Safety and Efficacy of Hyperbaric Oxygen for ARDS in Patients With COVID-19 (COVID-19-HBO)

• ClinicalTrials.gov Identifier: NCT04327505
• Recruitment Status: Terminated
• First Posted: March 31, 2020
• Last Update Posted: January 9, 2023
• Sponsor: Karolinska Institutet
• Collaborators: Karolinska Trial Alliance; University of California, San Diego; Blekinge County Council Hospital; JK Biostatistics AB; The Swedish Research Council; University of Regensburg
• Information provided by (Responsible Party): Anders Kjellberg, MD, Karolinska Institutet

Study Description

Brief Summary:

COVID-19 may cause severe pneumonitis that require ventilatory support in some patients, the ICU mortality is as high as 62%. Hospitals do not have enough ICU beds to handle the demand and to date there is no effective cure.

We explore a treatment administered in a randomized clinical trial that could prevent ICU admission and reduce mortality.

The overall hypothesis to be evaluated is that HBO reduce mortality, increase hypoxia tolerance and prevent organ failure in patients with COVID19 pneumonitis by attenuating the inflammatory response.

Condition or disease	Intervention/treatment	Phase
SARS (Severe Acute Respiratory Syndrome); Cytokine Storm; ARDS, Human; COVID-19; Sars-CoV2; Acute Respiratory Failure	Drug: Hyperbaric oxygen	Phase 2; Phase 3

Detailed Description:

Main objective: To evaluate if HBO reduce the number of ICU admissions compared to Best practice for COVID-19

Secondary objectives:

Main secondary objectives:

To evaluate if HBO:

• reduces mortality in severe cases of COVID-19.
• reduces morbidity associated with COVID-19.
• reduce the load on ICU resources in COVID-19.
• mitigate the inflammatory reaction in COVID-19.

Other secondary objectives (in selection):

To evaluate if HBO is safe for SARS-CoV-2 positive patients and staff.

Study design: Randomized, controlled, phase II, open label, multicentre

Study population: Adult patients with SARS-CoV-2 infection, with at least two risk factor for increased mortality, likely to develop ARDS criteria and need intubation within 7 days of admission to hospital.

Number of subjects: 200 (20+180)

Investigational product: Hyperbaric oxygen (HBO) compared with best practice treatment HBO: HBO 1.6-2.4 ATA for 30-60 min, maximum 5 treatments first 7 days Control: Best practice treatment for COVID-19

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized controlled, open label, multi-centre clinical trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Controlled, Open Label, Multicentre Clinical Trial to Explore Safety and Efficacy of Hyperbaric Oxygen for Preventing ICU Admission, Morbidity and Mortality in Adult Patients With COVID-19
• Actual Study Start Date: June 3, 2020
• Actual Primary Completion Date: June 30, 2022
• Actual Study Completion Date: December 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Hyperbaric oxygen; Hyperbaric oxygen 1,6-2.4 Bar for 30-60 minutes (compression/decompression time, according to local routines) in addition to best practice	Drug: Hyperbaric oxygen; 1.6- 2.4 ATA, 30-60 min (excluding compression/recompression); Other Name: HBO
No Intervention: Control; Best practice

Outcome Measures

Primary Outcome Measures :

1. ICU admission [ Time Frame: Through study completion 30 days ]

   The proportion of subjects admitted to ICU from day 1 to day 30, based on at least one of the following criteria:

   i) Rapid progression over hours ii) Lack of improvement on high flow oxygen >40L/min or non invasive ventilation with fraction of inspired oxygen (FiO2) > 0.6 iii) Evolving Hypercapnia or increased work of breathing not responding to increased oxygen despite maximum standard of care available outside ICU iv) Hemodynamic instability or multi organ failure with maximum standard of care available outside ICU

Secondary Outcome Measures :

1. 30-day mortality [ Time Frame: Through study completion 30 days ]
   Proportion of subjects with 30-day mortality, all cause Mortality, from day 1 to day 30.
2. Time-to-intubation [ Time Frame: Through study completion 30 days ]
   Time-to-Intubation, i.e. cumulative days free of invasive mechanical ventilation, from day 1 to day 30
3. Time-to-ICU [ Time Frame: Through study completion 30 days ]
   Time-to-ICU, i.e. cumulative ICU free days, derived as the number of days from day 1 to ICU, where all ICU free subjects are censored at day 30.
4. Inflammatory response [ Time Frame: Through study completion 30 days ]

   Mean change in inflammatory response from day 1 to day 30.

