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Trial registered on ANZCTR


Registration number
ACTRN12622001095752
Ethics application status
Approved
Date submitted
3/08/2022
Date registered
8/08/2022
Date last updated
8/08/2022
Date data sharing statement initially provided
8/08/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Neuroimaging Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Scientific title
Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional neuroimaging study towards its neuropathophysiology and diagnosis
Secondary ID [1] 307703 0
NHMRC GNT 1184219
Secondary ID [2] 307706 0
The Mason Foundation MAS2018F00024
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Fatigue Syndrome 327266 0
Condition category
Condition code
Neurological 324397 324397 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Data collection includes (1) symptom questionnaires, (2) actigraphy, (3) clinical interviews, and (4) MRIs. Given the limited capabilities of ME/CFS patients, a participant may take over one month to complete all symptom questionnaires. The other data collection will start after the questionnaires and be completed over three weeks. Participants may visit the research site (Thompson Institute at University of the Sunshine Coast) one to three times, dependent on participants’ preferences and availabilities of clinicians and MRI scan times.

(1) After informed consent has been obtained, the following assessments will be undertaken: 1) symptom information relevant to establishing CCC ME/CFS classification; 2) the 36-item Short-Form Health Survey; c) Hospital Anxiety and Depression Scale questionnaire; d) the Bell disability score; e) The Assessment of Quality of Life questionnaire; g) the Pittsburgh sleep quality index questionnaire. Symptom questionnaires will be undertaken only once at the start of participation. The questionnaires can be filled out online or mailed to participants upon their preferences. The total estimated time for the completed questionnaire is about 3 hours.

(2) Actigraphy: Participants will be given a GT3X-BT device with a heart rate monitor to wear seven days before the MRI. The heart rate monitor is to be worn for 24 hours. After the MRI scan, participants will be given another GT3X-BT device to wear for seven days with a 24-hours heart rate monitor to be worn on the following morning of the MRI scan. The actigraphy will be posted to or picked up by participants at the first clinical interview.

(3) Clinical interviews will only be undertaken by two clinicians independently with patients at a single time point. Each interview will happen at the research site and last about one hour. Before the clinical interviews, height, weight, BMI, blood pressure, pulse rate, oxygen saturation, and weighted standing time for evaluation of postural orthostatic tachycardia syndrome (POTS) for each participant will be collected and shared with the clinician. The Beighton scores (a measure of generalised joint hypermobility) for each participant will be collected during the second clinical interview.

(4) Multimodal MRI will be undertaken only at a single time point. Brain images are acquired using a 3T MRI scanner with a 64-channel head coil (Skyra, Siemens) at the research site. The scan takes about 1.5 hours, including an MRI safety screen and preparation. A fatigue state questionnaire that measures current fatigue levels will be completed before and after the MRI for each participant.
Intervention code [1] 324182 0
Diagnosis / Prognosis
Comparator / control treatment
This observational study aims to develop a diagnosis protocol for chronic fatigue syndrome (ME/CFS). The comparator includes healthy controls with sedentary lifestyles, individuals with chronic fatigue for other reasons but not ME/CFS, and patients with fibromyalgia. The healthy controls will undergo actigraphy and MRI assessments. The individual with chronic fatigue and fibromyalgia will undergo all evaluations described in the exposure section.
Control group
Active

Outcomes
Primary outcome [1] 332205 0
Hemodynamic Response Function (HRF) assessed using functional MRI (fMRI).
Timepoint [1] 332205 0
Once only during observation session.
Primary outcome [2] 332206 0
Dynamic glutamate acticity during cognitive tasks assessed using functional magnetic resonance spectroscopy (fMRS)
Timepoint [2] 332206 0
Once only during observation session
Secondary outcome [1] 412533 0
Brain volumetrics assessed using structural magnetic resonance imaging.
Timepoint [1] 412533 0
Once only during observation session
Secondary outcome [2] 412534 0
High-frequency heart rate variability assessed using pulse oximeter.
Timepoint [2] 412534 0
Once only during observation session.
Secondary outcome [3] 412535 0
Objective sleep quality assessed by actigraphy.
Timepoint [3] 412535 0
Once only during observation session.

Eligibility
Key inclusion criteria
The inclusion criteria include adult individuals who express an interest, meet each group definition, and are confirmed by clinicians.
The ME/CFS group is patients who meet ME/CFS Canadian Consensus Criteria and have a consistent diagnosis by two clinicians. The two clinicians will discuss to reach a consistent diagnosis if different results are generated during the independent interviews.
The chronic fatigue group is defined as (1) self-identified ME/CFS but not confirmed by the two clinicians (i.e., present with other conditions or lack core ME/CFS symptoms); (2) with other disorders (not ME/CFS or fibromyalgia) that fatigue is a significant symptom.
The fibromyalgia group is defined as individuals who meet the 2016 American College of Rheumatology fibromyalgia criteria and confirmed by the clinic interview.
The healthy controls are healthy individuals does not meet exclusion criteria and have a sedentary lifestyle. A sedentary lifestyle is defined as spending 4 or more hours/day (in addition to sleep) on activities that are less than 1.5 metabolic equivalents measured by the Actigraph GT3X-BT device.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
The exclusion criteria include individuals 1) out of the age range, 2) pregnant, 3) with severe intellectual or mental impairment preventing them from fully understanding the study to give consent, 4) with moderate or severe mental disorders who are taking medication as treatment, 5) with a known other neurological disorder, 6) who cannot read and communicate in English, 7) with an unequal relationship with the team unless there is the desire to be a volunteer with the right to withdraw at any time point, 8) with alcohol or substance related disorder, 9) with BMI >35, 10) smoking (including marijuana), 11) with diabetes, hypertension, or uncontrolled hyperlipidaemia, 12) currently on medication acting on the brain, 13) with a clinical diagnosis of hemochromatosis, 14) with a double copy of the Haemochromatosis gene, 15) who experienced migraines more than six times a year before the onset of their symptoms. Additional exclusion criteria for HCs include individuals 1) with a chronic disease and 2) who experience migraines more than six times a year, and 3) who do more than 60 minutes in moderate or high-intensity activity per week.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The hemodynamic response function, respiration response function, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.

