and depressive symptoms from baseline to week 26 in
      patients with RA and concomitant insomnia.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Application of PSG equipment prior to monitoring sleep efficiency and subsequent analysis of results will be conducted by neurophysiology assistants at the Danish Center for Sleep Medicine (DCSM) blinded to participants' allocation. Examination of participants' joints related to the secondary outcome of disease activity will be conducted by a project nurse specialized in rheumatology blinded to participants' allocation. Blood samples related to RA and disease activity will be taken and analysed by a medical laboratory technologist blinded to participants' allocation. Patient Reported Outcome Measures (PROMs) will be collected via questionnaires on tablets handed out by the project manager, who will also conduct the intervention of CBT-I, and therefore not able to be blinded to allocation.
measure: Polysomnography (PSG): Sleep efficiency.
time frame: Assessed at week 7.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Wake after sleep onset.
time frame: Assessed at week 26.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Total sleep time.
time frame: Assessed at week 26.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Sleep onset latency.
time frame: Assessed at week 26.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Insomnia Severity Index (ISI): Insomnia.
time frame: Assessed at week 26.
description: ISI measures self-reported insomnia severity the last two weeks. ISI is a seven-item questionnaire and each item is rated using a five-point Likert scale ranging from 0 (not at all) to 4 (very much), for a total score ranging from 0 (no insomnia) to 28 (clinical insomnia).
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep quality.
time frame: Assessed at week 26.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.
time frame: Assessed at week 26.
description: BRAF-MDQ measures self-reported RA-related fatigue for the previous seven days. It consists of 20 items with four responses ("not at all", "a bit", "part", "much"). Items are combined to create 5 scores, high is worse: Total fatigue score 0-70 Items 1-20 summed, Physical (severity) subscale 0-22 Items 1-4 summed, Living with fatigue subscale 0-21 Items 5-11 summed, Cognitive fatigue subscale 0-15 Items 12-16 summed.
measure: Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.
time frame: Assessed at week 26.
description: RAID measures self-reported impact of RA on daily life the last seven days. RAID consist of seven items, each item rated using af numerical rating scale (NRS 0-10), high is worse covering pain, physical function, fatigue, sleep, physical well-being, mental well-being and coping. RAID final value = (pain NRS value (range 0-10) x 0.21) + (function NRS value (range 0-10) x 0.16) + (fatigue NRS value (range 0-10) x 0.15) + (physical well-being NRS value (range 0-10) x 0.12) + (sleep NRS value (range 0-10) x 0.12) + (emotional well-being NRS value (range 0-10) x 0.12) + (coping NRS value (range 0-10) x 0.12).
measure: The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.
time frame: Assessed at week 26.
description: HADS-D measures self-reported depressive symptoms as psychological morbidity the last seven days. Seven items are rated on a four-point scale and scored from 0-3 with total scores therefore ranging from 0-21. Scores between 0 and 7 represent 'no case', 8 to 10 indicate 'possible case', 11-15 'moderate case' and '15-21' suggest a 'probable severe case of depression'.
measure: Actigraphy: Sleep efficiency.
time frame: Assessed at week 26.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Wake after sleep onset.
time frame: Assessed at week 26.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Total sleep time.
time frame: Assessed at week 26.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Sleep onset latency.
time frame: Assessed at week 26.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.
time frame: Assessed at week 26.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.
time frame: Assessed at week 26.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Total sleep time.
time frame: Assessed at week 26.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.
time frame: Assessed at week 26.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.
time frame: Assessed at week 26.
description: DAS28-CRP measures disease activity; an objective, reproducible and comparable assessment of the RA activity. A DAS28-CRP greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.
measure: 28-Joint Count: Tender joints.
time frame: Assessed at week 26.
description: 28-Joint Count measures tender joints by physical examination, reported as yes or no.
measure: 28-Joint Count: Swollen joints.
time frame: Assessed at week 26.
description: 28-Joint Count measures swollen joints by physical examination, reported as yes or no.
measure: C-reactive protein level (CRP): Acute-phase reactant value.
time frame: Assessed at week 26.
description: C-reactive protein level is a blood sample measuring Acute-phase reactant value. Higher value indicate inflammation.
measure: Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.
time frame: Assessed at week 26.
description: VAS global patient measures patient's self-reported global assessment of disease activity with numerical rating scale (NRS 0-10), high is worse.
measure: Physician's global assessment of the patient's current disease activity (VAS global physician): physician's global assessment of the patient's current disease activity.
time frame: Assessed at week 26.
description: VAS global physician measures physician's self-reported global assessment of the patient's current disease activity, an overall assessment of how the patient's arthritis is doing with numerical rating scale (NRS 0-10), high is worse.
measure: Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.
time frame: Assessed at week 26.
description: BRAF-NRS measures self-reported fatigue (severity, coping and effect) the last seven days with numerical rating scale (NRS 0-10), high is worse.