   1. White cell count + differentiation
   2. Procalcitonin
   3. C-Reactive protein
   4. Cytokines (IL-6) (if available at local laboratory)
   5. Ferritin
   6. D-Dimer
   7. LDH
5. Overall survival [ Time Frame: Through study completion 30 days ]
   Overall survival (Kaplan-Meier)

Other Outcome Measures:

1. Hospital mortality [ Time Frame: Through study completion 30 days ]
   Hospital mortality of any cause, proportion of subjects, from day 1 to day 30.
2. ICU mortality [ Time Frame: From ICU admission to study completion 30 days ]
   Proportion of subjects with ICU mortality, Mortality of any cause in ICU, from day 1 to day 30.
3. Time in Invasive Ventilation [ Time Frame: From ICU admission to study completion 30 days ]
   Time-to-stop of intubation/invasive mechanical ventilation, from ICU admission to day 30.
4. NEWS [ Time Frame: Through study completion 30 days ]
   Mean daily NEWS from day 1 to day 30.
5. PaO2/FiO2 (PFI) [ Time Frame: Through study completion 30 days ]
   Mean change in PaO2/FiO2 (PFI), from day 1 to day 2, … to day 30.
6. HBO Compliance [ Time Frame: Day 1 to day 7 ]
   1. Proportion of HBO treatments given vs planned.
   2. Proportion of subjects with HBO treatment administered within 24h after enrolment.
7. Hospital discharge [ Time Frame: Through study completion 30 days ]
   Time-to-discharge from hospital
8. Oxygen dose [ Time Frame: Through study completion 30 days ]
   Mean oxygen dose per day including HBO and cumulative pulmonary oxygen toxicity expressed as Units of oxygen pulmonary toxicity dose (UPTD) and Cumulative pulmonary toxicity dose (CPTD) from day 1 to day 30.
9. HBO dose [ Time Frame: Day 1 to day 7 ]
   Median number of HBO treatments and dose of HBO given, from day 1 to day 7
10. Micro RNA [ Time Frame: Through study completion 30 days ]
    Change in expression of Micro RNA in plasma from day 1 to day 30
11. Hypoxic response [ Time Frame: Through study completion 30 days ]
    Change in gene expression and Micro RNA interactions in Peripheral Blood Mononuclear Cells (PBMC) (20 Subjects) from day 1 to day 30
12. Immunological response [ Time Frame: Through study completion 30 days ]

    Immunological response (20 subjects) from day 1 to day 30 in the following.

    1. Cytokines extended including (IL-1β, IL-2, IL-6, IL33 and TNFα)
    2. Lymphocyte profile
    3. Flowcytometry with identification of monocyte/lymphocyte subsets including but not limited to CD3+/CD4+/CD8+ and CD4+/CD8+ ratio
    4. FITMaN panel/Flow cytometry, Interleukins (IL-1β, IL-2, IL-6, IL33 and TNFα),
    5. T-reg cells (CD3+/CD4+/CD25+/CD127+)
    6. Monocyte proliferation markers, Ex vivo monocyte function
13. Multi organ dysfunction [ Time Frame: Through study completion 30 days ]
    Mean change in routine biomarkers for organ dysfunction, from day 1to day 30.
14. Viral load [ Time Frame: Through study completion 30 days ]
    Viral load, review of records from day 1 to day 30.
15. Secondary infections [ Time Frame: Through study completion 30 days ]
    Number of secondary infections, review of records, number of events and patients from day 1 to day 30.
16. Pulmonary embolism [ Time Frame: Through study completion 30 days ]
    Diagnosed PE needing treatment, review of records, number of events and patients from day 1 to day 30.
17. Pulmonary CT [ Time Frame: Through study completion 30 days ]
    Changes on Pulmonary CT, review of records from day 1 to day 30.
18. Chest X-ray [ Time Frame: Through study completion 30 days ]
    Changes on Chest X-ray, review of records from day 1 to day 30.
19. Lung ultrasound [ Time Frame: Through study completion 30 days ]
    Changes in Lung ultrasound, review of records from day 1 to day 30.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Adults, all genders
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Aged 18-90 years
2. PaO2/FiO2 (PFI) below 200 mmHg (26.7 kPa)
3. Suspected or verified SARS-CoV-2 infection

4. At least two risk factors for increased morbidity/mortality

   • Age above 50 years
   • Hypertension
   • Cardiovascular disease
   • Diabetes or pre-diabetes
   • Active or cured cancer
   • Asthma/COPD
   • Smoking
   • D-Dimer > 1.0 mg/L
   • Auto-immune disease
5. Documented informed consent according to ICH-GCP and national regulations

Exclusion Criteria:

