Clinical trial NCT06786832: Characterization, Treatment, and Long-term Follow-up of Fatigued Patients in Primary Care
Official title: Characterization, Treatment, and Long-term Follow-up of Fatigued Patients in Primary Care
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Fatigue
Fatigue Post Viral
Exhaustion Disorder
Fatigue Symptom
Fatigue Related to Cancer Treatment
Keywords: Psychological treatment
Primary care
cognitive behavioral therapy
blended treatment
randomized controlled trial
Fatigue
burnout
chronic stress
register data
cognitive testing
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Academic Primary Health Care Centre, Region Stockholm
First posted: 2025-01-22
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 67
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized controlled trial
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Self-rated fatigue severity
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline))
Secondary outcomes:
measure: Concentration
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: Motivation
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: Activity
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: Self-rated depressive symptoms
timeFrame: 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.
measure: Somatic symptoms
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: General anxiety
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Insomnia Severity
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: Perceived Stress
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Burnout
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Self-rated health
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Cognitive and behavioral responses to symptoms
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: General self-efficacy
timeFrame: Baseline (Pre intervention), during treatment phase (every three weeks), post (6 months after baseline) and long term follow up (12 months after baseline)
measure: Functional disability
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Work and Social Adjustment
timeFrame: Baseline (Pre treatment), Post treatment (6 months), long-term follow-up (12 months).
measure: Self-rated exhaustion disorder (s-UMS)
timeFrame: Baseline, post treatment (6 months) and 12-month follow-up from baseline.
measure: Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
timeFrame: Baseline, post treatment (6 months) and 12-month follow-up from baseline.
Other outcomes:
measure: Treatment credibility
timeFrame: Three weeks after treatment start
measure: Patient satisfaction with treatment/healthcare
timeFrame: Post-treatment (6 months)
measure: Working alliance
timeFrame: Week 3 and 15 of treatment
measure: Negative effects of treatment
timeFrame: Post treatment (6 months from baseline)
measure: Adverse events related to study participation/treatment
timeFrame: weeks 6, 12, 18
measure: Cognitive functioning
timeFrame: Baseline and 12-month follow-up from baseline
measure: Healthcare consumption
timeFrame: Data will be collected from two years before inclusion in the study up to 60 months after inclusion, meaning from 2023-2030.
measure: Sickness absence
timeFrame: Data will be collected from two years before inclusion in the study up to 60 months after inclusion, meaning from 2023-2030.
measure: Individual-level socioeconomic information
timeFrame: Data will be collected from two years before inclusion in the study up to 60 months after inclusion, meaning from 2023-2030.
measure: Medication use
timeFrame: Data will be collected from two years before inclusion in the study up to 60 months after inclusion, meaning from 2023-2030.
measure: Cause of death
timeFrame: Data will be collected from two years before inclusion in the study up to 60 months after inclusion, meaning from 2023-2030.
measure: Heart rate variability
timeFrame: Continuous data-collection from baseline to 12-month follow-up.
measure: Sleep- and activity patterns
timeFrame: Continuous data-collection from baseline to 12-month follow-up.
measure: Body temperature fluctuations
timeFrame: Continuous data-collection from baseline to 12-month follow-up.
measure: Alcohol Use
timeFrame: Pre inclusion screening only
measure: Symptoms of autism
timeFrame: Pre inclusion screening only.
measure: Symptoms of adhd in childhood
timeFrame: Pre inclusion screening only
measure: Hypermobility
timeFrame: Pre inclusion screening only
measure: Comorbidity (self-registered)
timeFrame: Pre inclusion screening only
Locations:
city: Stockholm
country: Sweden
facility: Gustavsberg University Primary Care Clinic
state: Gustavsberg
Study officials:
affiliation: Region Stockholm and Karolinska Institutet
name: Elin Lindsäter, PhD, Ass. Prof
role: PRINCIPAL_INVESTIGATOR
References: