RELIEF: Multimodal Prehabilitation to Treat Fatigue in Patients With Primary Biliary Cholangitis
- Conditions
- Primary Biliary Cholangitis (PBC)
- Registration Number
- NCT07161245
- Lead Sponsor
- Hospital Clinic of Barcelona
- Brief Summary
The implementation of a non-pharmacological multimodal intervention program-including physical exercise, nutritional counseling, and psychological support-is expected to improve fatigue in patients with primary biliary cholangitis. Consequently, this improvement is anticipated to enhance quality of life and cognitive symptoms, while also positively impacting emotional, social, and occupational aspects.
From a pathophysiological perspective, it is hypothesized that chronic cholestasis and/or immune system activation, with the release of pro-inflammatory cytokines, leads to both central and peripheral alterations causing fatigue.
At the central level, systemic inflammation may induce neuronal senescence in the basal ganglia, resulting in altered functional connectivity networks dependent on these regions and/or structural and connectivity changes in areas involved in interoception, such as the insula and anterior cingulate cortex.
At the peripheral level, the hypothesis is that chronic inflammation mediated by anti-mitochondrial antibodies causes mitochondrial metabolic dysfunction in muscle cells, which would be reflected in changes observed in the gene expression analysis of these cells.
Improvement in fatigue following the multimodal intervention program is expected to be associated with normalization of the immunological profile, enhanced functional brain connectivity, and improved mitochondrial metabolism in muscle.
- Detailed Description
Primary biliary cholangitis (PBC) is a rare autoimmune disease that damages the small bile ducts and primarily affects women. Although it is a liver disease, its most common symptom is fatigue, affecting up to 60% of patients. Fatigue is a debilitating symptom, described by patients as "a brain fog" that causes concentration problems and memory loss, along with "a lack of energy" that leads to poor exercise tolerance and early exhaustion. This significantly impacts quality of life, negatively affecting family, social, and work-related activities. To the frustration of both patients and healthcare providers, fatigue is not correlated with the severity of liver disease, and there is currently no effective treatment.
Ursodeoxycholic acid (UDCA), the first-line treatment for PBC, has been shown to improve disease survival, but it does not appear to have an effect on fatigue, as demonstrated by a meta-analysis. Other treatments, such as bezafibrate, have also failed to show improvement in fatigue. Several clinical trials have tested treatments targeting different pathophysiological mechanisms, including selective serotonin reuptake inhibitors (SSRIs), stimulants like modafinil, and immunomodulatory therapies such as rituximab, all with negative results.
Currently, new drugs have been approved as second-line treatments for PBC, such as elafibranor and seladelpar. The latter may have some impact on fatigue; however, this was not the primary objective of the study, and the mechanisms associated with this improvement remain unclear.
One of the main reasons why no treatment exists is the lack of understanding of the underlying mechanisms. Fatigue is a complex and likely multifactorial symptom. It has been hypothesized that chronic immune system activation, leading to excessive production of inflammatory substances, could be a trigger. Additionally, it remains unknown whether alterations in bile acid composition, which are molecules with potent biological effects on multiple organs, could worsen fatigue. Furthermore, this chronic inflammation may induce changes in both the brain and muscles, contributing to the development of fatigue.
It has been demonstrated that physical exercise reduces systemic inflammation by lowering inflammatory substances and can also improve abnormalities in muscle energy production. Studies conducted in patients with other diseases associated with fatigue, such as multiple sclerosis, have shown that exercise programs can be beneficial for fatigue management.
At present, experience with physical training programs for PBC patients with fatigue is very limited. The results of a study conducted in the United Kingdom and another in Canada suggest that a home-based exercise program may improve fatigue. However, both studies have certain limitations, as the follow-up was remote, there was no supervision to ensure proper execution of the exercises or that they were performed at the prescribed intensity. Additionally, the effective exercise duration was only about 15 minutes, which, along with its moderate intensity, is unlikely to induce specific adaptations in mitochondrial biogenesis and efficiency. On the other hand, while patients with liver diseases generally express positive attitudes toward the benefits of supervised exercise, they also acknowledge a lack of confidence in initiating it independently.
