Non-invasive Approaches to Identify the Cause of Fatigue in Inflammatory Bowel Disease Patients
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 2
- 主要终点
- Peripheral fatigue - PCr resynthesis rate
研究概览
简要总结
Crohn's disease (CD) presents with severe symptoms, but fatigue is a very predominant symptom that negatively impacts upon quality of life. Fatigue affects ~40% of patients when well and 80% of patients when the disease is active. It is the second commonest symptom that an IBD patient gets throughout their life-time. The IBD priority-setting partnership between the James Lind Alliance and the British Society of Gastroenterology has recently identified fatigue as an area of unmet clinical need and a priority research field, in which diagnosis and therapeutic intervention are lacking.
Based on other diseases that present with fatigue, the cause of fatigue may be divided into peripheral fatigue, mainly driven by anomalies in muscle mass and function and central fatigue, mainly driven through decreased blood supply to the brain during exercise probably due to decreased heart and lung fitness.
Research in IBD fatigue until now has been patchy with no convincing evidence that any treatment helps. There has been no research aimed at studying whole body function. It is imperative to have a better understanding of the alterations in muscle, brain, heart and lung function seen in these patients before specific treatments are researched.
In this study, the investigators aim to recruit 32 CD patients, half with fatigue and half without. Subjects with active disease or with other known reasons of fatigue will be excluded. Findings in this group will be compared to 16 other healthy control volunteers of a similar age, gender and Body Mass Index. The study aims to recruit all participants over 36 months, and will target people aged from 16 to 60 years of age.
Once recruited, the participants will be asked to provide their consent to take-part in 3 experiments on two separate days. These experiments have been designed to carefully consider potential fatigue burden, experimental practicality, and participant availability.
Objective 1: The investigators aim to measure muscle fitness and strength by asking subjects to exercise using a stepper, whilst body mass and composition will be measured using an X-ray. This session will take 2 hours and be undertaken on one day.
Objective 2: Peripheral fatigue: The investigators aim to non-invasively measure the recovery of muscle physiology after exercise by using magnetic resonance imaging after 5 min of exercise undertaken with a limb cuff. This will take ~1 hour.
Objective 3: Central fatigue: while in the scanner and performing exercise, the investigators aim to non-invasively measure heart and brain blood flow before and after a few minutes of exercise using magnetic resonance imaging. This will take 2 hours.
Experimental work for Objectives 2 and 3 will be undertaken on the same day. There will be ample time for recovery in between and during the different studies. There will be no further commitment from the participants required after these 2 study visits.
IBD fatigue has never been studied in such detail. This unique work will allow identification of fatigue mechanisms, which can then be targeted with exercise, nutritional, or medical treatments.
详细描述
Background information Inflammatory bowel disease (IBD) fatigue is, with diarrhoea, the most common medical symptom in patients with active Crohn's disease (CD) and the second commonest complaint after arthralgia in CD patients in remission. The IBD priority-setting partnership between the James Lind Alliance and the British Society of Gastroenterology has highlighted that IBD fatigue is a top 10 UK research priority.
The prevalence of fatigue ranges from 41-48% when in remission, increasing up to 86% when the disease is active. Chronic fatigue is associated with an impaired health-related quality of life in IBD and a reduced physical activity, which in paediatric cohorts plays a major role in normal growth development. In the absence of reversible clinical causes such as anaemia, inflammatory burden or nutrient deficiency, it is as yet unclear what causes fatigue in these patients. Present approaches are limited in offering clues to potential therapeutic approaches or accurate clinical evaluation for CD patients. This is likely due to a lack of a multicomponent approach and poor methodological sensitivity and reliability when assessing fatigue. A multidimensional concept of physical, cognitive and affective components have been suggested for IBD fatigue. Yet, it remains unclear how to treat IBD fatigue. Exercise therapy, psychosocial interventions and solution-focused therapy, are all suggested as treatment options but none have been shown to be convincingly effective.
Fatigue arises from peripheral and central processes, which are both equally important. While peripheral fatigue is ascribed to muscle aetiology, central fatigue is a progressive exercise-induced reduction in voluntary activation to the muscle due to failure of the central nervous system (CNS). Present approaches have been limited in failing to adequately quantify peripheral fatigue at a muscle level and central fatigue at the level of the CNS.
Peripheral fatigue: the need of muscle activity
Physical fatigue is linked to reduced muscle mass and quality (sarcopenia) and consequently reduced muscle function. Drivers of muscle mass loss include physical inactivity and anabolic resistance, which to a large extent blunt the stimulatory effect of protein nutrition on muscle protein synthesis. In keeping with this, patients with active CD show a significant decrease in expression of hypertrophy skeletal muscle signalling pathways, but no changes in the expression of atrophy signals.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Non-Fatigued CD Patients:
- •Harvey Bradshaw index <4
- •CRP<5mg/dl or
- •Faecal calprotectin <50ug/g or,
- •As evidenced by recent endoscopy or cross-sectional imaging,
- •General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 <13
- •Score of <3 in the Fatigue questionnaire.
