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Hyperbaric Oxygen Therapy Effect in COVID-19 RCT (HBOTCOVID19) (HBOTCOVID19)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04358926
Recruitment Status : Completed
First Posted : April 24, 2020
Last Update Posted : November 3, 2020
Sponsor:
Information provided by (Responsible Party):
Assaf-Harofeh Medical Center

Tracking Information
First Submitted Date  ICMJE April 21, 2020
First Posted Date  ICMJE April 24, 2020
Last Update Posted Date November 3, 2020
Actual Study Start Date  ICMJE April 30, 2020
Actual Primary Completion Date October 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2020)
  • PaO2/FiO2 [ Time Frame: 5 days after randomization ]
    Oxygenation index of the lungs calculated PaO2 measured in the blood divided by the inhaled FiO2
  • SpO2 [ Time Frame: 5 days after randomization ]
    Oxygen saturation measured in % by oxygen apparatus
  • NEWS Score [ Time Frame: 5 days after randomization ]
    Early Warning Score (NEWS) calculated by the patient's vitals and condition
  • Inflammation level -CRP [ Time Frame: 5 days after randomization ]
    blood CRP level
  • white blood cells number [ Time Frame: 5 days after randomization ]
    white blood cells number
  • Cytokines - IL1 [ Time Frame: 5 days after randomization ]
    blood IL1 level
  • Cytokines - IL2 [ Time Frame: 5 days after randomization ]
    blood IL2 level
  • Cytokines - IL6 [ Time Frame: 5 days after randomization ]
    blood IL6 level
  • Cytokines - IL10 [ Time Frame: 5 days after randomization ]
    blood IL10 level
  • Cytokines - TNFalpha [ Time Frame: 5 days after randomization ]
    blood TNFalpha level
  • Inflammation level - procalcitonin [ Time Frame: 5 days after randomization ]
    blood procalcitonin level
  • Inflammation level - ferritin [ Time Frame: 5 days after randomization ]
    blood ferritin level
Original Primary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
  • PaO2/FiO2 [ Time Frame: 1 day and 7 days after the last intervention session ]
    Oxygenation index of the lungs calculated PaO2 measured in the blood divided by the inhaled FiO2
  • SpO2 [ Time Frame: One hour prior to and after every intervention session, 1 day and 7 days after the last intervention session ]
    Oxygen saturation measured in %
  • NEWS Score [ Time Frame: One hour prior to and after every intervention session, 1 day and 7 days after the last intervention session ]
    Early Warning Score (NEWS) calculated by the patient's vitals and condition
  • Inflammation level [ Time Frame: 1 day and 7 days after the last intervention session ]
    white blood cells number, CRP level, ESR and cytokines: IL-1,IL-2,IL-6,IL-10, TNFalpha, Procalcitonin, Ferritin
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2020)
  • Symptoms level [ Time Frame: 5 days after randomization ]
    Patient's reported symptoms including cough, dyspnea, etc.
  • Number of patients with IgM seroconversion [ Time Frame: 5 days after randomization ]
    number of patients who developed SARS-CoV-2 IgM antibodies
  • Number of patients with IgG seroconversion [ Time Frame: 5 days after randomization ]
    number of patients who developed SARS-CoV-2 IgG antibodies
  • FEV1/FVC [ Time Frame: 5 days after randomization ]
    Pulmonary function tests performed bedside
  • Time to symptoms recovery [ Time Frame: Within 30 days ]
    The measured time the patient suffered symptoms until complete recovery
  • Number of patients who required invasive ventilation [ Time Frame: Within 30 days ]
    The number of patients who required invasive ventilation during the trial
  • Time to negative virus PCR [ Time Frame: Within 30 days ]
    The measured time until the patient had two negative SARS-CoV-2 PCR
  • Mortality rate [ Time Frame: Within 30 days ]
    The number of patients who died
  • Number of barotrauma events (safety) [ Time Frame: 5 days after randomization ]
    The number of adverse events in each arm
Original Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
  • Symptoms level [ Time Frame: 1 day and 7 days after the last intervention session ]
    Patient's reported symptoms including cough, dyspnea, etc.
  • Average oxygen supply per day [ Time Frame: 1 day and 7 days after the last intervention session ]
    Oxygen amount supplied measured in IU
  • Viral load [ Time Frame: 1 day and 7 days after the last intervention session ]
    Quantitative measurement of viral load in the blood using quantitative RT-PCR
  • Chest Xray changes [ Time Frame: 1 day and 7 days after the last intervention session ]
    Chest xray changes evaluated qualitatively and quantitatively
  • Number of patients with IgG seroconverstion [ Time Frame: 1 day and 7 days after the last intervention session ]
    number of patients who develoepd SARS-CoV-2 IgG antibodies
  • Number of patients with IgM seroconverstion [ Time Frame: 1 day and 7 days after the last intervention session ]
    number of patients who develoepd SARS-CoV-2 IgM antibodies
  • FEV1/FVC [ Time Frame: 1 day and 7 days after the last intervention session ]
    Pulmonary function tests performed bedside
  • Time to symptoms recovery [ Time Frame: Within 30 days ]
    The measured time the patient suffered symptoms until complete recovery
  • Number of patients who required invasive ventilation [ Time Frame: Within 30 days ]
    The number of patients who required invasive ventilation during the trial
  • Time to negative virus PCR [ Time Frame: Within 30 days ]
    The measured time until the patient had two negative SARS-CoV-2 PCR
  • Mortality rate [ Time Frame: Within 30 days ]
    The number of patients who died
  • Number of barotrauma events (safety) [ Time Frame: Within 7 days after the last session ]
    The number of adverse events in each arm
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hyperbaric Oxygen Therapy Effect in COVID-19 RCT (HBOTCOVID19)
Official Title  ICMJE Hyperbaric Oxygen Therapy Effect in COVID-19 RCT (HBOTCOVID19)
Brief Summary

