Characterization, Treatment, and Long-term Follow-up of Fatigued Patients in Primary Care

Not Applicable

Recruiting

• Conditions: Fatigue; Fatigue Post Viral; Exhaustion Disorder; Fatigue Symptom; Fatigue Related to Cancer Treatment

• Registration Number: NCT06786832
• Lead Sponsor: Karolinska Institutet

Brief Summary

The overarching purpose of this project is to further the understanding of fatigue as a symptom in primary care patients, and to build evidence for a highly accessible treatment targeting fatigue that can be readily implemented in primary care clinics.

Data will be collected within a randomized controlled superiority trial (RCT; N = 500). The primary aim is to evaluate the effectiveness of a novel cognitive behavioral therapy (iFAS: Internet-delivered treatment of Fatigue Across Syndromes) for fatigued patients as compared to care as usual (CAU). Primary outcome will be change in fatigue severity (as measured by the Checklist Individual Strengths, fatigue subscale) pre- to post-treatment (6 months), with long-term controlled follow-up after 12 months. A registry-based follow-up will be conducted up to 60 months post baseline. Moderators and mechanisms of treatment effect will be investigated with the aim to identify potential subgroups of fatigued individuals across and within diagnostic categories that may respond differently to treatment. Lastly, a health economic evaluation of long-term treatment effects will be conducted, which incorporates much needed detailed mapping of care as usual for fatigued patients.

Detailed Description

Background:

Fatigue can be defined as extreme and persistent tiredness, weakness, or exhaustion that that could be mental physical, or both. Fatigue is associated with increased healthcare consumption, work disability, and excess mortality, and has been studied extensively under different labels since the 1800's (e.g., neurasthenia, burnout, chronic fatigue syndrome). Studies in primary care populations indicate that about 20-30% of patients report fatigue, with up to 10% of patients presenting with fatigue as their main complaint. Although often considered a disorder-specific characteristic, the etiology and pathogenesis of fatigue are largely unknown and are generally believed to be multifactorial. No biological markers or other objectively measurable factors (such as cognitive impairment) have been found thus far that consistently and sufficiently explain the onset and perpetuation of disorder-specific fatigue. The high prevalence and non-specific nature of fatigue presents a challenge to general practitioners who generally have limited time and resources for assessment and intervention.

Importantly, a potential break-through to how we can understand fatigue has been achieved in recent years, with studies showing that variance in fatigue severity is better explained by transdiagnostic factors (i.e., factors not attributable to a specific medical condition, such as demographic and psychosocial variables and aspects of daily functioning) than by disorder-specific pathophysiology. Further, similar cognitive and behavioral perpetuating mechanisms of fatigue (such as fear avoidance, symptom catastrophizing, self-efficacy, and resting-behavior) have been found across disorders. These findings suggest that a transdiagnostic approach to understanding and treating persistent fatigue might be beneficial for patients and healthcare practitioners, with potentially important implications for treatment.

Treatment of fatigue:

As with other aspects of fatigue, intervention research on fatigue has primarily been conducted in disorder-specific pipelines using disorder-specific protocols. CBT is the most studied treatment, with promising effects for patients with, for example, chronic fatigue syndrome, post-infectious fatigue, and various long-term medical conditions where fatigue is often central (both face-to-face and when delivered via the internet; ICBT). Results from previous RCTs conducted by the investigators have indicated that CBT can be an effective treatment to reduce symptom burden in patients diagnosed with stress-induced exhaustion disorder. Importantly, disorder-specific CBT-protocols for fatigue are largely similar across clinical groups, and the same cognitive and behavioral responses to fatigue have been found to moderate and mediate fatigue severity after CBT across a range of fatigued patient groups.

Even though CBT may hold promise to reduce fatigue severity in different clinical groups, many fatigued patients still do not receive treatment, and not all patients who receive CBT are sufficiently helped. Further research is needed to understand symptom presentation and development as well as treatment moderators, predictors, and mediators of change. Also, there is a significant knowledge gap regarding how fatigue can be identified and treated in an early phase in the primary care context. Given the similarities in effective treatment protocols across fatigued samples, together with potentially common change mechanisms, investigating the effectiveness of a transdiagnostic treatment protocol is a promising avenue with enormous potential utility to increase clinical effects, accessibility, and large-scale implementation. To date, no transdiagnostic treatment specifically targeting fatigue across patient groups has been evaluated.

The current study:

Based on previous disorder-specific treatment protocols aimed to reduce fatigue severity in various fatigued populations, the investigators have developed a transdiagnostic intervention adapted for primary care patients who suffer from persistent fatigue independent of primary diagnosis (iFAS: Internet-delivered treatment of Fatigue Across Syndromes). The treatment is delivered in a blended format (face-to-face therapy combined with internet-delivered texts and exercises) and is administrated over 4 - 6 months. The feasibility of iFAS has recently been evaluated in a non-randomized feasibility trial (Clinical trials ID: NCT06341751).

