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

Primary Purpose

SARS (Severe Acute Respiratory Syndrome), Cytokine Storm, ARDS, Human

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Hyperbaric oxygen
Sponsored by
Karolinska Institutet
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for SARS (Severe Acute Respiratory Syndrome) focused on measuring COVID-19, Hyperbaric oxygen, ARDS, SARS-CoV-2, ICU admission

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Krankenhaus St. Joesf
  • Blekingesjukhuset
  • Karolinska University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Hyperbaric oxygen

Control

Arm Description

Hyperbaric oxygen 1,6-2.4 Bar for 30-60 minutes (compression/decompression time, according to local routines) in addition to best practice

Best practice

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

30-day mortality
Proportion of subjects with 30-day mortality, all cause Mortality, from day 1 to day 30.
Time-to-intubation
Time-to-Intubation, i.e. cumulative days free of invasive mechanical ventilation, from day 1 to day 30
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.
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
Overall survival
Overall survival (Kaplan-Meier)

Full Information

First Posted
March 25, 2020
Last Updated
January 5, 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
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1. Study Identification

Unique Protocol Identification Number
NCT04327505
Brief Title
Safety and Efficacy of Hyperbaric Oxygen for ARDS in Patients With COVID-19
Acronym
COVID-19-HBO
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Terminated
Why Stopped
Futility, change of disease due to virus mutations and/or vaccination
Study Start Date
June 3, 2020 (Actual)
Primary Completion Date
June 30, 2022 (Actual)
Study Completion Date
December 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the 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

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SARS (Severe Acute Respiratory Syndrome), Cytokine Storm, ARDS, Human, COVID-19, Sars-CoV2, Acute Respiratory Failure
Keywords
COVID-19, Hyperbaric oxygen, ARDS, SARS-CoV-2, ICU admission

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Randomized controlled, open label, multi-centre clinical trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
34 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hyperbaric oxygen
Arm Type
Experimental
Arm Description
Hyperbaric oxygen 1,6-2.4 Bar for 30-60 minutes (compression/decompression time, according to local routines) in addition to best practice
Arm Title
Control
Arm Type
No Intervention
Arm Description
Best practice
Intervention Type
Drug
Intervention Name(s)
Hyperbaric oxygen
Other Intervention Name(s)
HBO
Intervention Description
1.6- 2.4 ATA, 30-60 min (excluding compression/recompression)
Primary Outcome Measure Information:
Title
ICU admission
Description
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
Time Frame
Through study completion 30 days
Secondary Outcome Measure Information:
Title
30-day mortality
Description
Proportion of subjects with 30-day mortality, all cause Mortality, from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Time-to-intubation
Description
Time-to-Intubation, i.e. cumulative days free of invasive mechanical ventilation, from day 1 to day 30
Time Frame
Through study completion 30 days
Title
Time-to-ICU
Description
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.
Time Frame
Through study completion 30 days
Title
Inflammatory response
Description
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
Time Frame
Through study completion 30 days
Title
Overall survival
Description
Overall survival (Kaplan-Meier)
Time Frame
Through study completion 30 days
Other Pre-specified Outcome Measures:
Title
Hospital mortality
Description
Hospital mortality of any cause, proportion of subjects, from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
ICU mortality
Description
Proportion of subjects with ICU mortality, Mortality of any cause in ICU, from day 1 to day 30.
Time Frame
From ICU admission to study completion 30 days
Title
Time in Invasive Ventilation
Description
Time-to-stop of intubation/invasive mechanical ventilation, from ICU admission to day 30.
Time Frame
From ICU admission to study completion 30 days
Title
NEWS
Description
Mean daily NEWS from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
PaO2/FiO2 (PFI)
Description
Mean change in PaO2/FiO2 (PFI), from day 1 to day 2, … to day 30.
Time Frame
Through study completion 30 days
Title
HBO Compliance
Description
Proportion of HBO treatments given vs planned. Proportion of subjects with HBO treatment administered within 24h after enrolment.
Time Frame
Day 1 to day 7
Title
Hospital discharge
Description
Time-to-discharge from hospital
Time Frame
Through study completion 30 days
Title
Oxygen dose
Description
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.
Time Frame
Through study completion 30 days
Title
HBO dose
Description
Median number of HBO treatments and dose of HBO given, from day 1 to day 7
Time Frame
Day 1 to day 7
Title
Micro RNA
Description
Change in expression of Micro RNA in plasma from day 1 to day 30
Time Frame
Through study completion 30 days
Title
Hypoxic response
Description
Change in gene expression and Micro RNA interactions in Peripheral Blood Mononuclear Cells (PBMC) (20 Subjects) from day 1 to day 30
Time Frame
Through study completion 30 days
Title
Immunological response
Description
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
Time Frame
Through study completion 30 days
Title
Multi organ dysfunction
Description
Mean change in routine biomarkers for organ dysfunction, from day 1to day 30.
Time Frame
Through study completion 30 days
Title
Viral load
Description
Viral load, review of records from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Secondary infections
Description
Number of secondary infections, review of records, number of events and patients from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Pulmonary embolism
Description
Diagnosed PE needing treatment, review of records, number of events and patients from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Pulmonary CT
Description
Changes on Pulmonary CT, review of records from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Chest X-ray
Description
Changes on Chest X-ray, review of records from day 1 to day 30.
Time Frame
Through study completion 30 days
Title
Lung ultrasound
Description
Changes in Lung ultrasound, review of records from day 1 to day 30.
Time Frame
Through study completion 30 days

