RELIEF: Multimodal Prehabilitation to Treat Fatigue in Patients With Primary Biliary Cholangitis

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое Multimodal prehabilitation
  The multimodal prehabilitation program will consist of: 1. twice-weekly supervised exercise training at the hospital gym for approximately 8 weeks (induction phase), followed by 16 weeks of telematic, supervised, home-based exercise (maintenance phase); 2. nutritional consultation, including diet optimization and supplementation if needed; 3. individual or group-based psychological support.
• Другое standard of care
  Participants in the control group will follow the standard of care provided by the hospital and will receive general recommendations on physical activity, nutrition, and stress/anxiety management.

Первичные конечные точки

• Change in Fatigue Severity Assessed by PBC-40 [Срок оценки: Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).]
• Change in Fatigue Severity Assessed by Visual Analogue Scale [Срок оценки: Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).]
• Change in Fatigue Impact Assessed by Fatigue Impact Scale (FIS) [Срок оценки: Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).]

Вторичные конечные точки (12)

• Change in Cognitive Symptoms Assessed by PBC-40 [Срок оценки: Baseline, week 8 and/or after the exercise phase, and end of trial.]
• Change in Extrahepatic Symptoms Assessed by PBC-40 [Срок оценки: Baseline, week 8 and/or after the exercise phase, and end of trial.]
• Change in Quality of Life Assessed by EQ-5D-5L Index Score [Срок оценки: 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 [Срок оценки: Baseline, week 8 and/or after the exercise phase, and end of trial.]
• Change in Disability Assessed by the WHO Disability Assessment Schedule (WHODAS 2.0) [Срок оценки: 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) [Срок оценки: Baseline, week 8 and/or after the exercise phase, and end of trial.]
• Change in Sleep Quality Assessed by the Epworth Sleepiness Scale (ESS) [Срок оценки: 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 [Срок оценки: Baseline, week 8 and/or after the exercise phase, and end of trial.]
• Change in Systemic Inflammation Assessed by Pro-Inflammatory Cytokines [Срок оценки: 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. [Срок оценки: Baseline and end of induction phase (2 months) for participants with fatigue; single time point for control groups.]
• Changes in Muscle Mitochondrial Metabolism Assessed by Gene Expression Analysis [Срок оценки: Baseline and end of induction phase (2 months) for participants with fatigue; single time point for control groups.]
• Change in Aerobic Capacity [Срок оценки: Baseline (week 0), post-intervention (week 8), and end of maintenance phase (6 months).]

Критерии участия

Критерии включения

• Age ≥18 years
• PBC diagnosis according to EASL guidelines
• Moderate - severe fatigue defined by ≥ 29 points in PBC-40 questionnaire

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Испания · 1 центр

• Hospital Clinic de Barcelona — Barcelona

Публикации

• Diaz-Feijoo B, Agusti N, Sebio R, Siso M, Carreras-Dieguez N, Domingo S, Diaz-Cambronero O, Torne A, Martinez-Palli G, Arguis MJ. A multimodal prehabilitation program for the reduction of post-operative complications after surgery in advanced ovarian cancer under an ERAS pathway: a randomized multicenter trial (SOPHIE). Int J Gynecol Cancer. 2022 Nov 7;32(11):1463-1468. doi: 10.1136/ijgc-2022-0036 PMID 35793862
• Gimeno-Santos E, Coca-Martinez M, Arguis MJ, Navarro R, Lopez-Hernandez A, Castel MA, Romano B, Lopez-Baamonde M, Sandoval E, Farrero M, Sanz M, Bofill A, Martinez-Palli G. Multimodal prehabilitation as a promising strategy for preventing physical deconditioning on the heart transplant waiting list. Eur J Prev Cardiol. 2020 Dec;27(19):2367-2370. doi: 10.1177/2047487319889709. Epub 2019 Nov 25. No PMID 31766879
• Barberan-Garcia A, Ubre M, Pascual-Argente N, Risco R, Faner J, Balust J, Lacy AM, Puig-Junoy J, Roca J, Martinez-Palli G. Post-discharge impact and cost-consequence analysis of prehabilitation in high-risk patients undergoing major abdominal surgery: secondary results from a randomised controlled trial. Br J Anaesth. 2019 Oct;123(4):450-456. doi: 10.1016/j.bja.2019.05.032. Epub 2019 Jun 25. PMID 31248644
• Williams FR, Vallance A, Faulkner T, Towey J, Kyte D, Durman S, Johnson J, Holt A, Perera MT, Ferguson J, Armstrong MJ. Home-based exercise therapy in patients awaiting liver transplantation: protocol for an observational feasibility trial. BMJ Open. 2018 Jan 21;8(1):e019298. doi: 10.1136/bmjopen-2017-019298. PMID 29358444
• Zenith L, Meena N, Ramadi A, Yavari M, Harvey A, Carbonneau M, Ma M, Abraldes JG, Paterson I, Haykowsky MJ, Tandon P. Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014 Nov;12(11):1920-6.e2. doi: 10.1016/j.cgh.2014.04.016. Epub 2014 Apr 24. PMID 24768811
• Watt M, Hyde A, Johnson E, Wright GM, Vander Well S, Sadasivan C, Lee-Baggley D, Spence JC, Mason A, Ko HH, Tam E, Tandon P. An online mind-body program improves mental health and quality of life in primary biliary cholangitis: A randomized controlled trial. Hepatol Commun. 2023 Nov 6;7(11):e0316. doi: 10.1097/HC9.0000000000000316. eCollection 2023 Nov 1. PMID 38346279
• Freer A, Williams FR, Durman S, Hayden J, Armstrong MJ, Trivedi PJ. A home-based exercise programme attenuates fatigue in primary biliary cholangitis: Results from the EXCITED clinical trial. JHEP Rep. 2024 Sep 6;6(12):101210. doi: 10.1016/j.jhepr.2024.101210. eCollection 2024 Dec. PMID 39640219
• Kowdley KV, Bowlus CL, Levy C, Akarca US, Alvares-da-Silva MR, Andreone P, Arrese M, Corpechot C, Francque SM, Heneghan MA, Invernizzi P, Jones D, Kruger FC, Lawitz E, Mayo MJ, Shiffman ML, Swain MG, Valera JM, Vargas V, Vierling JM, Villamil A, Addy C, Dietrich J, Germain JM, Mazain S, Rafailovic D, Tadde B, Miller B, Shu J, Zein CO, Schattenberg JM; ELATIVE Study Investigators' Group; ELATIVE St PMID 37962077

Идентификаторы

NCT: NCT07161245 · RELIEF/2025

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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