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Non-invasive Approaches to Identify the Cause of Fatigue in Inflammatory Bowel Disease Patients. (IBD Fatigue)

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ClinicalTrials.gov Identifier: NCT03670693
Recruitment Status : Recruiting
First Posted : September 13, 2018
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
University of Nottingham

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.


Condition or disease Intervention/treatment Phase
Crohn Disease Diagnostic Test: Muscle strength and fatigue assessment Diagnostic Test: Dual-energy X-ray absorptiometry (DEXA scan) Diagnostic Test: Supine cardiorespiratory fitness assessment Diagnostic Test: fMRI Exercise assessment Diagnostic Test: Muscle deconditioning assessment Not Applicable

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Non-invasive Approaches to Identify the Cause of Fatigue in Inflammatory Bowel Disease Patients
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Fatigued Crohn's Disease
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 assessment
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

Diagnostic Test: Dual-energy X-ray absorptiometry (DEXA scan)
Body composition will be assessed via DEXA scan (Lunar Prodigy, GE Medical Systems, Bucks, UK)

Diagnostic Test: Supine cardiorespiratory fitness assessment
VO2 peak will be quantified during completion of a continuous, incremental exercise test performed in the supine position on an MR adapted stepper machine (Ergospect, Innsbruck Austria)

Diagnostic Test: fMRI Exercise assessment
Measurement of cardiac output and, cerebral and regional perfusion using Blood-Oxygen-level-dependent (BOLD) measures and arterial spin-labelling (ASL)-MRI as well as fractional oxygen extraction using TRUST-MRI during supine exercise of the quadriceps with the MR compatible cardiostepper (Ergospect, Innsbruck, Austria) at 50% of relative VO2 peak as measured during the supine cardiorespiratory fitness assessment.

Diagnostic Test: Muscle deconditioning assessment
Limb blood flow will be occluded with a cuff, whilst participants perform repeated plantar flexion exercise in a MRI scanner. This will drive PCr, (the available reserve of ATP) to zero. Once the cuff is removed, they will undergo non-invasive and well-established in vivo 31P magnetic resonance (31P MRS) measurements on the gastrocnemius to determine PCr re-synthesis rate during resting recovery.

Experimental: Non-Fatigued Crohn's Disease
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.)
Diagnostic Test: Muscle strength and fatigue assessment
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

Diagnostic Test: Dual-energy X-ray absorptiometry (DEXA scan)
Body composition will be assessed via DEXA scan (Lunar Prodigy, GE Medical Systems, Bucks, UK)

Diagnostic Test: Supine cardiorespiratory fitness assessment
VO2 peak will be quantified during completion of a continuous, incremental exercise test performed in the supine position on an MR adapted stepper machine (Ergospect, Innsbruck Austria)

Diagnostic Test: fMRI Exercise assessment
Measurement of cardiac output and, cerebral and regional perfusion using Blood-Oxygen-level-dependent (BOLD) measures and arterial spin-labelling (ASL)-MRI as well as fractional oxygen extraction using TRUST-MRI during supine exercise of the quadriceps with the MR compatible cardiostepper (Ergospect, Innsbruck, Austria) at 50% of relative VO2 peak as measured during the supine cardiorespiratory fitness assessment.

Diagnostic Test: Muscle deconditioning assessment
Limb blood flow will be occluded with a cuff, whilst participants perform repeated plantar flexion exercise in a MRI scanner. This will drive PCr, (the available reserve of ATP) to zero. Once the cuff is removed, they will undergo non-invasive and well-established in vivo 31P magnetic resonance (31P MRS) measurements on the gastrocnemius to determine PCr re-synthesis rate during resting recovery.

Experimental: Healthy Volunteers
Age,gender,muscle mass, and physical activity-matched healthy controls.
Diagnostic Test: Muscle strength and fatigue assessment
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

Diagnostic Test: Dual-energy X-ray absorptiometry (DEXA scan)
Body composition will be assessed via DEXA scan (Lunar Prodigy, GE Medical Systems, Bucks, UK)

Diagnostic Test: Supine cardiorespiratory fitness assessment
VO2 peak will be quantified during completion of a continuous, incremental exercise test performed in the supine position on an MR adapted stepper machine (Ergospect, Innsbruck Austria)

Diagnostic Test: fMRI Exercise assessment
Measurement of cardiac output and, cerebral and regional perfusion using Blood-Oxygen-level-dependent (BOLD) measures and arterial spin-labelling (ASL)-MRI as well as fractional oxygen extraction using TRUST-MRI during supine exercise of the quadriceps with the MR compatible cardiostepper (Ergospect, Innsbruck, Austria) at 50% of relative VO2 peak as measured during the supine cardiorespiratory fitness assessment.

Diagnostic Test: Muscle deconditioning assessment
Limb blood flow will be occluded with a cuff, whilst participants perform repeated plantar flexion exercise in a MRI scanner. This will drive PCr, (the available reserve of ATP) to zero. Once the cuff is removed, they will undergo non-invasive and well-established in vivo 31P magnetic resonance (31P MRS) measurements on the gastrocnemius to determine PCr re-synthesis rate during resting recovery.




