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NCT Number: NCT07317401

Investigating the Effects of Intermittent Hypoxia-Hyperoxia Treatment (IHHT) in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) to Improve Fatigue, Pain, and Quality of Life by Targeting Mitochondrial Dysfunction and Autonomic Nervous System Impairment

This study is testing a new treatment for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long-term symptoms after COVID-19. Both conditions cause extreme fatigue, muscle pain, "brain fog," and trouble concentrating, which often get worse after physical or mental activity. Currently, no effective treatments are available.

The treatment being studied is called Intermittent Hypoxia-Hyperoxia Treatment (IHHT). It uses a machine called HypoxBreath to deliver short cycles of low oxygen (hypoxia) and high oxygen (hyperoxia) through a mask. Each session lasts 22-40 minutes and is carefully monitored to track oxygen levels, heart rate, and breathing. The therapy is customized for each patient to ensure comfort and effectiveness. IHHT is believed to help the body adapt to oxygen-related stress, improving energy production and reducing inflammation.

In this trial, 104 patients with ME/CFS will be randomly assigned to receive either IHHT or a placebo treatment with normal oxygen levels over eight weeks. The placebo group will follow a similar procedure without oxygen changes. An additional 20 healthy individuals will be recruited as a comparison group, but they will not undergo the treatment.

Participants will have medical check-ups before and after treatment to evaluate changes in fatigue, mental sharpness, pain, autonomic nervous system function, and overall quality of life. Blood samples and small skin biopsies will also be taken to study the biological processes behind ME/CFS and how the treatment works.

This research aims to find out if IHHT can improve the lives of people with ME/CFS or long-term COVID symptoms. The results could also provide new insights into the causes of these challenging conditions and guide future treatments.

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Key information

Conditions

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (ICD-10 G93.3) Chronic Disease Disease Attributes Encephalomyelitis Fatigue Syndrome, Chronic Muscular Diseases Musculoskeletal Diseases Nervous System Diseases Neuroinflammatory Diseases Neuromuscular Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

20 year–59 year

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

Aarhus University

Aarhus, Region Midt, 8200, Denmark

Location contact

English

CONTACT

Rikke KJ Olsen, PhD

CONTACT

[email protected]

+4561262471

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

ME/CFS Patients

Inclusion criteria

  • Female sex
  • Age 20-59 years
  • Established diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) according to the International Consensus Criteria (ICC)
  • Disease duration >6 months
  • Presence of post-exertional malaise (PEM)
  • Mild or moderate disease severity according to NICE guidelines
  • Body mass index (BMI) >18 and <30 kg/m²
  • Ability and willingness to attend study visits and complete the intervention protocol
  • Provision of written informed consent
  • Willingness to comply with all study procedures and restrictions throughout the study period
  • Use of highly effective contraception during study participation for women of childbearing potential

Exclusion criteria

  • Severe ME/CFS according to NICE guidelines
  • Participation in another clinical trial that may interfere with the present study
  • Pregnancy, planned pregnancy, or breastfeeding
  • Presence of clinically significant psychiatric disease not considered part of ME/CFS and likely to interfere with study participation or interpretation of results
  • Presence of clinically significant neurological disease, peripheral nerve disorder, or other neurological dysfunction not considered part of ME/CFS
  • Active internal disease or clinically significant cardiovascular, pulmonary, metabolic, renal, hepatic, endocrine, or systemic disease that may interfere with study participation or interpretation of outcomes
  • Obstructive lung disease
  • Claustrophobia
  • History of spontaneous pneumothorax
  • Presence of implanted medical devices, prostheses, or other conditions considered incompatible with IHHT
  • Chronic pain conditions not considered part of ME/CFS and likely to interfere with assessments
  • Current structured graded exercise therapy (GET) or structured exercise programme
  • Significant alcohol, tobacco, or cannabis use considered likely to interfere with study participation or interpretation of outcomes
  • Inability to comply with study procedures or communicate meaningfully with study personnel
  • Any condition which, in the opinion of the investigator, may compromise participant safety or study integrity

