Clinical trial NCT04378634: Epigenetics of Post-exertional Malaise in Patients With ME/CFS
Official title: The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fatigue Syndrome, Chronic
Keywords: Chronic Fatigue Syndrome
Exercise
Epigenetics
DNA methylation
Lead sponsor: Vrije Universiteit Brussel
Sponsor class: OTHER
First posted: 2020-05-07
Enrollment: 105
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised Controlled Trial
Primary purpose: BASIC_SCIENCE

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 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.

Eligibility 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 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;

Primary outcomes:
measure: DNA methylation
timeFrame: Baseline through 1 week post intervention
Secondary outcomes:
measure: Clinical Symptoms
timeFrame: Baseline through 1 week post intervention
measure: Pain sensitivity
timeFrame: Baseline through 1 week post intervention
measure: Serum BDNF
timeFrame: Baseline through 1 week post intervention
measure: Cortisol response
timeFrame: Baseline through 1 week post intervention
Other outcomes:
measure: General Health
timeFrame: Baseline
measure: Gene's polymorphisms
timeFrame: Baseline
Locations:
city: Brussels
country: Belgium
facility: UZ Brussel
Study officials:
affiliation: Vrije Universiteit Brussel
name: Jo Nijs, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Vangeel 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.
citation: Trivedi 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.