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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2020-001349-37
    Trial protocol
    		 SE   DE  
    Global end of trial date
    07 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2024
    First version publication date
    12 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COVID-19-HBO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04327505
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Karolinska Institutet: K-1199/2020, Karolinska University Hospital: K-2020/2611
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Solna, Sweden, 17177
    Public contact
    Anders Kjellberg, Karolinska Institutet, +46 760657355, anders.kjellberg@ki.se
    Scientific contact
    Anders Kjellberg, Karolinska Institutet, +46 760657355, anders.kjellberg@ki.se
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate if HBO reduce the number of ICU admissions compared to Best practice for COVID-19
    Protection of trial subjects
    The trial was approved by the Swedish Ethical Review Authority (2020-01705) and the Swedish Medical Products Agency (5.1-2020-36673) and conducted in accordance with the declaration of Helsinki and ICH-GCP. Participants provided written informed consent before enrollment. The trial was monitored by KTA, an independent organisation before the trial started, during the trial conduct and after the trial was completed, to ensure that the trial was carried out according to the protocol and that data were collected, documented and reported according to ICH-GCP and applicable ethical and regulatory requirements. Monitoring was performed as per the trial’s monitoring plan and to ensure that the subject’s rights, safety and well-being were met as well as data in the eCRF are complete, correct and consistent with the source data. The monitoring was performed by an independent experienced monitor qualified in ICH-GCP, applicable national and international regulations and the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    16
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between June 4, 2020, and Dec 1, 2021, 79 patients were assessed for eligibility, 34 subjects were randomly assigned to Hyperbaric Oxygen Therapy (HBOT, N=18) or best practise (BP, N=16). The trial was prematurely terminated for futility.

    Pre-assignment
    Screening details
    		 Patients 18–90 years, hospitalised for severe COVID–19 with moderate to severe ARDS, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) below 200 mmHg (26·7 kPa), based on arterial blood gas measurement with at least 2 risk factors for increased risk of ICU admission/mortality, likely to need intubation.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hyperbaric oxygen
    Arm description
    		 The HBOT group received in addition to best practice: HBOT with medical oxygen 100%, 2·4 ATA for 80–90 min, with two five–min air–breaks, once a day, maximum five treatments within seven days from randomisation in addition to best practice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Conoxia 100%, Medicinal gas, cryogenic
    Investigational medicinal product code
    SUB14733MIG
    Other name
    Pharmaceutical forms
    Medicinal gas, cryogenic
    Routes of administration
    Inhalation use
    Dosage and administration details
    The HBOT group received in addition to best practice: HBOT with medical oxygen 100%, 2·4 ATA for 80–90 min, with two five–min air–breaks, once a day, maximum five treatments within seven days from randomisation in addition to best practice.

    Arm title
    		 Best practice
    Arm description
    		 Recieved best practice treatment for COVID–19, including normobaric medical oxygen 100% administrated as needed, low dose steroids, low molecular weight heparin.
    Arm type
    		 Best practice

    Investigational medicinal product name
    Conoxia 100%, Medicinal gas, compressed
    Investigational medicinal product code
    SUB14733MIG
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Received best practice treatment for COVID–19, including normobaric medical oxygen 100% administrated as needed.

    Number of subjects in period 1
    		Hyperbaric oxygen Best practice
    Started
    18
    16
    Completed
    12
    15
    Not completed
    6
    1
         Adverse event, serious fatal
    4
    -
         Consent withdrawn by subject
    2
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 34 34
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.4 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 19 19
    Concomitant medications: Dexamethasone/Betamethasone
    Units: Subjects
        Yes
    		 32 32
        No
    		 2 2
    Concomitant medication: LMWH
    Units: Subjects
        Yes
    		 33 33
        No
    		 1 1
    Concomitant medication: Remdesivir
    Units: Subjects
        Yes
    		 11 11
        No
    		 23 23
    Concomitant medication: Rituximab
    Units: Subjects
        Yes
    		 1 1
        No
    		 33 33
    Concomitant medication: Tocilizumab
    Units: Subjects
        Yes
    		 3 3
        No
    		 31 31
    Concomitant medication: Casirivimab/Imdevimab
    Units: Subjects
        Yes
    		 1 1
        No
    		 33 33
    Concomitant medication: Methotrexate
    Units: Subjects
        Yes
    		 1 1
        No
    		 33 33

