Cognitive Behavioural Therapy for Insomnia on Sleep in Rheumatoid Arthritis.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Rheumatoid Arthritis, Insomnia

Intervention / Treatment
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* Behavioral: Cognitive behavioural therapy (CBT-i)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with RA according to American College of Rheumatology/European League Against Rheumatism criteria 2010 18 years of age or older Patients with low-to-moderate disease activity (DAS28-CRP ≤ 5.1) Sleep score ≥ 2 (DANBIO) Insomnia severity Index (ISI) ≥ 11 Unchanged medical treatment with anti-rheumatics > 3 months No indication for change of medical treatment with anti-rheumatic drugs the next three months Understand and read Danish. Exclusion Criteria: Glucocorticoid administration (i.m., i.a., i.v.) < four weeks Oral glucocorticoid administration > 5 mg/day Change in oral glucocorticoid dose < three month Prior or current contact with rheumatic sleep outpatient clinic Night work during the intervention Pregnant or breastfeeding Current alcohol or drug use disorder Patient related circumstances (physical or mental) that impede the ability to give informed consent or adhere to the trial programme.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Cognitive Behavioural Therapy for Insomnia (CBT-i). | Behavioral: Cognitive behavioural therapy (CBT-i)<br>* 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.<br>|
| No Intervention: Control group<br>Insomnia is untreated. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polysomnography (PSG): Sleep efficiency. | 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. | Assessed at week 7. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polysomnography (PSG): Wake after sleep onset. | 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. | Assessed at week 26. | 
| Polysomnography (PSG): Total sleep time. | 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. | Assessed at week 26. | 
| Polysomnography (PSG): Sleep onset latency. | 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. | Assessed at week 26. | 
| Insomnia Severity Index (ISI): Insomnia. | 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). | Assessed at week 26. | 
| Pittsburgh Sleep Quality Index (PSQI): Sleep quality. | 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). | Assessed at week 26. | 
| Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue. | 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. | Assessed at week 26. | 
| Rheumatoid Arthritis Impact of Disease (RAID): impact of disease. | 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). | Assessed at week 26. | 
| The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms. | 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'. | Assessed at week 26. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Insomnia, Sleep, Cognitive Behavioural Therapy for Insomnia, CBT-I, Non-pharmacological treatment, Polysomnography, Actigraphy, Patient reported outcomes