Fatigue Syndrome, ChronicEPIMENCT04378634
Epigenetics of Post-exertional Malaise in Patients With ME/CFS
A study testing Exercise and Mental Stress Test in people with Fatigue Syndrome, Chronic, run by Vrije Universiteit Brussel at 1 site in Belgium.
Trial summary
Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored. Read more about this study
- Who is it for?
- Ages 18 to 70 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Fatigue Syndrome, Chronic
- What is being tested?
- Exercise and Mental Stress Test
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 105 participants
- Where
- 1 siteBelgium
- Study dates
- 1 Apr 2021to 30 Apr 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- Women only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Canadian Consensus Criteria (CCC);
- age between 18 and 70 years old;
- body mass index (BMI) below 30 (no obesity).
Who cannot join
- presence of other neurological disorders (Parkinson's disease, Multiple Sclerosis, etc);
- presence of systemic disorders (lupus erythematosus, rheumatoid arthritis, etc.);
- presence or history of cardiac disorders (coronary heart disease, history of heart failure, etc);
- presence or history of cancer;
- presence or history of neuropathic pain (e.g. pain related to herpes zoster virus);
- pregnancy;
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored.
The investigators designed a randomised controlled trial and will enrol 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups and receive either one session of aerobic exercise or a validated test designed to trigger mental stress and mental fatigue. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.
Read the detailed description
The only way to improve the diagnosis and treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is to better understand the mechanisms underlying its pathophysiology. Central nervous system dysfunctions play a major role in ME/CFS and help explaining patients' symptoms, such as general malaise occurring after physical activity (i.e. post-exertional malaise). Therefore, post-exertional malaise in relation to three major candidates involved in central nervous system functioning - brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT) and histone de-acetylases (HDAC) - will be explored.
BDNF is a protein involved in crucial functions such as nerve growth, memory and learning, and plays a role in neuronal sensitisation and pain. However, no study has explored the role of BDNF in ME/CFS. Our research group performed a preliminary study which focussed on BDNF in ME/CFS. In a previous study, the investigators assessed DNA methylation (an epigenetic mechanism that contribute to gene expression silencing), and protein expression in serum of the BDNF in patients with ME/CFS and healthy controls. Patients showed significantly less DNA methylation and significantly more BDNF protein. Given these exciting findings, further study is warranted.
COMT is an enzyme encoded by its homonymous gene. The enzyme degrades catecholamines like dopamine, epinephrine and norepinephrine. Catecholamines have been repeatedly associated with pain, stress, and depression. Lower COMT activity increases catecholamines level, causes hyperalgesia, and has been associated with depressive symptoms.
Similarly, research on histone acetylation shows that another group of enzymes (Histone de-acetylases, HDACs) are increased during neural sensitisation and pain. However, no research has been done on HDACs in patients with ME/CFS. Interestingly, aerobic exercise has been shown to increase BDNF release and decrease COMT and HDACs activity. Given the detrimental acute effects that exercise can have on patients with ME/CFS, investigators hypothesised that understanding the role of BDNF, COMT, and HDACs following exercise would help elucidating both mechanisms of post-exertional malaise and ME/CFS pathophysiology.
A randomised controlled trial has been designed including 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups. One group will undergo one session of aerobic exercise, and the other group undergoes a validated test designed to trigger mental stress and mental fatigue. All participants will undergo clinical assessments, measurements of pain thresholds, and blood withdrawal before and after the exercise/mental stress exposure. The aims are to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes, as well as the expression of these factors in blood and serum in patients with ME/CFS.
- Conditions
- Fatigue Syndrome, Chronic
- Being tested
- Exercise, Mental Stress Test
- Keywords
- Chronic Fatigue Syndrome, Exercise, Epigenetics, DNA methylation
- Medical subject headings
- Fatigue Syndrome, Chronic, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ExerciseBehavioural
Also called Aerobic Power Index
Sub-maximal exercise test
Mental Stress TestOther
Also called Montreal Imaging Stress Task
Computerised mental arithmetic challenges and social evaluative threat tasks
| Study group | Role | What they receive |
|---|---|---|
| ME/CFS Exercise | Experimental | Patients undergoing the physical stress test (aerobic power index) Receives: Behavioral: Exercise; Other: Mental Stress Test |
| Patients Stress | Experimental | Patients undergoing the mental stress task (MIST) Receives: Behavioral: Exercise; Other: Mental Stress Test |
| Healthy Exercise | Active comparator | Healthy controls undergoing the physical stress test (aerobic power index) Receives: Behavioral: Exercise; Other: Mental Stress Test |
| Healthy Stress | Active comparator | Healthy controls undergoing the mental stress task (MIST) Receives: Behavioral: Exercise; Other: Mental Stress Test |
What is being measured
The primary outcome is the main question the study is designed to answer.
