Blood Ozonization in Patients With SARS-CoV-2 Respiratory Failure

Study Overview
=================
Brief Summary
-----------------
Aim. The emerging outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. Beside the prescription of some promising drugs as chloroquine, azithromycin, antivirals (lopinavir/ritonavir, darunavir/cobicistat) and immunomodulating agents (steroids, tocilizumab), in our patients with mild to moderate pneumonia due to SARS-CoV-2 we planned a randomize study to evaluate, respect the best available therapy (BAT), the use of autohemotherapy treatement with an oxygen/ozone (O3) gaseous mixture as adjuvant therapy. Design. Multicentric, randomized study. Participants. Clinical presentations are based upon clinical phenotypes identified by the Italian Society of Emergency and Urgency Medicine (SIMEU - Società Italiana di Medicina di Emergenza-Urgenza) and patients that meet criteria of phenotypes 2 to 4 were treat with best available therapy (BAT), and randomized to receive or not O3-autohemotherapy. Main outcome measures. The end-point were the time of respiratory improvement and earlier weaning from oxygen support: these parameters were included in the SIMEU clinical phenotypes classification.

Detailed Description
-----------------
Recruitment Details. The investigator enrolled, in the study, subjects with COVID-19 modest to moderate respiratory insufficiency (SIMEU clinical phenotypes 2-4) thus cared in an infectious disease ward. To note that The Italian Society of Emergency and Urgency Medicine (SIMEU - Società Italiana di Medicina di Emergenza-Urgenza) suggest to classified the COVID-19 patients in 5 clinical phenotypes: Phenotype 1: subjects with fever and without respiratory failure (normal Arterial Blood Gas analysis - ABG -, six-minute walking test - 6mWT - and Chest XR). These patients usually can manage at home maintaining quarantine period. Phenotype 2: subjects with fever but with ABG and/or Chest XR indicative of modest respiratory insufficiency (PO2> 60 mmHg in ambient air) and / or pulmonary consolidation area. These patients need to be hospitalized because they can get quickly worse. Phenotype 3: subjects with fever associate to moderate-severe respiratory insufficiency (at triage PO2< 60 mmHg in ambient air) and /or bilateral pulmonary consolidation area at Chest XR. These patients need to be treated with high flow oxygen therapy. Phenotype 4: subjects with respiratory failure with suspected ARDS (Adult Respiratory Distress Syndrome) or complicated pneumonia. These patients require hospitalization in sub-intensive care unit. Phenotype 5: subject with ARDS at the beginning. These patients will require Intensive Care Unit (ICU) admission and non-invasive positive pressure ventilation (NIPPV) or mechanical ventilation.

Official Title
-----------------
Blood Ozonization in Patients With SARS-CoV-2 Respiratory Failure

Conditions
-----------------
SARS-CoV-2 Respiratory Failure

Intervention / Treatment
-----------------
* Procedure: Medical Ozone procedure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and no pregnant female patients 18 years of age or older were eligible if they had a diagnostic specimen that was positive on RT-PCR, had pneumonia confirmed by chest imaging and gave their informed consent to participate at the study Exclusion Criteria: Exclusion criteria were pregnancy, G6PHD (glucose 6 phosphate dehydrogenase) deficiency, concomitant serious disease and failure to obtain informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study includes 2 arms: Arm A: Blood ozonization plus BAT (n= 45 subjects) Arm B: Standard of Care only without Blood ozonization (n= 45 subjects) To note that the Standard of Care are therapy with antiretroviral therapy (lopinavir/ritonavir 2 tablets every 12 hours or darunavir/cobicistat 1 tablet per day) and hidrossycloroquine 400 mg every 12 hours then first day, followed by 200 mg every 12 hours for other 4 days
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blood ozonization<br>Blood ozonization plus BAT | Procedure: Medical Ozone procedure<br>* The systemic ozone treatment procedure was decided by the physician on duty and started preliminarily at the patient's bed with the drawing of autologous blood and, after proper O2/O3 mixing, with its re-infusion. After junction of an adequate venous patient's way with a dedicated latex free plastic bag containing 35 ml of sodium citrate, a blood amount of 200 ml is taken. At the end, the withdrawal line was washed and the re-infusion one was filled with saline solution. The blood, without any patient disconnection, was then mixed with a gas mixture of a 200 cc composed by 96% of Oxygen and 4% of Ozone with a therapeutic O3 range of 40 μg/mL of gas per mL of blood. In order to guarantee the O2/O3 homogeneous diffusion into the blood, the bag was gently mixed for about 10 minutes, therefore the blood was re-infused into the patients. The duration of ozone treatment lasted for 3 consecutive days.<br>|
| No Intervention: Standard of Care<br>BAT only To note that the BAT are therapy with antiretroviral therapy (lopinavir/ritonavir 2 tablets every 12 hours or darunavir/cobicistat 1 tablet per day) and hidrossycloroquine 400 mg every 12 hours then first day, followed by 200 mg every 12 hours for other 4 days. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of respiratory improvement and earlier weaning from oxygen support | Evaluation of ABG paramethers the day after the last blood ozonization procedure (Day 3) | 3 days | 
| The time of respiratory improvement and earlier weaning from oxygen support | Evaluation of ABG paramethers the one week after the last blood ozonization procedure (Day 10) | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the length of hospitalization | Asse the lenghth of hospital stay in the two arms | up to 90 days | 
| Assessment of the length of Intensive Care Unit (ICU) stay | Asse the lenghth of ICU stay in the two arms | up to 90 days | 
| Improvment in chest imaging finding | improving, worsening or stability of the chest imaging (chest CT, Chest XR and/or Point-of-Care Ultrasound) finding in the two arms | 10 days | 
| Improvment in cytokine release syndrome | Evaluation of plasmatic cytochine (IL-6, lymphocyte typing for CD4, CD3, CD8, HLA-DR, CD45) response in the two arms | 10 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, Respiratory Failure, COVID-19, medical ozone, ozone therapy, cytokine release syndrome