Oxygen-Ozone as Adjuvant Treatment in Early Control of COVID-19 Progression and Modulation of the Gut Microbial Flora

Study Overview
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Brief Summary
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Italy was the first European country affected by a severe outbreak of the Severe Acute Respiratory Syndrome - CoronaVirus-2 (SARS-CoV-2) epidemic emerged from Wuhan region (China), with a high morbidity and mortality associated with the disease. In light of its pandemic spread and the very limited therapeutic options, COronaVIrus Disease 19 (COVID-19) is considered an unprecedented global health challenge. Therefore, the evaluation of new resources, designed in the first instance for other pathologies but potentially active against COVID-19, represents a priority in clinical research. This is an interventional, non-pharmacological, open, randomized, prospective, non-profit study on the adjuvant use of oxygen ozone therapy plus probiotic supplementation in the early control of disease progression in patients with COVID-19. Contextually, all patients are treated with the current standard of care on the basis of the interim guidelines of the Italian Society of Infectious and Tropical Diseases. The main purpose of the study is to evaluate the effectiveness of an ozone therapy-based intervention (accompanied by supplementation with probiotics) in containing the progression of COVID-19 and in preventing the need for hospitalization in intensive care units.

Detailed Description
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Several studies analyzed the mechanisms by which ozone therapy could combat viral infections. In particular, 1) the improvement of the release of oxygen in the peripheral tissues, 2) the anti-inflammatory action 3) a virucidal activity have been described. In view of these properties, a number of international clinical trials on the topic are currently ongoing. Hospitalization, dietary changes, use of antibiotics and systemic inflammation related to COVID-19 are all variables that contribute to changes in the intestinal and lung microbiota with significant repercussions on the outcomes of the disease. Furthermore, the use of ozone therapy could also lead to a modification of the microbial flora. Probiotic supplementation can help to correct these issues.

Official Title
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Oxygen-Ozone as Adjuvant Treatment in Early Control of Disease Progression in Patients With COVID-19 Associated With Modulation of the Gut Microbial Flora

Conditions
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COVID, SARS-CoV 2, Pneumonia, Viral, Coronavirus Infection

Intervention / Treatment
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* Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care
* Dietary Supplement: SivoMixx (200 billion)
* Drug: Azithromycin
* Drug: hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Nasopharyngeal swab positive for COVID-19 COVID-19 stages I - II - III (*1) Hospitalization in the Department of Infectious Diseases Exclusion Criteria: COVID-19 stages IV - V - VI (*1) Hospitalization in Intensive Care Units Pregnancy Glucose-6-phosphate dehydrogenase (G6PD) deficiency Patients who deny consent to the proposed treatment Inability to provide informed consent Contraindications to performing oxygen-ozone therapy hyperhomocysteinemia favism or thyroiditis coagulopathies neurodegenerative diseases angina (in particular Prinzmetal's angina) or with previous myocardial infarction (*1) Compliant with indications published by: Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI). Care pathway for the patient with COVID-19. Section 2 - Recommendations for local management of the critically ill patient - Version 2 Available on http://www.siaarti.it/SiteAssets/News/COVID19%20-%20documenti%20SIAARTI/Percorso%20COVID-19%20-%20Sezione%202%20-%20Raccomandazioni%20per%20la%20gestione%20locale%20-%20Rev%202.0.pdf Last accessed 20/04/2020 Posted on 26.03.2020 On page 2 of the previous document : 6 identified stages: sick disease - mild COVID-19 (I stage) light pneumonia - mild COVID-19 (II stage) serious pneumonia - severe COVID-19 (III stage) Acute respiratory distress syndrome (ARDS) - critical COVID-19 (IV stage) sepsis - critical COVID-19 (V stage) septic shock - critical COVID-19 (VI stage)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br>Azithromycin 500mg 1 cp / day (alternatively lopinavir/ritonavir cps 200/50 mg, 2 cps x 2 / day or darunavir 800 mg 1 cp / day + ritonavir 100 mg 1 cp / day or darunavir/cobicistat 800/150 mg 1 cp / day), plus hydroxychloroquine cp 200 mg, 1 cp x 2 / day. | Drug: Azithromycin<br>* dose: 500mg 1 cp / day (alternatively lopinavir/ritonavir cps 200/50 mg, 2 cps x 2 / day or darunavir 800 mg 1 cp / day + ritonavir 100 mg 1 cp / day or darunavir/cobicistat 800/150 mg 1 cp / day)<br>Drug: hydroxychloroquine<br>* dose: 200 mg, 1 cp x 2 / day<br>|
| Experimental: Oxygen-ozone and probiotic<br>Oxygen-ozone therapy, probiotic supplementation plus standard of care Oxygen-ozone therapy: systemic autohemotherapy (twice a day). Probiotic supplementation: SivoMixx 200 billion (six sachets twice a day). | Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care<br>* - systemic autohemotherapy with Ozone 30 mcg / ml 250ml 2 times / day for 7 days<br>Dietary Supplement: SivoMixx (200 billion)<br>* Composition of SivoMixx: Streptococcus thermophilus DSM322245, Bifidobacterium lactis DSM 32246, Bifidobacterium lactis DSM 32247, Lactobacillus acidophilus DSM 32241, Lactobacillus helveticus DSM 32242, Lactobacillus paracasei DSM 32243, Lactobacillus plantarum DSM 32244, Lactobacillus brevis DSM 27961 (NB: DSM n°... : bacterial strain identification code)<br>Drug: Azithromycin<br>* dose: 500mg 1 cp / day (alternatively lopinavir/ritonavir cps 200/50 mg, 2 cps x 2 / day or darunavir 800 mg 1 cp / day + ritonavir 100 mg 1 cp / day or darunavir/cobicistat 800/150 mg 1 cp / day)<br>Drug: hydroxychloroquine<br>* dose: 200 mg, 1 cp x 2 / day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta in the number of patients requiring orotracheal intubation despite treatment | Comparison between the two groups | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta of crude mortality | Comparison between the two groups | 21 days | 
| Delta of length of stay for patients in hospital | Comparison between the two groups | 90 days | 
| delta in the value of interleukin (IL)-1 | Comparison between the two groups | 21 days | 
| delta in the value of IL-6 | Comparison between the two groups | 21 days | 
| delta in the value of IL-10 | Comparison between the two groups | 21 days | 
| delta in the value of Tumor Necrosis Factor (TNF)-alpha | Comparison between the two groups | 21 days | 
| delta in the value of cluster of differentiation (CD)4+ CD38/ Human Leukocyte Antigen-DR isotype (HLA-DR) | Comparison between the two groups | 21 days | 
| delta in the value of CD8+ CD38/ HLA-DR | Comparison between the two groups | 21 days | 
| delta in the value of fecal calprotectin | Comparison between the two groups | 21 days | 
| delta in the value of lipopolysaccharide (LPS) | Comparison between the two groups | 21 days | 
| delta in the value of zonulin | Comparison between the two groups | 21 days | 
| delta in the value of alpha1-antitrypsin | Comparison between the two groups | 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oxygen-ozone therapy, gut microbiota