REenergizeME: intermittent hypoxia-hyperoxia treatment for myalgic encephalomyelitis/chronic fatigue syndrome-protocol for a randomised, placebo-controlled trial.

INTRODUCTION

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling condition characterised by post-exertional malaise (PEM), autonomic dysfunction and markedly reduced quality of life. Its prevalence has increased following the COVID-19 pandemic, yet no effective disease-modifying treatments are available and underlying mechanisms remain unclear. Evidence implicates immune-metabolic dysregulation, impaired energy metabolism, vascular dysfunction and altered oxygen handling. Intermittent hypoxia-hyperoxia treatment (IHHT) is a non-pharmacological intervention proposed to induce adaptive physiological and cellular responses via hypoxia- and redox-sensitive pathways. This trial evaluates the clinical efficacy of IHHT in ME/CFS and explores associated mechanisms.

METHODS AND ANALYSIS: This randomised, placebo-controlled, participant- and assessor-blinded clinical trial will enrol 104 female patients aged 20-59 years who meet the International Consensus Criteria for ME/CFS along with a healthy control group for mechanistic comparisons. Participants will be randomised 1:1 to IHHT or placebo following baseline assessments. The intervention will be delivered over 8 weeks. The primary endpoint is change in quality of life measured by the vitality domain of the Short Form-36 Health Survey. Secondary endpoints include PEM severity, fatigue severity, cognitive severity, functional capacity and autonomic symptoms assessed using validated patient-reported outcome measures and objective tests. Exploratory endpoints include pain phenotyping, autonomic, sudomotor and neurophysiological assessments, tissue oxygenation by near-infrared spectroscopy, peripheral small-fibre nerve assessments using corneal confocal microscopy and skin biopsy and immune-metabolic and oxidative stress biomarkers. Assessments will be conducted at baseline; post-treatment; and at 3, 6 and 12 months follow-up.

ETHICS AND DISSEMINATION: The trial is conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation - Good Clinical Practice guidelines and was approved by the Danish Scientific Ethical Committees (De Videnskabsetiske Medicinske Komitéer, VMK; approval no. 2500959). Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publications and scientific conferences.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT07317401.