Healthy Controls

Inclusion criteria

  • Female sex
  • Age 20-59 years
  • Body mass index (BMI) >18 and <30 kg/m²
  • Ability and willingness to attend study visits
  • Provision of written informed consent
  • Good general health without clinically significant chronic medical, neurological, psychiatric, or pain conditions
  • Activity level and BMI broadly matched to ME/CFS participants
  • Willingness to comply with all study procedures and restrictions throughout the study period
  • Use of highly effective contraception during study participation for women of childbearing potential

Exclusion criteria

  • Current or previous diagnosis of ME/CFS
  • Participation in another clinical trial that may interfere with the present study
  • Pregnancy, planned pregnancy, or breastfeeding
  • Presence of clinically significant psychiatric, neurological, cardiovascular, pulmonary, metabolic, renal, hepatic, endocrine, or systemic disease
  • Chronic pain conditions, migraine disorder, or recurrent headache/back pain likely to interfere with study assessments
  • Obstructive lung disease
  • Claustrophobia
  • History of spontaneous pneumothorax
  • Presence of implanted medical devices, prostheses, or other conditions considered incompatible with study procedures
  • Current structured exercise programme or recent major change in exercise habits
  • Significant alcohol, tobacco, or cannabis use considered likely to interfere with study participation or interpretation of outcomes
  • Inability to comply with study procedures or communicate meaningfully with study personnel
  • Any condition which, in the opinion of the investigator, may compromise participant safety or study integrity

Treatment and study plan

Intermittent hypoxia-hyperoxia treatment (IHHT)

Other

The apparatus used to deliver the IHHT is the HypoxBreath machine (TUR GmbH, Rostock, Germany, CE Medical device class IIa). The HypoxBreath machine is constructed with a built-in compressor, an air reservoir, and a set of membranes, making it possible for the machine to either add or remove oxygen from the atmospheric air, thus delivering a dynamic FiO2 (fraction of inspired oxygen). The individualized therapy settings are regulated via the attached user interface. It is connected to a desk monitor and a data-collecting server.

PLACEBO

Device

The placebo group will undergo 'sham treatment' with air breathing at 21% FiO2. To equate the sensation of oxygen therapy, airbrakes will be simulated similar to the oxygen therapy intervals in the treatment protocol.

Primary outcomes

  1. Change in SF-36 Vitality Domain score from baseline to post-treatment

    Time frame: Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

    Change in the vitality domain of the 36-Item Short Form Health Survey (SF-36), assessing fatigue and energy-related quality of life.

Secondary outcomes

  1. Change in health-related quality of life (SF-36 domains)

    Time frame: Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

    Assessment of additional SF-36 quality-of-life domains.

  2. Change in fatigue severity (Fatigue Severity Scale, FSS)

    Time frame: Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

    Assessment of fatigue severity and functional impact using the Fatigue Severity Scale (FSS).

  3. Change in functional capacity (FUNCAP-27)

    Time frame: Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

    Assessment of functional capacity using the FUNCAP-27 questionnaire.

  4. Change in autonomic symptoms (COMPASS-31)

    Time frame: Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

    Assessment of autonomic symptom burden using the Composite Autonomic Symptom Score-31 (COMPASS-31).

  5. Objective autonomic, neurophysiological, and functional performance measures

    Time frame: Baseline and post-treatment (~8-10 weeks)

    Objective assessments of autonomic function, sudomotor function, neurophysiology, tissue oxygenation, cognitive performance, and physical performance.

Study contacts

Contact information is provided by the study sponsor or research team.

Mastaneh Nochi

CONTACT

[email protected]

+45 50559530

Rikke KJ Olsen

CONTACT

[email protected]

+45 61262471

Sponsors and collaborators

Lead sponsor

University of Aarhus

Other

Collaborators

  • Independent Research Fund Denmark

Registry information

Official study title

REenergizeME: Oxygen Therapy (OT) as a Novel Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Acronym: REenergizeME

Important dates

Study start
2026
Primary completion
2027
Study completion
2029
First posted
Jan 5, 2026
Registry last updated
May 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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