Primary Outcome Measures :
  1. Central fatigue - Cerebral perfusion [ Time Frame: 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.

  2. Central fatigue - Oxygen extraction [ Time Frame: 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.

  3. Central fatigue - Cardiac Output [ Time Frame: 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.

  4. Peripheral fatigue - PCr resynthesis rate [ Time Frame: 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.


Secondary Outcome Measures :
  1. Cardiorespiratory fitness [ Time Frame: 20 minutes ]
    VO2 peak obtained during an incremental supine exercise test performed on an MR compatible stepper. VO2 peak will be expressed in ml/min/kg, with a higher value reflecting an individuals ability to utilise a higher volume of oxygen during exercise.

  2. Muscle strength [ Time Frame: 10 minutes ]
    Maximum voluntary contraction performed on an isokinetic dynomometer. Torque values will be recorded in Newton-meters (NM).

  3. Muscle fatigue [ Time Frame: 10 minutes ]
    Rate of torque decrement (Newton-meters) during 20 knee extension repetitions performed on an isokinetic dynamometer at a constant angular velocity of 90 degrees per second.

  4. General fatigue - MFI 20 [ Time Frame: 30 minutes ]
    The Multiple Fatigue Inventory- 20 consists of 20 questions quantifying 20 sub-sections of fatigue. Questions 1,5,12 and 16 assess general fatigue. A higher score reflects a higher degree of fatigue. Patients scoring >14 on the general fatigue questions will be grouped into the "fatigued group" whilst patients scoring <14 will be grouped into the "non-fatigued" group. We will actively exclude any healthy volunteer participants (controls) who score >14 on the generl fatigue section of the MFI-20.

  5. Body composition [ Time Frame: 15 minutes ]
    Regional fat quantified in grams (g) via DEXA scan.

  6. Body Composition [ Time Frame: 15 minutes ]
    Lean masses quantified in grams (g) via DEXA scan.

  7. Physical Fatigue - MFI 20 [ Time Frame: 30 minutes ]
    The Multiple Fatigue Inventory- 20 consists of 20 questions quantifying 20 sub-sections of fatigue. Questions 2,8,14 and 20 assess physical fatigue. A higher score reflects a higher degree of fatigue. Patients scoring >14 on the physical fatigue questions will be grouped into the "fatigued group" whilst patients scoring <14 will be grouped into the "non-fatigued" group. We will actively exclude any healthy volunteer participants (controls) who score >14 on the physical fatigue section of the MFI-20.

  8. Anxiety and depression - Hospital Anxiety & Depression scale (HADS) [ Time Frame: 15 minutes ]
    Scores obtained from completion of the Hospital Anxiety and Depression questionnaire. This compromises separate sections of questions related to the assessment of depression and anxiety, yielding a final score for each. A higher anxiety score reflects a higher level of anxiety, whilst a lower depression score reflects more severe depression. Regarding both Anxiety & Depression scales: A score of 8-10 indicates Mild, 11-14 Moderate and 15-21 severe. We will actively exclude participants scoring >8 on either anxiety, depression, or both.

  9. Quality of life (CUCQ-32) [ Time Frame: 15 minutes ]
    Scores obtained from completion of the CUCQ-32 questionnaire can range from 0-272, where a higher score reflects a worse quality of life. There are no pre-existing, published cut off scores for this questionnaire. Mean scores will be compared across the three experimental groups to identify any differences in self-reported quality of life.

  10. Physical activity level [ Time Frame: 7 days ]
    Obtained from pedometer worn for 7 day period during the study.

  11. Cognition [ Time Frame: 30 minutes ]
    Obtained from Cognitive Assessment: Montreal Cognitive Assessment (MoCA) performed at screening. The maximum score is 30 marks, with >26 considered as normal.

  12. Inflammatory markers [ Time Frame: 15 minutes ]
    Concentrations of IL-1, IL-6, and TNFα obtained from blood sampling during screening.

  13. Serum Vitamin D concentrations [ Time Frame: 15 minutes ]
    Obtained from blood sampling during screening



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   16 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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:
  • Gender
  • Muscle mass
  • Physical activity
  • General fatigue and physical fatigue score on the Multiple Fatigue Inventory-20 <7.

All participants should have a good command of both verbal and written English and be able to give informed consent.

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03670693


Contacts
Contact: Shellie J Radford, BSc +44 115 924 9924 ext 70614 shellie.radford@nuh.nhs.uk
Contact: Gordon W Moran, MD, PhD +44 0115 9249924 ext 70608 Gordon.Moran@nottingham.ac.uk

Locations
United Kingdom
Nottingham Biomedical Research Centre Recruiting
Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
Contact: Shellie Radford, BSc       shellie.radford@nuh.nhs.uk   
Contact: Gordon Moran, PhD, MD       gordon.moran@nottingham.ac.uk   
Sponsors and Collaborators
University of Nottingham
Investigators
Principal Investigator: Gordon W Moran, MD, PhD University of Nottingham

Publications:

Responsible Party: University of Nottingham
ClinicalTrials.gov Identifier: NCT03670693     History of Changes
Other Study ID Numbers: 17083
First Posted: September 13, 2018    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Crohn Disease
Fatigue
Intestinal Diseases
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Signs and Symptoms