measure: Visual Analogue Scale (VAS pain): Pain.
time frame: Assessed at week 26.
description: VAS pain measures self-reported current level of RA related pain (VAS 0-100), high is worse.
measure: Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.
time frame: Assessed at week 26.
description: MD-HAQ measures self-reported physical function the last seven days and contains 10 items covering: dressing, rising, eating, walking, hygiene, reach, grip and everyday activities. Mean of the score = HAQ-score (0,0-3,0), high is worse.
measure: The Short Form [36] Health Survey (SF-36): Health related quality of life.
time frame: Assessed at week 26.
description: SF-36 measures self-reported health related physical and metal quality of life. SF-36 consists of eight scaled scores, which are the weighted sums of the items in their section. Each scale is transformed into a 0-100 scale. The lower the score the more disability.
measure: Polysomnography (PSG): Sleep efficiency.
time frame: Assessed at week 26.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Wake after sleep onset.
time frame: Assessed at week 7.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Total sleep time.
time frame: Assessed at week 7.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Polysomnography (PSG): Sleep onset latency.
time frame: Assessed at week 7.
description: PSG is a multi-parametric test that is used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is a comprehensive recording of the biophysiological changes that occur in the human body when the person is asleep. In Sleep-RA, 17 electrodes are attached to each participant, monitoring: electroencephalogram (EEG), eye movements electro-oculogram (EOG), electromyogram muscle activity or skeletal muscle activation (EMG), heart rhythm (ECG), respiratory airflow, respiratory effort and peripheral pulse oximetry.
measure: Insomnia Severity Index (ISI): Insomnia.
time frame: Assessed at week 7.
description: ISI measures self-reported insomnia severity the last two weeks. ISI is a seven-item questionnaire and each item is rated using a five-point Likert scale ranging from 0 (not at all) to 4 (very much), for a total score ranging from 0 (no insomnia) to 28 (clinical insomnia).
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep quality.
time frame: Assessed at week 7.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.
time frame: Assessed at week 7.
description: BRAF-MDQ measures self-reported RA-related fatigue for the previous seven days. It consists of 20 items with four responses ("not at all", "a bit", "part", "much"). Items are combined to create 5 scores, high is worse: Total fatigue score 0-70 Items 1-20 summed, Physical (severity) subscale 0-22 Items 1-4 summed, Living with fatigue subscale 0-21 Items 5-11 summed, Cognitive fatigue subscale 0-15 Items 12-16 summed.
measure: Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.
time frame: Assessed at week 7.
description: RAID measures self-reported impact of RA on daily life the last seven days. RAID consist of seven items, each item rated using af numerical rating scale (NRS 0-10), high is worse covering pain, physical function, fatigue, sleep, physical well-being, mental well-being and coping. RAID final value = (pain NRS value (range 0-10) x 0.21) + (function NRS value (range 0-10) x 0.16) + (fatigue NRS value (range 0-10) x 0.15) + (physical well-being NRS value (range 0-10) x 0.12) + (sleep NRS value (range 0-10) x 0.12) + (emotional well-being NRS value (range 0-10) x 0.12) + (coping NRS value (range 0-10) x 0.12).
measure: The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.
time frame: Assessed at week 7.
description: HADS-D measures self-reported depressive symptoms as psychological morbidity the last seven days. Seven items are rated on a four-point scale and scored from 0-3 with total scores therefore ranging from 0-21. Scores between 0 and 7 represent 'no case', 8 to 10 indicate 'possible case', 11-15 'moderate case' and '15-21' suggest a 'probable severe case of depression'.
measure: Actigraphy: Sleep efficiency.
time frame: Assessed at week 7.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Wake after sleep onset.
time frame: Assessed at week 7.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Total sleep time.
time frame: Assessed at week 7.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Actigraphy: Sleep onset latency.
time frame: Assessed at week 7.
description: Actigraph is an objective measurement to assess sleep/wake behaviour for several continuous nights. It allows the participant to be mobile and to continue their normal routines while the required data are being recorded in a natural sleep environment. In Sleep-RA actigraph is worn on the non-dominant wrist for one week.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.
time frame: Assessed at week 7.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.
time frame: Assessed at week 7.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Total sleep time.
time frame: Assessed at week 7.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.
time frame: Assessed at week 7.
description: PSQI measures self-reported sleep over the last four weeks. Nine items/18 questions with seven categories, defined with a global sum score for the seven sleep categories differs between good sleep (PSQI global sum score < 5) and bad sleep (PSQI global sum score > 5).
measure: Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.
time frame: Assessed at week 7.
description: DAS28-CRP measures disease activity; an objective, reproducible and comparable assessment of the RA activity. A DAS28-CRP greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.
measure: 28-Joint Count: Tender joints.
time frame: Assessed at week 7.
description: 28-Joint Count measures tender joints by physical examination, reported as yes or no.
measure: 28-Joint Count: Swollen joints.
time frame: Assessed at week 7.