DNA methylation
DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology
Measured: Baseline through 1 week post intervention
Secondary outcomes (4)
Clinical Symptoms
Symptoms reported by the patients using the DePaul Symptoms Questionniare
Measured: Baseline through 1 week post intervention
Pain sensitivity
Sensitivity to mechanical stimuli using a digital algometer (FPXTM, Fisher, Wagner Instruments, Greenwich) as well as heat and cold stimuli using the TSA-II device (Medoc, CA, USA). The devices will be placed, in random order to prevent test order effects, at three different body sites: the skin web between thumb and index finger, trapezius muscle, and proximal third of tibialis anterior muscle, in order to test pain thresholds on non-specific locations both on the extremities and the trunk.
Measured: Baseline through 1 week post intervention
Serum BDNF
BDNF protein expression in serum using Enzyme-Linked Immunosorbent Assay (ELISA) kit for human BDNF
Measured: Baseline through 1 week post intervention
Cortisol response
Cortisol will be measured in saliva and used as a measure of stress responses using LC/MS-MS method.
Measured: Baseline through 1 week post intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2020
- Study start1 Apr 2021
- Primary completion30 Apr 2023
- Study completion30 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Fatigue Syndrome, ChronicStudies of the same condition, open and under way.
- More trials run by Vrije Universiteit BrusselThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomised Controlled Trial
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 105 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vrije Universiteit Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea Polli, Vrije Universiteit Brussel
- Investigators
- Jo Nijs, PhD, Study director, Vrije Universiteit Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04378634
- Sponsor's protocol ID
- EPIME
- Acronym
- EPIME
- Status last verified
- Nov 2023
- First submitted
- 27 Apr 2020
- Last updated
- 7 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
de Vega WC, Vernon SD, McGowan PO. DNA methylation modifications associated with chronic fatigue syndrome. PLoS One. 2014 Aug 11;9(8):e104757. doi: 10.1371/journal.pone.0104757. eCollection 2014.
PubMed 25111603Vangeel EB, Kempke S, Bakusic J, Godderis L, Luyten P, Van Heddegem L, Compernolle V, Persoons P, Lambrechts D, Izzi B, Freson K, Claes S. Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20.
PubMed 29275786Trivedi MS, Oltra E, Sarria L, Rose N, Beljanski V, Fletcher MA, Klimas NG, Nathanson L. Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns. PLoS One. 2018 Jul 23;13(7):e0201066. doi: 10.1371/journal.pone.0201066. eCollection 2018.
PubMed 30036399
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
- ClinicalTrials.gov ID
- NCT04378634
- Acronym / sponsor ID
- EPIME / EPIME
- Conditions
- Fatigue Syndrome, Chronic
- Keywords
- Chronic Fatigue Syndrome, Exercise, Epigenetics, DNA methylation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 105 participants (actual)
- Lead sponsor
- Vrije Universiteit BrusselUniversity, hospital or other
- Study start
- 1 Apr 2021 (actual)
- Primary completion
- 30 Apr 2023 (actual)
- Study completion
- 30 Apr 2023 (actual)
- First posted
- 7 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored.
The investigators designed a randomised controlled trial and will enrol 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups and receive either one session of aerobic exercise or a validated test designed to trigger mental stress and mental fatigue. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.
Detailed description
The only way to improve the diagnosis and treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is to better understand the mechanisms underlying its pathophysiology. Central nervous system dysfunctions play a major role in ME/CFS and help explaining patients' symptoms, such as general malaise occurring after physical activity (i.e. post-exertional malaise). Therefore, post-exertional malaise in relation to three major candidates involved in central nervous system functioning - brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT) and histone de-acetylases (HDAC) - will be explored.
BDNF is a protein involved in crucial functions such as nerve growth, memory and learning, and plays a role in neuronal sensitisation and pain. However, no study has explored the role of BDNF in ME/CFS. Our research group performed a preliminary study which focussed on BDNF in ME/CFS. In a previous study, the investigators assessed DNA methylation (an epigenetic mechanism that contribute to gene expression silencing), and protein expression in serum of the BDNF in patients with ME/CFS and healthy controls. Patients showed significantly less DNA methylation and significantly more BDNF protein. Given these exciting findings, further study is warranted.
