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 (REenergizeME)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (ICD-10 G93.3)
• Intervention / Treatment: Device: Placebo; Other: Intermittent hypoxia-hyperoxia treatment (IHHT)

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rikke KJ Olsen; Phone Number: +45 61262471; Email: rikke.olsen@clin.au.dk
• Study Contact Backup: Name: Mastaneh Nochi; Phone Number: +45 50559530; Email: nochi@clin.au.dk

Study Locations

• Denmark
  • Region Midt
    • Aarhus, Region Midt, Denmark, 8200
      • Aarhus University
      • Contact: Rikke KJ Olsen, PhD; Phone Number: +4561262471; Email: rikke.olsen@clin.au.dk
      • Contact: English

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intermittent hypoxia-hyperoxia treatment (IHHT); An individualized treatment is administered to patients in 4-7 intervals, within 22-40 minutes. Blood oxygen saturation (O2-Sat) rises and falls cyclically, due to fluctuating fractions of inspired oxygen (FiO2): 9-13% in the hypoxic phase and 36% in the hyperoxic restitution phase.	Other: Intermittent hypoxia-hyperoxia treatment (IHHT); 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 Comparator: Sham treatment; The placebo group will undergo 'sham treatment' with air breathing at 21% FiO2. To equate the sensation of IHHT, airbrakes will be simulated similar to the IHHT intervals in the treatment protocol.	Device: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in SF-36 Vitality Domain score from baseline to post-treatment	Change in the vitality domain of the 36-Item Short Form Health Survey (SF-36), assessing fatigue and energy-related quality of life.	Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in health-related quality of life (SF-36 domains)	Assessment of additional SF-36 quality-of-life domains.	Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up
Change in fatigue severity (Fatigue Severity Scale, FSS)	Assessment of fatigue severity and functional impact using the Fatigue Severity Scale (FSS).	Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up
Change in functional capacity (FUNCAP-27)	Assessment of functional capacity using the FUNCAP-27 questionnaire.	Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up
Change in autonomic symptoms (COMPASS-31)	Assessment of autonomic symptom burden using the Composite Autonomic Symptom Score-31 (COMPASS-31).	Baseline, post-treatment (~8-10 weeks), and 3-, 6-, and 12-month follow-up
Objective autonomic, neurophysiological, and functional performance measures	Objective assessments of autonomic function, sudomotor function, neurophysiology, tissue oxygenation, cognitive performance, and physical performance.	Baseline and post-treatment (~8-10 weeks)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Independent Research Fund Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: December 19, 2025
• First Submitted That Met QC Criteria: December 19, 2025
• First Posted (Actual): January 5, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathological Conditions, Signs and Symptoms; Fatigue Syndrome, Chronic
• Other Study ID Numbers: Sagsnr.: 2500959; 10.46540/3165-00221B (Other Grant/Funding Number: Independent Research Fund Denmark)

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