Based on this evidence, an integrated exercise program is proposed, consisting of two phases: an initial supervised phase lasting eight weeks and a subsequent remote phase, combined with nutritional counseling and psychological support. It is hypothesized that this program will improve fatigue and consequently enhance quality of life, as well as alleviate associated cognitive symptoms (such as depression and sleep disturbances).
To better understand the changes occurring in the organs involved in fatigue, the investigators aim to analyze immune responses and bile acids to determine their potential association with fatigue, as has been observed in other autoimmune diseases. Additionally, potential alterations at both the brain and muscle levels will be explored.
At the neurological level, functional connectivity alterations in brain regions involved in fatigue will be studied using functional magnetic resonance imaging (fMRI). At the muscular level, changes in muscle metabolism will be analyzed by studying gene expression in muscle fibers. Muscle samples will be obtained using a minimally invasive technique called muscle microbiopsy, which involves a fine-needle puncture of a muscle and is not associated with complications. These studies will be conducted before and after the exercise program, aiming to observe the positive changes expected at all levels.
These studies will be conducted before and after the training program.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 64
- Age ≥18 years
- PBC diagnosis according to EASL guidelines
- Moderate - severe fatigue defined by ≥ 29 points in PBC-40 questionnaire
- Age > 80 years
- Severe pruritus
- Decompensated cirrhosis
- Other causes of liver disease than PBC
- Liver transplant (LT) o placement on a waiting-list for LT
- Uncontrolled thyroid disesase
- Anemia with haemoglobin <11g/dl
- Uncontrolled cardiovascular risk factors
- BMI > 35,
- Acute myocardial infarct or unstable angina the past 6 months
- Muscle disease or systemic disease with potential muscle involvement
- Dysautonomy
- Untreated osteoporosis
- Untreated celiac disease
- Alcohol consumption > 14 standard drinks (SD) in women and >21 (SD) in men per week
- Chronic kidney disease ≥ 4 KDIGO stage
- Malignancy in the past two years (except for non melanoma skin cancer and in situ cervical carcinoma)
- Not capable of performing or following the prehabilitation program
- Involvement in a clinical trial the previous 2 months
- Refusal of informed consent
For the study of the pathophysiology of fatigue, additional exclusion criteria will be established: Severe depression or neuropsychiatric disease, 2) Treatment with centrally acting drugs, 3) Muscular or systemic disease with potential muscle involvement, 4) Immunosuppressive treatment, 5) Sleep disorder, 6) Obesity (BMI >30).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Primary Outcome Measures
Name Time Method Change in Fatigue Severity Assessed by PBC-40 Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Primary Biliary Cholangitis-40 (PBC-40) fatigue domain, which consists of 11 items scored from 1 to 5. Scoring Range: 11 to 55; higher scores indicate greater fatigue.
Change in Fatigue Severity Assessed by Visual Analogue Scale Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Visual Analogue Scale (VAS) for fatigue, which captures the participant's perception of fatigue severity. Scoring Range: 0 (no fatigue) to 10 (worst imaginable fatigue).
Change in Fatigue Impact Assessed by Fatigue Impact Scale (FIS) Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Modified Fatigue Impact Scale (MFIS), which assesses the impact of fatigue on physical, cognitive, and psychosocial functioning. Scoring Range: 0 to 84; higher scores indicate greater fatigue-related impairment
- Secondary Outcome Measures
Name Time Method Change in Extrahepatic Symptoms Assessed by PBC-40 Baseline, week 8 and/or after the exercise phase, and end of trial. To evaluate changes in extrahepatic symptoms using the Primary Biliary Cholangitis-40 (PBC-40) questionnaire. The symptoms domain ranges from 7 to 35 points. Higher scores indicate worse symptoms.
Change in Systemic Inflammation Assessed by Pro-Inflammatory Cytokines Baseline and end of induction phase (2 months) for participants with fatigue; single time point for control groups. To evaluate systemic inflammation and bile acid metabolism by analyzing a panel of pro-inflammatory cytokines (measured via ELISA), lysophosphatidic acid, autotaxin, and bile acids. Each biomarker will be quantified by the laboratory using standardized assays.
