Acute Respiratory Failure, ARDS, Human, COVID-19, Cytokine Storm, Sars-CoV2, SARS (Severe Acute Respiratory Syndrome)
Conditions
Keywords
COVID-19, Hyperbaric oxygen, ARDS, SARS-CoV-2, ICU admission
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
Interventions
DRUGHyperbaric oxygen
1.6- 2.4 ATA, 30-60 min (excluding compression/recompression)
Sponsors
Karolinska Trial Alliance
University of California, San Diego
Blekinge County Council Hospital
JK Biostatistics AB
The Swedish Research Council
University of Regensburg
Karolinska Institutet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized controlled, open label, multi-centre clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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 (
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ICU admission | 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
| Measure | Time frame | Description |
|---|---|---|
| Time-to-intubation | Through study completion 30 days | Time-to-Intubation, i.e. cumulative days free of invasive mechanical ventilation, from day 1 to day 30 |
| 30-day mortality | Through study completion 30 days | Proportion of subjects with 30-day mortality, all cause Mortality, from day 1 to day 30. |
| Time-to-ICU | 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. |
| Inflammatory response | 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 |
| Overall survival | Through study completion 30 days | Overall survival (Kaplan-Meier) |
Other
| Measure | Time frame | Description |
|---|---|---|
| PaO2/FiO2 (PFI) | Through study completion 30 days | Mean change in PaO2/FiO2 (PFI), from day 1 to day 2, … to day 30. |
| HBO Compliance | 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. |
| Hospital discharge | Through study completion 30 days | Time-to-discharge from hospital |
| Micro RNA | Through study completion 30 days | Change in expression of Micro RNA in plasma from day 1 to day 30 |
| Hypoxic response | 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 |
| Immunological response | 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 |
| Oxygen dose | 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. |
| Viral load | Through study completion 30 days | Viral load, review of records from day 1 to day 30. |
| Secondary infections | Through study completion 30 days | Number of secondary infections, review of records, number of events and patients from day 1 to day 30. |
| Pulmonary embolism | Through study completion 30 days | Diagnosed PE needing treatment, review of records, number of events and patients from day 1 to day 30. |
| Pulmonary CT | Through study completion 30 days | Changes on Pulmonary CT, review of records from day 1 to day 30. |
| Chest X-ray | Through study completion 30 days | Changes on Chest X-ray, review of records from day 1 to day 30. |
| Lung ultrasound | Through study completion 30 days | Changes in Lung ultrasound, review of records from day 1 to day 30. |
| Multi organ dysfunction | Through study completion 30 days | Mean change in routine biomarkers for organ dysfunction, from day 1to day 30. |
| HBO dose | Day 1 to day 7 | Median number of HBO treatments and dose of HBO given, from day 1 to day 7 |
| Hospital mortality | Through study completion 30 days | Hospital mortality of any cause, proportion of subjects, from day 1 to day 30. |
| ICU mortality | 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. |
| Time in Invasive Ventilation | From ICU admission to study completion 30 days | Time-to-stop of intubation/invasive mechanical ventilation, from ICU admission to day 30. |
| NEWS | Through study completion 30 days | Mean daily NEWS from day 1 to day 30. |
Countries
Germany, Sweden
Outcome results
None listed