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

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ClinicalTrials.gov Identifier: NCT04378634
Recruitment Status : Not yet recruiting
First Posted : May 7, 2020
Last Update Posted : May 7, 2020
Sponsor:
Information provided by (Responsible Party):
Andrea Polli, Vrije Universiteit Brussel

Brief 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.

The investigators designed a randomised controlled trial with cross-over design and will enrol 80 patients with ME/CFS and 25 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 first. Then the two groups will cross over after a week wash period. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.


Condition or disease Intervention/treatment Phase
Fatigue Syndrome, Chronic Behavioral: Exercise Other: Mental Stress Test Not Applicable

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 with cross-over has been designed including 80 patients with ME/CFS and 25 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomised Cross-Over Trial
Masking: Single (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Estimated Study Start Date : October 1, 2020
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ME/CFS Exercise
Patients undergoing exercise first and the mental stress task after wash-out
Behavioral: Exercise
Sub-maximal exercise test
Other Name: Aerobic Power Index

Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Name: Montreal Imaging Stress Task

Experimental: Patients Stress
Patients undergoing the mental stress task first and exercise after wash-out
Behavioral: Exercise
Sub-maximal exercise test
Other Name: Aerobic Power Index

Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Name: Montreal Imaging Stress Task

Active Comparator: Healthy Exercise
Healthy controls undergoing exercise first and the mental stress task after wash-out
Behavioral: Exercise
Sub-maximal exercise test
Other Name: Aerobic Power Index

Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Name: Montreal Imaging Stress Task

Active Comparator: Healthy Stress
Healthy controls undergoing the mental stress task first and exercise after wash-out
Behavioral: Exercise
Sub-maximal exercise test
Other Name: Aerobic Power Index

Other: Mental Stress Test
Computerised mental arithmetic challenges and social evaluative threat tasks
Other Name: Montreal Imaging Stress Task




Primary Outcome Measures :
  1. DNA methylation [ Time Frame: Baseline through 1 week post intervention ]
    DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology


Secondary Outcome Measures :
  1. Clinical Symptoms [ Time Frame: Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week ]
    Symptoms reported by the patients using the DePaul Symptoms Questionniare

  2. Pain sensitivity [ Time Frame: Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week ]
    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.

  3. Serum BDNF [ Time Frame: Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week ]
    BDNF protein expression in serum using Enzyme-Linked Immunosorbent Assay (ELISA) kit for human BDNF

  4. Salivary Cortisol [ Time Frame: Baseline (pre-intervention), immediately post-intervention, at 24-hours, at 1-week ]
    Cortisol levels will be measured in saliva and used as a measure of stress responses using LC/MS-MS method.


Other Outcome Measures:
  1. 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.

  2. Gene's polymorphisms [ Time Frame: Baseline ]
    Genes' polymorphisms might mediate epigenetic changes. They will be assessed using pyrosequencing technology.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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 Centre for Disease Control and Prevention (CDC);
  • 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;

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): NCT04378634


Contacts
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Contact: Andrea Polli, MSc +32(0)24774420 andrea.polli@vub.be

Sponsors and Collaborators
Vrije Universiteit Brussel
Investigators
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Study Director: Jo Nijs, PhD Vrije Universiteit Brussel
Publications:
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Responsible Party: Andrea Polli, PhD researcher, principal investigator, Vrije Universiteit Brussel
ClinicalTrials.gov Identifier: NCT04378634    
Other Study ID Numbers: EPIME
First Posted: May 7, 2020    Key Record Dates
Last Update Posted: May 7, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andrea Polli, Vrije Universiteit Brussel:
Chronic Fatigue Syndrome
Exercise
Epigenetics
DNA methylation
Additional relevant MeSH terms:
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Fatigue Syndrome, Chronic
Syndrome
Fatigue
Disease
Pathologic Processes
Virus Diseases
Muscular Diseases
Musculoskeletal Diseases
Encephalomyelitis
Central Nervous System Diseases
Nervous System Diseases
Neuromuscular Diseases