Brief Summary

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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at P25-P50 for not_applicable

Timeline

Completed

Started Aug 2018

Longer than P75 for not_applicable

Geographic Reach

1 country

1 active site

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

3.4 years study duration

First Submitted

Initial submission to the registry

May 10, 2018

Completed

3 months until next milestone

Study Start

First participant enrolled

August 1, 2018

Completed

1 month until next milestone

First Posted

Study publicly available on registry

September 13, 2018

Completed

3.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 12, 2021

Completed

24 days until next milestone

Study Completion

Last participant's last visit for all outcomes

January 5, 2022

Completed

Last Updated

January 19, 2023

Status Verified

January 1, 2023

Enrollment Period

3.4 years

First QC Date

May 10, 2018

Last Update Submit

January 18, 2023

Conditions

Crohn Disease

Outcome Measures

Primary Outcomes (4)

Central fatigue - Cerebral perfusion
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.
2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
Central fatigue - Oxygen extraction
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.
2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
Central fatigue - Cardiac Output
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.
2 hours (All central fatigue measures quantified during a single 2-hour fMRI scan)
Peripheral fatigue - PCr resynthesis rate
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.
1 hour Magnetic Resonance Spectroscopy (MRS) scan

Secondary Outcomes (13)

Cardiorespiratory fitness
20 minutes
Muscle strength
10 minutes
Muscle fatigue
10 minutes
General fatigue - MFI 20
30 minutes
Body composition
15 minutes
+8 more secondary outcomes

Study Arms (3)

Fatigued Crohn's Disease

EXPERIMENTAL

Crohns disease patients in remission(Harvey Bradshaw index \<4 and CRP\<5mg/dl and faecal calprotectin \<50ug/g) suffering from fatigue (General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 \>14, and a score of \>4 in the Fatigue questionnaire.)

Diagnostic Test: Muscle strength and fatigue assessmentDiagnostic Test: Dual-energy X-ray absorptiometry (DEXA scan)Diagnostic Test: Supine cardiorespiratory fitness assessmentDiagnostic Test: fMRI Exercise assessmentDiagnostic Test: Muscle deconditioning assessment

Non-Fatigued Crohn's Disease

EXPERIMENTAL

Crohns disease patients in remission(Harvey Bradshaw index \<4 and CRP\<5mg/dl and faecal calprotectin \<50ug/g) without fatigue (General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 \<14, and a score of \<4 in the Fatigue questionnaire.)

Healthy Volunteers

EXPERIMENTAL

Age,gender,muscle mass, and physical activity-matched healthy controls.

Interventions

Muscle strength and fatigue assessmentDIAGNOSTIC_TEST

Measurement of maximum voluntary isometric contraction of the quadricep muscle on a cybex isokinetic dynomometer. This will be followed by a fatigue assessment where the torque decrement over 20 isokinetic knee extensions at a fixed angular velocity will be quantified to assess muscle fatigue