description: 28-Joint Count measures swollen joints by physical examination, reported as yes or no.
measure: C-reactive protein level (CRP): Acute-phase reactant value.
time frame: Assessed at week 7.
description: C-reactive protein level is a blood sample measuring Acute-phase reactant value. Higher value indicate inflammation.
measure: Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.
time frame: Assessed at week 7.
description: VAS global patient measures patient's self-reported global assessment of disease activity with numerical rating scale (NRS 0-10), high is worse.
measure: Physician's global assessment of the patient's current disease activity (VAS global physician): physician's global assessment of the patient's current disease activity.
time frame: Assessed at week 7.
description: VAS global physician measures physician's self-reported global assessment of the patient's current disease activity, an overall assessment of how the patient's arthritis is doing with numerical rating scale (NRS 0-10), high is worse.
measure: Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.
time frame: Assessed at week 7.
description: BRAF-NRS measures self-reported fatigue (severity, coping and effect) the last seven days with numerical rating scale (NRS 0-10), high is worse.
measure: Visual Analogue Scale (VAS pain): Pain.
time frame: Assessed at week 7.
description: VAS pain measures self-reported current level of RA related pain (VAS 0-100), high is worse.
measure: Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.
time frame: Assessed at week 7.
description: MD-HAQ measures self-reported physical function the last seven days and contains 10 items covering: dressing, rising, eating, walking, hygiene, reach, grip and everyday activities. Mean of the score = HAQ-score (0,0-3,0), high is worse.
measure: The Short Form [36] Health Survey (SF-36): Health related quality of life.
time frame: Assessed at week 7.
description: SF-36 measures self-reported health related physical and metal quality of life. SF-36 consists of eight scaled scores, which are the weighted sums of the items in their section. Each scale is transformed into a 0-100 scale. The lower the score the more disability.
arm group label: Intervention group
arm group type: Experimental
description: Cognitive Behavioural Therapy for Insomnia (CBT-i).
arm group label: Control group
arm group type: No Intervention
description: Insomnia is untreated.
intervention type: Behavioral
intervention name: Cognitive behavioural therapy (CBT-i)
description: CBT-i aims to alter behaviours that sustain or add to insomnia and correct cognitions that drive these behaviours. The behavioural components of CBT-i are stimulus control (SC) and Sleep Restriction Therapy (SRT). SC works through the extinction of a conditioned arousal that emerges when bed and bedroom have become associated with wakefulness. With SRT time in bed is reduced to build up sleep pressure. When wakefulness is decreased, time in bed is gradually increased until optimal sleep is attained. With the cognitive component, insomnia is treated by identifying and changing unhelpful or inaccurate thinking regarding sleep and distressing emotional responses to insomnia. The last component of CBT-i aims to reduce hyperarousal with relaxation techniques, scheduled worry time, creating a time to unwind, and employing cognitive therapy strategies.
arm group label: Intervention group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bente Appel Esbensen
role: Principal Investigator
affiliation: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark.
facility: 
country: Denmark
url: https://www.rigshospitalet.dk/english/departments/centre-of-head-and-orthopaedics/centre-for-rheumatology-and-spine-diseases/copecare/Pages/default.aspx
description: Copenhagen Center for Arthritis Research (COPECARE)
citation: Abad VC, Sarinas PS, Guilleminault C. Sleep and rheumatologic disorders. Sleep Med Rev. 2008 Jun;12(3):211-28. doi: 10.1016/j.smrv.2007.09.001.
PMID: 18486034
citation: Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018 Oct 2;320(13):1360-1372. doi: 10.1001/jama.2018.13103.
PMID: 30285183
citation: Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA. 2001 Apr 11;285(14):1856-64. doi: 10.1001/jama.285.14.1856.
PMID: 11308399
citation: Davidson JR, Dawson S, Krsmanovic A. Effectiveness of Group Cognitive Behavioral Therapy for Insomnia (CBT-I) in a Primary Care Setting. Behav Sleep Med. 2019 Mar-Apr;17(2):191-201. doi: 10.1080/15402002.2017.1318753. Epub 2017 May 2.
PMID: 28463015
citation: Smith MT, Finan PH, Buenaver LF, Robinson M, Haque U, Quain A, McInrue E, Han D, Leoutsakis J, Haythornthwaite JA. Cognitive-behavioral therapy for insomnia in knee osteoarthritis: a randomized, double-blind, active placebo-controlled clinical trial. Arthritis Rheumatol. 2015 May;67(5):1221-33. doi: 10.1002/art.39048.
PMID: 25623343
responsible party type: Sponsor-Investigator
investigator affiliation: Glostrup University Hospital, Copenhagen
investigator full name: Bente Appel Esbensen
investigator title: Researcher Manager, Associate professor
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Sleep Initiation and Maintenance Disorders
sharing ipd: Undecided
ipd description: Full dataset to replicate the main analysis will be available from the corresponding author on reasonable request.