{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:30:06Z","timestamp":1786714206689,"version":"build-2736575974"},"reference-count":107,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"unspecified","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R359-2020-2620"],"award-info":[{"award-number":["R359-2020-2620"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Independent Research Fund Denmark","award":["3165-00221B"],"award-info":[{"award-number":["3165-00221B"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,7,24]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This randomised, placebo-controlled, participant- and assessor-blinded clinical trial will enrol 104 female patients aged 20\u201359 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\u2009weeks. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The trial is conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation \u2013 Good Clinical Practice guidelines and was approved by the Danish Scientific Ethical Committees (De Videnskabsetiske Medicinske Komit\u00e9er, VMK; approval no. 2500959). Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publications and scientific conferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov Identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial results\" xlink:href=\"NCT07317401\">NCT07317401<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2026-117729","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:40:21Z","timestamp":1786711221000},"page":"e117729","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["REenergizeME: intermittent hypoxia\u2013hyperoxia treatment for myalgic encephalomyelitis\/chronic fatigue syndrome\u2014protocol for a randomised, placebo-controlled trial"],"prefix":"10.1136","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct07317401","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct07317401","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-1666","authenticated-orcid":false,"given":"Mastaneh","family":"Nochi","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Central Denmark Region, Denmark"},{"name":"Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie Kjerstein","family":"Kristensen","sequence":"additional","affiliation":[{"name":"SANA Medical Systems ApS, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niloufar","family":"Mehrani","sequence":"additional","affiliation":[{"name":"Remedical.Me ApS, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Marie Dahl","family":"N\u00f8rholm","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9096-7491","authenticated-orcid":false,"given":"Shreyas","family":"Chandra","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Central Denmark Region, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Olufsen","sequence":"additional","affiliation":[{"name":"Department of Mathematics, North Carolina State University at Raleigh, Raleigh, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise Rindel","family":"Gudbergsen","sequence":"additional","affiliation":[{"name":"Remedical.Me ApS, Copenhagen, Capital Region of Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise Schouborg","family":"Brinth","sequence":"additional","affiliation":[{"name":"Department of Imaging and Radiology, 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