10. Eligibility

Sex
All
Gender Based
Yes
Gender Eligibility Description
Adults, all genders
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Aged 18-90 years PaO2/FiO2 (PFI) below 200 mmHg (26.7 kPa) Suspected or verified SARS-CoV-2 infection 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 Documented informed consent according to ICH-GCP and national regulations Exclusion Criteria: ARDS/pneumonia caused by other viral infections (positive for other virus) ARDS/pneumonia caused by other non-viral infections or trauma Known pregnancy or positive pregnancy test in women of childbearing age Patients with previous lung fibrosis more than 10% CT- or Spirometry-verified severe COPD with Emphysema Contraindication for HBO according to local guidelines 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) Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation Prisoner (Exclusion criteria according to IRB at UCSD)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anders Kjellberg, MD
Organizational Affiliation
Karolinska Institutet
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Peter Lindholm, MD, PhD
Organizational Affiliation
Karolinska Institutet
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Kenny Rodriguez-Wallberg, MD, PhD
Organizational Affiliation
Karolinska Institutet
Official's Role
Study Chair
Facility Information:
Facility Name
Krankenhaus St. Joesf
City
Regensburg
ZIP/Postal Code
93053
Country
Germany
Facility Name
Blekingesjukhuset
City
Karlskrona
State/Province
Blekinge
Country
Sweden
Facility Name
Karolinska University Hospital
City
Stockholm
ZIP/Postal Code
171 76
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
32171076
Citation
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.
Results Reference
background
PubMed Identifier
31537473
Citation
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;:
Results Reference
background
PubMed Identifier
32412891
Citation
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.
Results Reference
background
PubMed Identifier
32931666
Citation
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.
Results Reference
background
PubMed Identifier
33254531
Citation
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.
Results Reference
background
PubMed Identifier
34226219
Citation
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.
Results Reference
derived
Links:
URL
https://ki.se/en/fyfa/hyperbaric-medicine
Description
Hyperbaric medicine research group, Karolinska Institutet
URL
http://www.eubs.org/?p=1074
Description
COVID-19 EUBS-ECHM position statement on HBOT
URL
https://news.ki.se/ki-researchers-to-evaluate-effect-of-hyperbaric-oxygen-treatment-against-covid-19
Description
KI News-description of trial in layman language

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

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