The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator - regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group.

The hemodynamic response function features and dynamic glutamate changes associated with a cognitive task in individuals with fatigue and ME/CFS will be tested for the first time. Therefore, there are no preliminary results on these two groups' variances and means of these measures. This study's total sample size (N = 288) was determined to detect the effect size of 0.25. For the same reason, the learning curve for neuromarker identification cannot be determined. However, one previous study determined that a test sample size of 100 would be needed to test a classifier to achieve reasonable precision in the validation.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
3/08/2020
Date of last participant enrolment
Anticipated
5/08/2024
Actual
Date of last data collection
Anticipated
22/08/2024
Actual
Sample size
Target
288
Accrual to date
110
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 22902 0
University of the Sunshine Coast Clinical Trials Centre - Sippy Downs - Sippy Downs
Recruitment postcode(s) [1] 38209 0
4575 - Birtinya
Recruitment postcode(s) [2] 38210 0
4556 - Sippy Downs

Funding & Sponsors
Funding source category [1] 311972 0
Government body
Name [1] 311972 0
National Health and Medical Research Council
Country [1] 311972 0
Australia
Funding source category [2] 311975 0
Charities/Societies/Foundations
Name [2] 311975 0
The Mason Foundation
Country [2] 311975 0
Australia
Primary sponsor type
University
Name
University of the Sunshine Coast
Address
90 Sippy Downs Drive
Sippy Downs
Queensland 4556
Australia
Country
Australia
Secondary sponsor category [1] 313460 0
None
Name [1] 313460 0
Address [1] 313460 0
Country [1] 313460 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311401 0
Unversity of the Sunshine Coast Human Ethics Committee
Ethics committee address [1] 311401 0
90 Sippy Downs Drive
Sippy Downs
Queensland 4556
Australia
Ethics committee country [1] 311401 0
Australia
Date submitted for ethics approval [1] 311401 0
20/08/2019
Approval date [1] 311401 0
01/11/2019
Ethics approval number [1] 311401 0
A191288

Summary
Brief summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis.

A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.

This study will investigate NVC using multimodal MRIs: 1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modelled from a cognitive task fMRI; 2) respiration response function (RRF) that represents autoregulation of regional blood flow due to carbon dioxide and will be modelled from breath holding fMRI; 3) neural activity associated glutamate changes that will be modelled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework.

This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by an agreed diagnosis made by two clinicians using the Canadian Consensus Criteria. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.

The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.
The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator - regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group.
Trial website
https://www.usc.edu.au/thompson-institute/research/chronic-fatigue-syndrome-me-cfs-study
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120966 0
Dr Zack Shan
Address 120966 0
Thompson Institute
UNIVERSITY OF THE SUNSHINE COAST
12 Innovation Pkwy
Birtinya
QLD 4575
Country 120966 0
Australia
Phone 120966 0
+61 7 54563951
Fax 120966 0
Email 120966 0
[email protected]
Contact person for public queries
Name 120967 0
Zack Shan
Address 120967 0
Thompson Institute
UNIVERSITY OF THE SUNSHINE COAST
12 Innovation Pkwy
Birtinya
QLD 4575
Country 120967 0
Australia
Phone 120967 0
+61 7 54563951
Fax 120967 0
Email 120967 0
[email protected]
Contact person for scientific queries
Name 120968 0
Zack Shan
Address 120968 0
Thompson Institute
UNIVERSITY OF THE SUNSHINE COAST
12 Innovation Pkwy
Birtinya
QLD 4575
Country 120968 0
Australia
Phone 120968 0
+61 7 54563951
Fax 120968 0
Email 120968 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification, will be available.
When will data be available (start and end dates)?
The data will be available when the project was completed from March 2025 to March 2028.
Available to whom?
The data will be available to research scientists dependent on the request and review of the purpose of data usage.
Available for what types of analyses?
The data could be potentially used for the understanding aetiology of other disorders such as fibromyalgia and PTSD and development of diagnosis and prognosis biomarker for these disorders.
How or where can data be obtained?
The data will be available to research scientists dependent on the request and review of the purpose of data usage by contact the principal investigator by email [email protected].


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseMultimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis.2022https://dx.doi.org/10.3389/fneur.2022.954142
N.B. These documents automatically identified may not have been verified by the study sponsor.