Units of Measure: Concentrations reported in appropriate laboratory units (e.g., pg/mL, nmol/L) depending on the biomarker.Functional Connectivity Alterations in Brain Regions Assessed by fMRI. Baseline and end of induction phase (2 months) for participants with fatigue; single time point for control groups. To examine changes in functional connectivity in gray matter regions, including the basal ganglia and insula, using functional magnetic resonance imaging (fMRI).
Change in Quality of Life Assessed by EQ-5D-5L Index Score Baseline, week 8 and/or after the exercise phase, and end of trial. To assess health-related quality of life using only the EQ-5D-5L index score derived from five health dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The index score ranges from -0.594 to 1, where higher scores indicate better health status.
Change in Self-Perceived Health Status Assessed by EQ Visual Analogue Scale Baseline, week 8 and/or after the exercise phase, and end of trial. To evaluate self-perceived overall health using the EQ Visual Analogue Scale (EQ-VAS), part of the EQ-5D-5L instrument, reported separately. The EQ-VAS ranges from 0 to 100, where 0 = worst imaginable health and 100 = best imaginable health.
Change in Disability Assessed by the WHO Disability Assessment Schedule (WHODAS 2.0) Baseline, week 8 and/or after the exercise phase, and end of trial. To measure disability and functional impairment. Scoring Range: 0 to 100; higher scores indicate greater disability.
Change in Work Productivity and Activity Impairment Assessed by the WPAI Questionnaire Baseline, week 8 and/or after the exercise phase, and end of trial. To measure absenteeism and work productivity impairment. Percentage scores for absenteeism, presenteeism, overall work impairment, and activity impairment; higher percentages indicate greater impairment.
Change in Cognitive Symptoms Assessed by PBC-40 Baseline, week 8 and/or after the exercise phase, and end of trial. To evaluate changes in cognitive symptoms using the Primary Biliary Cholangitis-40 (PBC-40) questionnaire. The cognitive domain ranges from 6 to 30 points. Higher scores indicate worse symptoms.
Change in Sleep Quality Assessed by the Epworth Sleepiness Scale (ESS) Baseline, week 8 and/or after the exercise phase, and end of trial. To assess daytime sleepiness as a proxy for sleep quality. Scoring Range: 0 to 24; higher scores indicate greater daytime sleepiness.
Change in Anxiety and Depression Assessed by the Hospital Anxiety and Depression Scale (HADS) Baseline, week 8 and/or after the exercise phase, and end of trial. To evaluate levels of anxiety and depression. Scoring Range: 0 to 21 for each subscale (anxiety and depression); higher scores indicate greater symptom severity.
Changes in Muscle Mitochondrial Metabolism Assessed by Gene Expression Analysis Baseline and end of induction phase (2 months) for participants with fatigue; single time point for control groups. To analyze gene expression profiles related to mitochondrial metabolism in muscle fibers obtained via muscle microbiopsy. Units of measure: Relative gene expression (fold change compared to baseline or control).
Change in Aerobic Capacity Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). Aerobic capacity will be evaluated to measure changes in functional exercise tolerance using the 6-Minute Walk Test (6MWT), which measures distance walked in meters (0-700 m typical; higher distances = better capacity).
Unit of Measure: Meters.Change in Physical Activity Levels Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). Physical activity levels will be assessed to determine changes in habitual activity, with scores ranging from 0 to 142, where higher scores indicate greater overall physical activity.
Change in Frailty Status Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months). Frailty will be evaluated using the Liver Frailty Index (LFI), a continuous scale derived from a combination of grip strength, chair-stand time, and balance testing. In adult liver disease populations, median LFI values range approximately from 2.7 in individuals without liver disease to 3.6 in those with cirrhosis. Established thresholds classify LFI scores of \< 3.2 as "robust", 3.2-4.4 as "prefrail", and \> 4.4 as "frail"
Feasibility and Satisfaction of a Multimodal Rehabilitation Program for the Treatment of Fatigue From enrollment to the end of treatment at 6 months Participant experience will be assessed using satisfaction questionnaires. Adherence to the intervention and loss to follow-up will be evaluated by analyzing reasons for non-compliance or withdrawal.
Trial Locations
- Locations (1)
Hospital Clinic de Barcelona
🇪🇸Barcelona, Barcelona, Spain
Hospital Clinic de Barcelona🇪🇸Barcelona, Barcelona, Spain