A Randomized Clinical Trial on the Improvement of Fatigue in Patients With Primary Biliary Cholangitis by Implementation of a Multimodal Rehabilitation Program and Study of Its Pathophysiological Mechanisms
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Change in Fatigue Severity Assessed by PBC-40
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age ≥18 years
- •PBC diagnosis according to EASL guidelines
- •Moderate - severe fatigue defined by ≥ 29 points in PBC-40 questionnaire
排除标准
- •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).
研究组 & 干预措施
Multimodal prehabilitation
8 weeks program of tailored physical exercise program with nutritional and psychological counselling to be carried out to a patient on the basis of his/her health condition, social circumstances and adherence profile.
干预措施: Multimodal prehabilitation (Other)
Standard of care
Standard Counselling: Patients in the control group will follow standard of care of the hospital and will be given general recommendations on physical activity, nutrition and stress/anxiety management.
干预措施: standard of care (Other)
结局指标
主要结局
Change in Fatigue Severity Assessed by PBC-40
时间窗: 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
时间窗: 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)
时间窗: 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
次要结局
- 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.)
- 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.)
- Change in Extrahepatic Symptoms Assessed by PBC-40(Baseline, week 8 and/or after the exercise phase, and end of trial.)
- 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.)
- 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.)
- 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.)
- 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.)
- Change in Cognitive Symptoms Assessed by PBC-40(Baseline, week 8 and/or after the exercise phase, and end of trial.)
- Change in Sleep Quality Assessed by the Epworth Sleepiness Scale (ESS)(Baseline, week 8 and/or after the exercise phase, and end of trial.)
- 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.)
- 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.)
- Change in Aerobic Capacity(Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).)
- Change in Physical Activity Levels(Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).)
- Change in Frailty Status(Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).)
- Feasibility and Satisfaction of a Multimodal Rehabilitation Program for the Treatment of Fatigue(From enrollment to the end of treatment at 6 months)