COMT is an enzyme encoded by its homonymous gene. The enzyme degrades catecholamines like dopamine, epinephrine and norepinephrine. Catecholamines have been repeatedly associated with pain, stress, and depression. Lower COMT activity increases catecholamines level, causes hyperalgesia, and has been associated with depressive symptoms.
Similarly, research on histone acetylation shows that another group of enzymes (Histone de-acetylases, HDACs) are increased during neural sensitisation and pain. However, no research has been done on HDACs in patients with ME/CFS. Interestingly, aerobic exercise has been shown to increase BDNF release and decrease COMT and HDACs activity. Given the detrimental acute effects that exercise can have on patients with ME/CFS, investigators hypothesised that understanding the role of BDNF, COMT, and HDACs following exercise would help elucidating both mechanisms of post-exertional malaise and ME/CFS pathophysiology.
A randomised controlled trial has been designed including 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups. One group will undergo one session of aerobic exercise, and the other group undergoes a validated test designed to trigger mental stress and mental fatigue. All participants will undergo clinical assessments, measurements of pain thresholds, and blood withdrawal before and after the exercise/mental stress exposure. The aims are to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes, as well as the expression of these factors in blood and serum in patients with ME/CFS.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 4
- Model description
- Randomised Controlled Trial
| Arm | Type | Receives |
|---|---|---|
| ME/CFS Exercise | Experimental | Behavioral: Exercise, Other: Mental Stress TestPatients undergoing the physical stress test (aerobic power index) |
| Patients Stress | Experimental | Behavioral: Exercise, Other: Mental Stress TestPatients undergoing the mental stress task (MIST) |
| Healthy Exercise | Active comparator | Behavioral: Exercise, Other: Mental Stress TestHealthy controls undergoing the physical stress test (aerobic power index) |
| Healthy Stress | Active comparator | Behavioral: Exercise, Other: Mental Stress TestHealthy controls undergoing the mental stress task (MIST) |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Canadian Consensus Criteria (CCC);
- age between 18 and 70 years old;
- body mass index (BMI) below 30 (no obesity).
Key exclusion criteria (6 listed)
- presence of other neurological disorders (Parkinson's disease, Multiple Sclerosis, etc);
- presence of systemic disorders (lupus erythematosus, rheumatoid arthritis, etc.);
- presence or history of cardiac disorders (coronary heart disease, history of heart failure, etc);
- presence or history of cancer;
- presence or history of neuropathic pain (e.g. pain related to herpes zoster virus);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ExerciseAlso: Aerobic Power IndexSub-maximal exercise test | Behavioural | Healthy Exercise, Healthy Stress, ME/CFS Exercise, Patients Stress |
| Mental Stress TestAlso: Montreal Imaging Stress TaskComputerised mental arithmetic challenges and social evaluative threat tasks | Other | Healthy Exercise, Healthy Stress, ME/CFS Exercise, Patients Stress |
Primary outcome
DNA methylation
Time frame: Baseline through 1 week post intervention
DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology
4 secondary outcomes
Clinical Symptoms
Time frame: Baseline through 1 week post intervention
Pain sensitivity
Time frame: Baseline through 1 week post intervention
Serum BDNF
Time frame: Baseline through 1 week post intervention
Cortisol response
Time frame: Baseline through 1 week post intervention
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2023.
- Background: PubMed 25111603de Vega WC, Vernon SD, McGowan PO. DNA methylation modifications associated with chronic fatigue syndrome. PLoS One. 2014 Aug 11;9(8):e104757. doi: 10.1371/journal.pone.0104757. eCollection 2014.
- Background: PubMed 29275786Vangeel EB, Kempke S, Bakusic J, Godderis L, Luyten P, Van Heddegem L, Compernolle V, Persoons P, Lambrechts D, Izzi B, Freson K, Claes S. Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20.
- Background: PubMed 30036399Trivedi MS, Oltra E, Sarria L, Rose N, Beljanski V, Fletcher MA, Klimas NG, Nathanson L. Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns. PLoS One. 2018 Jul 23;13(7):e0201066. doi: 10.1371/journal.pone.0201066. eCollection 2018.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jo Nijs, PhD study director
Vrije Universiteit Brussel
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exercise and Mental Stress Test in people with Fatigue Syndrome, Chronic, run by Vrije Universiteit Brussel at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
DNA methylation (time frame: Baseline through 1 week post intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04378634, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2023; AzTrials last refreshed its copy on 8 Nov 2026.