Study design:

The planned study is a randomized clinical superiority trial that will recruit fatigued patients listed at primary healthcare clinics in Region Stockholm. Study participants (N=500) will be randomized to iFAS (n=250) or to CAU (n=250) by a person not related to the study. Due to the nature of the study, blinding to treatment condition will not be possible.

Data collection includes clinician-rated data, self-rated symptom measures, and registry data using interlinked microdata from regional and national registers. Cognitive functioning will be assessed using a digital cognitive test-battery that will be administered at baseline and at the 12-month follow up. Additionally, the study will explore changes in physiological variables (in a subset of participants) from baseline to the 12-month follow-up using continuous data collected from biometric rings.

Research questions:

RQ1. Is iFAS associated with a greater post-treatment reduction in fatigue severity (primary outcome) and secondary outcome domains (self-rated symptoms, cognitive functioning, net days on sick leave) compared to CAU?

RQ2. What characterizes the fatigued sample at baseline in terms of sociodemographic, clinical, and biometric variables? Can clinically relevant subgroups of patients be identified that share similar characteristics?

RQ3. Which factors moderate and mediate the effect of iFAS vs. CAU and which factors predict symptom development? We hypothesize (1) that there will be transdiagnostic subgroups of patients that differ in treatment response based on baseline characteristics as identified in RQ2, that (2) these characteristics can be used to model treatment outcomes using supervised machine learning, and further that (3) changes in cognitive and behavioral responses to fatigue (e.g., fear avoidance, catastrophizing about symptoms, all-or-nothing behavior) as well as sleep- and physical activity patterns will mediate the effect of iFAS vs. CAU.

RQ4. Are there differences between participants who received iFAS vs. CAU at the 12- and 60-month follow-up and do individual characteristics moderate these differences?

RQ5. Is iFAS vs. CAU a cost-effective treatment at the 12 month follow-up? Indirect (e.g., work absenteeism, sick leave) and direct (e.g., healthcare consumption) costs will be evaluated using data from national registers.

RQ6. Which healthcare interventions are provided for participants who are randomized to CAU, and do sociodemographic, geographic, and clinical factors predict the type and extent of treatment delivered?

Recruitment procedure:

This study will recruit participants directly from primary care clinics in Region Stockholm. Hence, no advertisement in newspapers or in social media will be conducted to target potential study participants. All information about the study, aimed at both study participants and primary care staff, will be made available on a study webpage.

Patients can be referred to the study by their primary care physician if they (a) report at least three months of persistent, functionally disabling fatigue as a central symptom and (b) the general practitioner (GP) has assessed that the fatigue is not a direct effect of an active disease process motivating another treatment (e.g., hypo-/hyperthyroidism, anemia, cancer, dementia, sleep apnea, post-traumatic stress disorder) or a side-effect of medication. See below ("Eligibility") for inklusion/exclusion criteria.

Estimated sample size and power:

For 90% power to detect a standardized between-group effect size of d=0.25 on the primary outcome (α=.05), an intraclass correlation between measurements of 0.7, and an expected attrition of 20%, 250 patients will be included in each arm (total sample size: N=500).

Statistical methods:

Analyses will be based on an intention-to-treat approach. Change in the primary outcome measure will be analyzed using mixed effects linear regression. Change from baseline to treatment completion (6 months post baseline) will be the primary endpoint. Fixed predictors in these analyses will be time, group and their interaction effect while taking individual variation in baseline symptom levels and change over time into account (i.e., random intercept and/or slope).

Study Timeline

• Study First Submitted: 2025-01-13
• Study First Submitted QC: 2025-01-19
• Study First Posted: 2025-01-22
• Status Verified: 2025-02
• Study Start: 2025-02-06
• Last Update Submitted: 2025-02-26
• Last Update Posted: 2025-02-27
• Primary Completion: 2027-06
• Study Completion: 2033-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

1. age 18-67
2. enrollment at a primary care clinic in Region Stockholm
3. severe, functionally disabling fatigue as a central symptom for at least 3 months
4. The fatigue has an identifiable start and hence has not been life-long;
5. The fatigue is not a direct effect of an active disease process motivating another treatment (e.g., hypo-/hyperthyroidism, anemia, cancer, dementia) or the effect of medication
6. regular access to a computer and to the Internet
7. ability to read and write in Swedish.
8. ability to visit a study center for participation in potential assessments and treatment sessions (maximum 60 minutes) and to take part of written material via the internet.

