Clinical trial NCT03766100: Cognitive Behavioural Therapy for Insomnia on Sleep in Rheumatoid Arthritis.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Rheumatoid Arthritis
Insomnia
Keywords: Rheumatoid Arthritis
Insomnia
Sleep
Cognitive Behavioural Therapy for Insomnia
CBT-I
Non-pharmacological treatment
Polysomnography
Actigraphy
Patient reported outcomes
Lead sponsor: Glostrup University Hospital, Copenhagen
Sponsor class: OTHER
Collaborators: name: University of Copenhagen
name: Rigshospitalet, Denmark
name: Danish Cancer Society
name: Parker Research Institute
First posted: 2018-12-06
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Polysomnography (PSG): Sleep efficiency.
timeFrame: Assessed at week 7.
Secondary outcomes:
measure: Polysomnography (PSG): Wake after sleep onset.
timeFrame: Assessed at week 26.
measure: Polysomnography (PSG): Total sleep time.
timeFrame: Assessed at week 26.
measure: Polysomnography (PSG): Sleep onset latency.
timeFrame: Assessed at week 26.
measure: Insomnia Severity Index (ISI): Insomnia.
timeFrame: Assessed at week 26.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep quality.
timeFrame: Assessed at week 26.
measure: Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.
timeFrame: Assessed at week 26.
measure: Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.
timeFrame: Assessed at week 26.
measure: The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.
timeFrame: Assessed at week 26.
Other outcomes:
measure: Actigraphy: Sleep efficiency.
timeFrame: Assessed at week 26.
measure: Actigraphy: Wake after sleep onset.
timeFrame: Assessed at week 26.
measure: Actigraphy: Total sleep time.
timeFrame: Assessed at week 26.
measure: Actigraphy: Sleep onset latency.
timeFrame: Assessed at week 26.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.
timeFrame: Assessed at week 26.
measure: Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.
timeFrame: Assessed at week 26.
measure: Pittsburgh Sleep Quality Index (PSQI): Total sleep time.
timeFrame: Assessed at week 26.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.
timeFrame: Assessed at week 26.
measure: Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.
timeFrame: Assessed at week 26.
measure: 28-Joint Count: Tender joints.
timeFrame: Assessed at week 26.
measure: 28-Joint Count: Swollen joints.
timeFrame: Assessed at week 26.
measure: C-reactive protein level (CRP): Acute-phase reactant value.
timeFrame: Assessed at week 26.
measure: Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.
timeFrame: Assessed at week 26.
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.
timeFrame: Assessed at week 26.
measure: Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.
timeFrame: Assessed at week 26.
measure: Visual Analogue Scale (VAS pain): Pain.
timeFrame: Assessed at week 26.
measure: Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.
timeFrame: Assessed at week 26.
measure: The Short Form [36] Health Survey (SF-36): Health related quality of life.
timeFrame: Assessed at week 26.
measure: Polysomnography (PSG): Sleep efficiency.
timeFrame: Assessed at week 26.
measure: Polysomnography (PSG): Wake after sleep onset.
timeFrame: Assessed at week 7.
measure: Polysomnography (PSG): Total sleep time.
timeFrame: Assessed at week 7.
measure: Polysomnography (PSG): Sleep onset latency.
timeFrame: Assessed at week 7.
measure: Insomnia Severity Index (ISI): Insomnia.
timeFrame: Assessed at week 7.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep quality.
timeFrame: Assessed at week 7.
measure: Bristol Rheumatoid Arthritis Fatigue -Multidimensional Questionnaire (BRAF-MDQ): Fatigue.
timeFrame: Assessed at week 7.
measure: Rheumatoid Arthritis Impact of Disease (RAID): impact of disease.
timeFrame: Assessed at week 7.
measure: The Hospital Anxiety and Depression Scale for Depression (HADS-D): Depressive symptoms.
timeFrame: Assessed at week 7.
measure: Actigraphy: Sleep efficiency.
timeFrame: Assessed at week 7.
measure: Actigraphy: Wake after sleep onset.
timeFrame: Assessed at week 7.
measure: Actigraphy: Total sleep time.
timeFrame: Assessed at week 7.
measure: Actigraphy: Sleep onset latency.
timeFrame: Assessed at week 7.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep efficiency.
timeFrame: Assessed at week 7.
measure: Pittsburgh Sleep Quality Index (PSQI): Wake after sleep onset.
timeFrame: Assessed at week 7.
measure: Pittsburgh Sleep Quality Index (PSQI): Total sleep time.
timeFrame: Assessed at week 7.
measure: Pittsburgh Sleep Quality Index (PSQI): Sleep onset latency.
timeFrame: Assessed at week 7.
measure: Disease Activity Score 28-Joint Count C reactive protein' (DAS28-CRP): Disease activity.
timeFrame: Assessed at week 7.
measure: 28-Joint Count: Tender joints.
timeFrame: Assessed at week 7.
measure: 28-Joint Count: Swollen joints.
timeFrame: Assessed at week 7.
measure: C-reactive protein level (CRP): Acute-phase reactant value.
timeFrame: Assessed at week 7.
measure: Patients global assessment of disease activity (VAS global patient): patient's global assessment of disease activity.
timeFrame: Assessed at week 7.
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.
timeFrame: Assessed at week 7.
measure: Bristol Rheumatoid Arthritis Fatigue -Numerical Rating Scale (BRAF-NRS): Fatigue.
timeFrame: Assessed at week 7.
measure: Visual Analogue Scale (VAS pain): Pain.
timeFrame: Assessed at week 7.
measure: Multi Dimensional Health Assessment Questionnaire (MDHAQ): Physical function.
timeFrame: Assessed at week 7.
measure: The Short Form [36] Health Survey (SF-36): Health related quality of life.
timeFrame: Assessed at week 7.
Locations:
city: Glostrup
country: Denmark
facility: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases
Study officials:
affiliation: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark.
name: Bente Appel Esbensen
role: PRINCIPAL_INVESTIGATOR
References:
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: 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: 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: 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: 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: Latocha KM, Loppenthin KB, Ostergaard M, Jennum PJ, Hetland ML, Rogind H, Lundbak T, Midtgaard J, Christensen R, Esbensen BA. The effect of group-based cognitive behavioural therapy for insomnia in patients with rheumatoid arthritis: a randomized controlled trial. Rheumatology (Oxford). 2023 Mar 1;62(3):1097-1107. doi: 10.1093/rheumatology/keac448.
citation: Latocha KM, Loppenthin KB, Ostergaard M, Jennum PJ, Christensen R, Hetland M, Rogind H, Lundbak T, Midtgaard J, Esbensen BA. Cognitive behavioural therapy for insomnia in patients with rheumatoid arthritis: protocol for the randomised, single-blinded, parallel-group Sleep-RA trial. Trials. 2020 May 29;21(1):440. doi: 10.1186/s13063-020-04282-6.