- •Fatigued CD Patients:
- •Harvey Bradshaw index <4 and,
- •CRP<5mg/dl or,
- •Faecal calprotectin <50ug/g or,
- •As evidenced by recent endoscopy or cross-sectional imagining and,
- •General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 >14
- •Score of >4 in the Fatigue questionnaire.
- •Inclusion criteria (Healthy volunteer participants)
- •26 Healthy Volunteers 16-75 years old matched for:
- •Muscle mass
- •Physical activity
- •General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 <
- •All participants should have a good command of both verbal and written English and be able to give informed consent.
排除标准
- •Exclusion criteria (CD and Healthy volunteer participants)
- •Potential participants with any of the following criteria will be excluded:
- •>8 on the Hospital Anxiety and Depression score
- •Haematological or biochemical abnormalities (e.g. anaemia (haemoglobin <13g/dl in a male and 12g/dl in a female)
- •Renal failure
- •Hypokalaemia
- •Pregnancy or childbearing in the last 6 months
- •Vitamin B complex deficiencies)
- •Active or previous prescriptions of corticosteroids in the last 12 weeks
- •Overt muscle wasting (defined as 2 standard deviations outside the age-related norm as measured by DEXA)
- •Fatigue starting after the onset of thiopurine therapy
- •Present arthritis or arthralgia
- •Surgical intervention in the last 12 weeks
- •Other aetiologies of chronic liver disease, specifically alcohol or drug induced liver disease, autoimmune or viral hepatitis, cholestatic or metabolic/genetic liver disease by specific clinical, biochemical, radiographic and /or histological criteria.
- •Significant cardiovascular or respiratory disease
- •Thyroid disease
- •Current Infection
- •Neurological or cognitive impairment
- •Significant physical disability
- •Pregnancy or breastfeeding. Participants will be informed before the DEXA scan that pregnancy is an exclusion and standard NHS procedures will be followed- pregnancy tests will be available in the female toilets of the Physiology Unit for self-testing)
- •Any other conditions in addition to the above that the investigators consider may affect study measurements or safety
- •Inability to understand verbal and/or written explanation of the study requirements
- •>5mSv ionizing radiation exposure in the past 12 months
结局指标
主要结局
Peripheral fatigue - PCr resynthesis rate
时间窗: 1 hour Magnetic Resonance Spectroscopy (MRS) scan
Quantification of phosphocreatine (PCr) re-synthesis rate following depletion via repeated plantar flexion exercise under blood flow occluded conditions. Since the rate of phosphocreatine re-synthesis is directly proportional to mitochondrial mass and oxygen delivery is not limiting during exercise recovery, this will allow measurement of muscle metabolic deconditioning in vivo. The rate of muscle PCr resynthesis will be expressed in (mmol.kg) and plotted as a function of time. The speed of PCr recovery rate will be compared across groups and provide a gold standard measurement of muscle deconditioning and reveal any peripheral contributions to premature fatigue development.
Central fatigue - Cerebral perfusion
时间窗: 2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
Cerebral perfusion will be used as a surrogate measure of central fatigue: Arterial spin labelling (ASL) data will be motion corrected and modelled to quantify brain perfusion in ml/100g/min. Both global and regional perfusion will be measured pre , during and post exercise.
Central fatigue - Oxygen extraction
时间窗: 2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
T2 relaxation under spin tagging (TRUST) data will be used to compute fractional oxygen extraction. Data will be expressed as a percentage of cerebral blood flow and quantified pre, during and post exercise.
Central fatigue - Cardiac Output
时间窗: 2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
Phase contrast MRI (PC-MRI) will be used to quantify realtime cardiac output. This will be quantified in the pre, during and post exercise period via quantification of heart rate and stroke volume using Phillips intellispace software. Data will be presented in L/min.
次要结局
- Cardiorespiratory fitness(20 minutes)
- Muscle strength(10 minutes)
- Muscle fatigue(10 minutes)
- General fatigue - MFI 20(30 minutes)
- Body composition(15 minutes)
- Body Composition(15 minutes)
- Physical Fatigue - MFI 20(30 minutes)
- Anxiety and depression - Hospital Anxiety & Depression scale (HADS)(15 minutes)
- Quality of life (CUCQ-32)(15 minutes)
- Physical activity level(7 days)
- Cognition(30 minutes)
- Inflammatory markers(15 minutes)
- Serum Vitamin D concentrations(15 minutes)