Exclusion Criteria

1. substance abuse disorder in the past 6 months
2. Current or past psychosis or bipolar disorder
3. Primary psychiatric disorder of such severity that it merits evidence-based treatment (e.g., obsessive compulsive disorder, moderate to severe depression, post-traumatic stress disorder, anorexia nervosa)
4. elevated risk for suicide
5. deliberate self harm in the past 6-months (e.g., cutting, burning, poisoning);
6. BMI>40
7. Initiated or changed psychopharmacological medication (e.g., for depression or anxiety disorders) in the past month
8. ongoing chemotherapy
9. intellectual disability (e.g., severe autism) that affects ability to work with the treatment
10. pregnancy
11. life circumstances that complicate or make treatment impossible (e.g., domestic violence, ongoing legal disputes, disputes with social insurance agency, planed or on-going work capacity assesment regarding permanent work disability pension or planed surgery)
12. ongoing psychological treatment and/or multimodal rehabilitation.
13. working night shifts

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Self-rated fatigue severity	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline))	Fatigue severity (self-rated) using the Checklist Individual Strengths - Fatigue severity subscale (CIS-F). The domain Fatigue severity contains 8 items scored on a 7-point Likert scale (range 8-56; higher scores=more severe fatigue).

Secondary Outcome Measures

Name	Time	Method
Concentration	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	Concentration is a subscale in the Checklist Individual Strengths (CIS). The subscale contains 5 items scored on a 7-point Likert scale. Higher ratings indicate more problems with concentration.
Motivation	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	Motivation is a subscale in the Checklist Individual Strengths (CIS). The subscale contains 4 items scored on a 7-point Likert scale. Higher ratings indicate more difficulties with motivation.
Activity	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	Activity is a subscale in the Checklist Individual Strengths (CIS). The subscale contains 3 items scored on a 7-point Likert scale. Higher ratings indicate reduced activity.
Self-rated depressive symptoms	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months). Suicide-item will be administered every three weeks during the treatment phase.	Patient Health Questionnaire-9 (PHQ-9). Scale range is from 0 to 27, higher scores representing more depressive symptoms. NOTE: The suicide-item will be administered every three weeks during the treatment phase).
Somatic symptoms	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	Physical Health Questionnaire-15 (PHQ-15). Scale range is from 0 to 30, higher scores representing more somatic symptoms
General anxiety	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	The General Anxiety Questionnaire (GAD-7). Scale range is from 0 to 21, higher scores representing more anxiety.
Insomnia Severity	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	The Insomnia Severity Inventory (ISI) 7 items. Scale range is from 0 to 28, higher scores representing higher insomnia severity.; An additional item will be added to assess hypersomnia.
Perceived Stress	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	The Perceived Stress Scale (PSS-10). Scale range is from 0 to 40, higher scores representing a higher level of perceived stress.
Burnout	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	The Shirom-Melamed Burnout Questionnaire (SMBQ-18). Scale range is from 0 to 6, higher scores representing a higher level of burnout.
Self-rated health	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	The Self-rated health questionnaire (SRH-5). A single item with 5 response-categories, 0 (very bad health); 4 (very good health)
Cognitive and behavioral responses to symptoms	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	Process measure: Cognitive and behavioral responses to symptoms questionnaire (CBRQ), 18-items. The scale assesses six domains: Fear avoidance (3 items, scale range 0-12); Damage beliefs (3 items, scale range 0-12); Embarrassment avoidance (3 items, scale range 0-12); Symptom focusing (3 items, scale range 0-12); All-or-nothing behaviour (3 items, scale range 0-12); Resting behaviour (3 items, scale range 0-12).
General self-efficacy	Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)	Process measure: The General self-efficacy scale (GSE), 10 items. Scale range is from 10 to 40, higher scores representing a higher level of self-efficacy.
Functional disability	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), 12 items. Scoring from 0 (maximum functional disability) to 100 (no functional disability)
Work and Social Adjustment	Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).	The Work and Social Adjustment Scale (WSAS), 5 items. Scale range 0 to 40 with higher scores representing better work and social adjustment.
Self-rated exhaustion disorder (s-UMS)	Baseline, post treatment (6 months) and 12-month follow-up from baseline.	s-UMS is a questionnaire developed for self-assessment of diagnostic criteria for exhaustion disorder. Eight diagnostic items are responded to as "yes" or "no". The last item pertains to consequences and functional disability and is responded to on a scale of 0 (no functional disability), 1 (yes, some functional disability), or 2 (yes, significant functional disability).
Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)	Baseline, post treatment (6 months) and 12-month follow-up from baseline.	A 25-item self-rated symptom questionnaire in which respondents first respond yes/no to each symptom and then in a second step, if "Yes", respond to the severity level of that symptom on a scale from 1-4 ("mild", "moderate", "severe", "very severe").; Scores of symptom severity are added for a scale range of 1-100 (higher scores indicate higher symptom severity).

Trial Locations

Locations (1)

Gustavsberg University Primary Care Clinic; 🇸🇪 Stockholm, Gustavsberg, Sweden