The 2019-20 coronavirus disease, caused by COVID-19, is an ongoing pandemic.So far, no specific treatment has proven efficacy. Recent case series reported the use of Hyperbaric Oxygen Therapy (HBOT) on 5 severe COVID-19 patients who developed respiratory insufficiency. HBOT mechanisms of tissue oxygenation and anti-inflammatory effect may explain these findings.

The purpose of the current study is the evaluate the efficacy of HBOT in moderate-severe COVID-19 patients in a randomized controlled manner.

Detailed Description

The 2019-20 coronavirus disease, caused by COVID-19, is an ongoing pandemic. The outbreak started in Wuhan, Hubei province, China, in December 2019 and the World Health Organization (WHO) recognized it as a pandemic on 11 March 2020. Up to Apr 9. 2020 there are more than 2 million confirmed cases, and over 140,000 deaths. In Israel, COVID-19 was confirmed in more 12,000 cases and took the life of 140 victims. There are 323 mild admitted cases, 170 moderate admitted cases and 170 severe admitted cases (16.04.2020) .

Even though the general mortality rate is low (0.2-7%, country based), patients who develop Acute Respiratory Distress Syndrome (ARDS) have a significantly higher mortality rate, up to 61-90%. COVID-19 ARDS is different, causing a rapidly progressive disease including respiratory insufficiency and pulmonary fibrosis. The mechanism behind isn't clear yet, but evidence points to the direction of an acute cytokines storm which include: IL-2, IL-7, GCSF, InterferonGamma, TNF-alpha, Macrophage chemoattractant protein . Poor prognosis include high levels of IL-6 and Ferritin.

More than 160 clinical trials have been registered, but as of April 2020, there is no proven effective treatment.

The use of hyperbaric oxygen therapy (HBOT) includes breathing 100% oxygen in pressures higher than 1 absolute atmospheres (ATA), increasing the amount of oxygen dissolved in the plasma and the different tissues. In the last month, Chen et al. reported a case series of 5 severe COVID-19 patients treated with 3-8 HBOT sessions in addition to the standard therapy. In all cases, they reported an increase in oxygen saturation, arterial oxygen content,lactate levels reduction,fibrinogen levels decrease and increase in lymphocytes number.In addition, the patients chest CT showed improved signs. Symptomatic relief started following the 2nd session. No significant adverse events were reported.

