Epigenetics of Post-exertional Malaise in Patients With ME/CFS (EPIME)

November 4, 2023 updated by: Andrea Polli, Vrije Universiteit Brussel

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

105

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Belgium
      • Brussels, Belgium, 1090
        • UZ Brussel

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • 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).

Exclusion Criteria:

  • 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;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ME/CFS Exercise
Patients undergoing the physical stress test (aerobic power index)
Behavioral: Exercise
Sub-maximal exercise test
Other Names:
  • Aerobic Power Index
Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Names:
  • Montreal Imaging Stress Task
Experimental: Patients Stress
Patients undergoing the mental stress task (MIST)
Behavioral: Exercise
Sub-maximal exercise test
Other Names:
  • Aerobic Power Index
Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Names:
  • Montreal Imaging Stress Task
Active Comparator: Healthy Exercise
Healthy controls undergoing the physical stress test (aerobic power index)
Behavioral: Exercise
Sub-maximal exercise test
Other Names:
  • Aerobic Power Index
Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Names:
  • Montreal Imaging Stress Task
Active Comparator: Healthy Stress
Healthy controls undergoing the mental stress task (MIST)
Behavioral: Exercise
Sub-maximal exercise test
Other Names:
  • Aerobic Power Index
Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Names:
  • Montreal Imaging Stress Task

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DNA methylation
Time Frame: Baseline through 1 week post intervention
DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology
Baseline through 1 week post intervention

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Symptoms
Time Frame: Baseline through 1 week post intervention
Symptoms reported by the patients using the DePaul Symptoms Questionniare
Baseline through 1 week post intervention
Pain sensitivity
Time Frame: Baseline through 1 week post intervention
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.
Baseline through 1 week post intervention
Serum BDNF
Time Frame: Baseline through 1 week post intervention
BDNF protein expression in serum using Enzyme-Linked Immunosorbent Assay (ELISA) kit for human BDNF
Baseline through 1 week post intervention
Cortisol response
Time Frame: Baseline through 1 week post intervention
Cortisol will be measured in saliva and used as a measure of stress responses using LC/MS-MS method.
Baseline through 1 week post intervention

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
General Health
Time Frame: Baseline
General health will be measured using the Short Form-36 Health Survey (SF-36) questionnaire. The questionnaire returns a score from 0 to 100 where higher scores mean less disability.
Baseline
Gene's polymorphisms
Time Frame: Baseline
Genes' polymorphisms might mediate epigenetic changes. They will be assessed using pyrosequencing technology.
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vrije Universiteit Brussel

Investigators

  • Study Director: Jo Nijs, PhD, Vrije Universiteit Brussel

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2021

Primary Completion (Actual)

April 30, 2023

Study Completion (Actual)

April 30, 2023

Study Registration Dates

First Submitted

April 27, 2020

First Submitted That Met QC Criteria

May 5, 2020

First Posted (Actual)

May 7, 2020

Study Record Updates

Last Update Posted (Actual)

November 7, 2023

Last Update Submitted That Met QC Criteria

November 4, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EPIME

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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