1. ARDS/pneumonia caused by other viral infections (positive for other virus)
2. ARDS/pneumonia caused by other non-viral infections or trauma
3. Known pregnancy or positive pregnancy test in women of childbearing age
4. Patients with previous lung fibrosis more than 10%
5. CT- or Spirometry-verified severe COPD with Emphysema
6. Contraindication for HBO according to local guidelines
7. Not likely to need ICU admission < 7 days of screening (Subjective criteria that may exclude any patients that fulfil the other inclusion criteria but where the treating physician suspect a spontaneous recovery)
8. Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation
9. Prisoner (Exclusion criteria according to IRB at UCSD)

Contacts and Locations

Locations

Germany

Krankenhaus St. Joesf

Regensburg, Germany, 93053

Sweden

Blekingesjukhuset

Karlskrona, Blekinge, Sweden

Karolinska University Hospital

Stockholm, Sweden, 171 76

Sponsors and Collaborators

Karolinska Institutet

Karolinska Trial Alliance

University of California, San Diego

Blekinge County Council Hospital

JK Biostatistics AB

The Swedish Research Council

University of Regensburg

Investigators

• Principal Investigator: Anders Kjellberg, MD; Karolinska Institutet
• Study Chair: Peter Lindholm, MD, PhD; Karolinska Institutet
• Study Chair: Kenny Rodriguez-Wallberg, MD, PhD; Karolinska Institutet

More Information

Additional Information:

UHMS position statement and information on HBO for COVID-19 

Hyperbaric medicine research group, Karolinska Institutet 

COVID-19 EUBS-ECHM position statement on HBOT 

KI News-description of trial in layman language 

Publications:

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.

Oscarsson N, Muller B, Rosen A, Lodding P, Molne J, Giglio D, Hjelle KM, Vaagbo G, Hyldegaard O, Vangedal M, Salling L, Kjellberg A, Lind F, Ettala O, Arola O, Seeman-Lodding H. Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial. Lancet Oncol. 2019 Nov;20(11):1602-1614. doi: 10.1016/S1470-2045(19)30494-2. Epub 2019 Sep 16. Erratum In: Lancet Oncol. 2019 Sep 23;:

Thibodeaux K, Speyrer M, Raza A, Yaakov R, Serena TE. Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series. J Wound Care. 2020 May 1;29(Sup5a):S4-S8. doi: 10.12968/jowc.2020.29.Sup5a.S4.

Gorenstein SA, Castellano ML, Slone ES, Gillette B, Liu H, Alsamarraie C, Jacobson AM, Wall SP, Adhikari S, Swartz JL, McMullen JJS, Osorio M, Koziatek CA, Lee DC. Hyperbaric oxygen therapy for COVID-19 patients with respiratory distress: treated cases versus propensity-matched controls. Undersea Hyperb Med. 2020 Third Quarter;47(3):405-413. doi: 10.22462/01.03.2020.1.

Kjellberg A, De Maio A, Lindholm P. Can hyperbaric oxygen safely serve as an anti-inflammatory treatment for COVID-19? Med Hypotheses. 2020 Nov;144:110224. doi: 10.1016/j.mehy.2020.110224. Epub 2020 Aug 30.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kjellberg A, Douglas J, Pawlik MT, Kraus M, Oscarsson N, Zheng X, Bergman P, Franberg O, Kowalski JH, Nyren SP, Silvanius M, Skold M, Catrina SB, Rodriguez-Wallberg KA, Lindholm P. Randomised, controlled, open label, multicentre clinical trial to explore safety and efficacy of hyperbaric oxygen for preventing ICU admission, morbidity and mortality in adult patients with COVID-19. BMJ Open. 2021 Jul 5;11(7):e046738. doi: 10.1136/bmjopen-2020-046738.

• Responsible Party: Anders Kjellberg, MD, ICU Consultant/PhD student, Karolinska Institutet
• ClinicalTrials.gov Identifier: NCT04327505
• Other Study ID Numbers: COVID-19-HBO; 2020-001349-37 ( EudraCT Number ); K-1199/2020 ( Registry Identifier: Karolinska Institutet )
• First Posted: March 31, 2020
• Last Update Posted: January 9, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The full study protocol, statistical plan and consent form will be publicly available when results are published. Data will be available on patient level; data will be pseudonymized. The full dataset and statistical code will be available upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Starting after publication and for 36 months
• Access Criteria: A full description of the intended use of the data must be sent to the corresponding author for review and approval. Participant consent for data sharing is conditioned and new ethics approval may be required.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Anders Kjellberg, MD, Karolinska Institutet:

COVID-19; Hyperbaric oxygen; ARDS; SARS-CoV-2; ICU admission

Additional relevant MeSH terms:

COVID-19; Severe Acute Respiratory Syndrome; Respiratory Insufficiency; Respiratory Distress Syndrome; Cytokine Release Syndrome; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Shock