    End points

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    End points reporting groups
    Reporting group title
    Hyperbaric oxygen
    Reporting group description
    		 The HBOT group received in addition to best practice: HBOT with medical oxygen 100%, 2·4 ATA for 80–90 min, with two five–min air–breaks, once a day, maximum five treatments within seven days from randomisation in addition to best practice.

    Reporting group title
    Best practice
    Reporting group description
    		 Recieved best practice treatment for COVID–19, including normobaric medical oxygen 100% administrated as needed, low dose steroids, low molecular weight heparin.

    Primary: ICU Admission

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    End point title
    		 ICU Admission
    End point description
    End point type
    Primary
    End point timeframe
    Until EOT, 30 days.
    End point values
    		 Hyperbaric oxygen Best practice
    Number of subjects analysed
    18
    15
    Units: Percent
        ICU Addmission: Yes
    13
    5
        ICU Admission: No
    5
    10
    Statistical analysis title
    		 Proportion of subjects selected for ICU
    Comparison groups
    Hyperbaric oxygen v Best practice
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 10.39
    Notes
    [1] - Primary endpoint evaluated at the type I error rate of 0.05 using a two-sided test. There was no adjustment for multiplicity as there were only one primary endpoint and secondary endpoints are to be interpreted as exploratory. Corrected for gender.

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    30–day mortality, all–cause
    End point type
    Secondary
    End point timeframe
    Until EOT, 30 days
    End point values
    		 Hyperbaric oxygen Best practice
    Number of subjects analysed
    18
    15
    Units: Subjects deceased
    4
    1
    Statistical analysis title
    		 Mortality, time to event
    Comparison groups
    Hyperbaric oxygen v Best practice
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Logrank
    Confidence interval

    Secondary: Time–to–Intubation

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    End point title
    		 Time–to–Intubation
    End point description
    End point type
    Secondary
    End point timeframe
    Until EOT, 30 days
    End point values
    		 Hyperbaric oxygen Best practice
    Number of subjects analysed
    18
    15
    Units: Days
        arithmetic mean (confidence interval 95%)
    25.3 (19.7 to 30.9)
    24.5 (19.8 to 29.3)
    Statistical analysis title
    		 Time–to–Intubation difference
    Comparison groups
    Hyperbaric oxygen v Best practice
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Logrank
    Confidence interval

    Secondary: Time–to–ICU

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    End point title
    		 Time–to–ICU
    End point description
    End point type
    Secondary
    End point timeframe
    Until EOT, 30 days
    End point values
    		 Hyperbaric oxygen Best practice
    Number of subjects analysed
    18
    15
    Units: Cumulative ICU free days
        number (not applicable)
    1
    14
    Statistical analysis title
    		 Difference in cumulative ICU free days
    Comparison groups
    Hyperbaric oxygen v Best practice
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Median time 14.0 for Best Practice vs 1.0 for HBOT.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until EOT, 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    All study subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All study subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 34 (47.06%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Endotracheal intubation
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    8 / 34 (23.53%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    Pneumothorax
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All study subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 34 (82.35%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Hypotension
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Thrombophlebitis
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    4
    Bradycardia
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Shivering
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    12 / 34 (35.29%)
         occurrences all number
    15
    Pneumomediastinum
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Claustrophobia
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Bacteraemia
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Cystitis
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Malnutrition
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2020
    V3, Change of sites
    27 Feb 2021
    V4, Change of limits for safety endpoints and reporting (Safety was re-assessed after Safety interim analysis)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39059726
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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