These findings may be explained by the known physiological effects of HBOT, related to the SARS-CoV-2 virus pathogenesis:

  1. Increased competitive binding of oxygen to the hemoglobin molecule - it has been postulated recently the SARS-CoV-2 bind to the heme component in the hemoglobin molecule and reduces the oxygen affinity to hemoglobin. During HBOT, the increased amount of available oxygen molecules increases the binding to the hemoglobin molecules. This has shown significant beneficial effects in cases of another competitive molecule such as carbon monoxide intoxication.
  2. Tissue oxygenation - The oxygen content in the different tissues is multiplied by 25-30 times. This effect has two therapeutic aspects: First, overcoming pulmonary hypoxia (either shunt or VQ mismatch) by increasing the FiO2 significantly. By increasing the pulmonary oxygen gradient, oxygen diffusion increases and can overcome the inflammation in the alveoli and the thickened fibrosis caused by ARDS. Second, during HBOT, the amount of oxygen dissolved in the plasma becomes significant and enables tissue oxygenation without the need of red blood cells.
  3. Anti inflammatory - HBOT reduces the following inflammatory cytokines both in the protein level and genes expression (mRNA): IL-2, TNF-alpha, IL-6, IL-1beta. The anti-inflammatory effect has been shown in chronic diseases as well as models of acute infection and massive hemorrhage.

The purpose of the current study is the evaluate the efficacy of HBOT in moderate-severe COVID-19 patients in a randomized controlled manner.

Protocol

Due to the national IRB requirements the protocol includes 2 phases:

The first phase includes 5 patients who following signing an informed consent will be treated with 8 sessions of HBOT , 2 sessions per day, in 4 consecutive days. During the sessions, the symptoms and vitals will be monitored. 1 day following the last session, revaluation will be performed.

The second phase will include 24 patients, who following signing an informed consent, will be randomized 2:1 to hyperbaric oxygen therapy group and standard of care control group. Following the randomization the patients will undergo baseline evaluation including symptoms, vitals, pulmonary function and blood tests.

The HBOT group patients will undergo 8 sessions of either hyperbaric oxygen therapy, 2 sessions per day, in 4 consecutive days. During the sessions, the symptoms and vitals will be monitored. 1 day following the last session, revaluation will be performed.

The control group will continue standard of care and undergo similar vitals and symptoms monitoring. 5 days after baseline evaluation, revaluation will be performed.

The long 30 days outcomes of both groups will be collected.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized controlled study
Masking: Single (Outcomes Assessor)
Masking Description:
The outcome assessors will receive anonymous blinded data.
Primary Purpose: Treatment
Condition  ICMJE
  • COVID-19
  • Desaturation of Blood
Intervention  ICMJE Device: Hyperbaric oxygen therapy
8 sessions in 4 days of breathing 100% oxygen in 2.2 ATA. Each session is 60 minutes. 1 meter/minute compression/decompression
Study Arms  ICMJE
  • Active Comparator: Hyperbaric oxygen therapy
    8 sessions in 4 days hyperbaric oxygen therapy
    Intervention: Device: Hyperbaric oxygen therapy
  • No Intervention: Control
    Standard of care
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 21, 2020)
30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 1, 2020
Actual Primary Completion Date October 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Within 7 days of patient's need of oxygen supply
  • Positive SARS-CoV-2 RT-PCR
  • At least one risk factor for bad prognosis of COVID-19: Moderate-severe Asthma, Diabetes mellitus, Cardiac conditions (congestive heart failure, coronary disease, cardiomyopathy, pulmonary hypertension), severe obesity (BMI>40), age>65, immunodeficiency, chronic liver disease.
  • Respiratory insufficiency : Room Air SpO2 <94% or PaO2/FiO2<300mmHg
  • Age>18
  • Ability to sign an informed consent

Exclusion Criteria:

  • HBOT contraindication: pneumothorax, pneumomediastinum, claustrophobia, ear/sinus disease which aren't allowed in HBOT, known chronic pulmonary disease: severe emphysema or known pulmonary bullae.
  • Pregnancy
  • Inability to sign an informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04358926
Other Study ID Numbers  ICMJE 120-20-ASF
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Sharing upon specific requests will be considered
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Within 1 month of request
Access Criteria: Specific requests
Responsible Party Assaf-Harofeh Medical Center
Study Sponsor  ICMJE Assaf-Harofeh Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amir Hadanny, MD Shamir Medical Center
PRS Account Assaf-Harofeh Medical Center
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP