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

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

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.

Study Overview

• Status: Terminated
• Conditions: COVID-19; Cytokine Storm; SARS (Severe Acute Respiratory Syndrome); Acute Respiratory Failure; ARDS, Human; Sars-CoV2
• Intervention / Treatment: Drug: Hyperbaric oxygen

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 Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Anders Kjellberg, MD; Phone Number: +46812375212; Email: anders.kjellberg@ki.se
• Study Contact Backup: Name: Peter Lindholm, MD, PhD; Phone Number: +16508230735; Email: plindholm@health.ucsd.edu

Study Locations

• Germany
  • Regensburg, Germany, 93053
    • Krankenhaus St. Joesf
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska University Hospital
  • Blekinge
    • Karlskrona, Blekinge, Sweden
      • Blekingesjukhuset

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: HBO
No Intervention: Control; Best practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU admission	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	Through study completion 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day mortality	Proportion of subjects with 30-day mortality, all cause Mortality, from day 1 to day 30.	Through study completion 30 days
Time-to-intubation	Time-to-Intubation, i.e. cumulative days free of invasive mechanical ventilation, from day 1 to day 30	Through study completion 30 days
Time-to-ICU	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.	Through study completion 30 days
Inflammatory response	Mean change in inflammatory response from day 1 to day 30.; White cell count + differentiation; Procalcitonin; C-Reactive protein; Cytokines (IL-6) (if available at local laboratory); Ferritin; D-Dimer; LDH	Through study completion 30 days
Overall survival	Overall survival (Kaplan-Meier)	Through study completion 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital mortality	Hospital mortality of any cause, proportion of subjects, from day 1 to day 30.	Through study completion 30 days
ICU mortality	Proportion of subjects with ICU mortality, Mortality of any cause in ICU, from day 1 to day 30.	From ICU admission to study completion 30 days
Time in Invasive Ventilation	Time-to-stop of intubation/invasive mechanical ventilation, from ICU admission to day 30.	From ICU admission to study completion 30 days
NEWS	Mean daily NEWS from day 1 to day 30.	Through study completion 30 days
PaO2/FiO2 (PFI)	Mean change in PaO2/FiO2 (PFI), from day 1 to day 2, … to day 30.	Through study completion 30 days
HBO Compliance	Proportion of HBO treatments given vs planned.; Proportion of subjects with HBO treatment administered within 24h after enrolment.	Day 1 to day 7
Hospital discharge	Time-to-discharge from hospital	Through study completion 30 days
Oxygen dose	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.	Through study completion 30 days
HBO dose	Median number of HBO treatments and dose of HBO given, from day 1 to day 7	Day 1 to day 7
Micro RNA	Change in expression of Micro RNA in plasma from day 1 to day 30	Through study completion 30 days
Hypoxic response	Change in gene expression and Micro RNA interactions in Peripheral Blood Mononuclear Cells (PBMC) (20 Subjects) from day 1 to day 30	Through study completion 30 days
Immunological response	Immunological response (20 subjects) from day 1 to day 30 in the following.; Cytokines extended including (IL-1β, IL-2, IL-6, IL33 and TNFα); Lymphocyte profile; Flowcytometry with identification of monocyte/lymphocyte subsets including but not limited to CD3+/CD4+/CD8+ and CD4+/CD8+ ratio; FITMaN panel/Flow cytometry, Interleukins (IL-1β, IL-2, IL-6, IL33 and TNFα),; T-reg cells (CD3+/CD4+/CD25+/CD127+); Monocyte proliferation markers, Ex vivo monocyte function	Through study completion 30 days
Multi organ dysfunction	Mean change in routine biomarkers for organ dysfunction, from day 1to day 30.	Through study completion 30 days
Viral load	Viral load, review of records from day 1 to day 30.	Through study completion 30 days
Secondary infections	Number of secondary infections, review of records, number of events and patients from day 1 to day 30.	Through study completion 30 days
Pulmonary embolism	Diagnosed PE needing treatment, review of records, number of events and patients from day 1 to day 30.	Through study completion 30 days
Pulmonary CT	Changes on Pulmonary CT, review of records from day 1 to day 30.	Through study completion 30 days
Chest X-ray	Changes on Chest X-ray, review of records from day 1 to day 30.	Through study completion 30 days
Lung ultrasound	Changes in Lung ultrasound, review of records from day 1 to day 30.	Through study completion 30 days

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: University of California, San Diego; The Swedish Research Council; University of Regensburg; Blekinge County Council Hospital; Karolinska Trial Alliance; JK Biostatistics AB
• 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

Publications and helpful links

General 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.
• 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.

Helpful Links

• 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

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2020
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: March 25, 2020
• First Submitted That Met QC Criteria: March 27, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 5, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; ARDS; Hyperbaric oxygen; ICU admission
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Severe Acute Respiratory Syndrome; COVID-19; Respiratory Insufficiency; Respiratory Distress Syndrome; Cytokine Release Syndrome
• Other Study ID Numbers: COVID-19-HBO; 2020-001349-37 (EudraCT Number); K-1199/2020 (Registry Identifier: Karolinska Institutet)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing Time Frame: Starting after publication and for 36 months
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• 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