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

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

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.

Study Overview

• Status: Unknown
• Conditions: Coronavirus Infection; Pneumonia, Viral; SARS-CoV 2; COVID
• Intervention / Treatment: Drug: Azithromycin; Drug: hydroxychloroquine; Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care; Dietary supplement: SivoMixx (200 billion)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 152
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Francesco Pugliese, MD, PhD; Phone Number: 00390649978024; Email: f.pugliese@uniroma1.it
• Study Contact Backup: Name: Fabio Araimo, MD; Email: f.araimo@policlinicoumberto1.it

Study Locations

• Italy
  • RM
    • Rome, RM, Italy, 00161
      • Recruiting
      • Francesco Pugliese
      • Contact: Francesco Pugliese, MD PhD; Phone Number: 00390649978024; Email: f.pugliese@uniroma1.it
      • Sub-Investigator: Fabio Araimo, MD
      • Sub-Investigator: Carmela Imperiale, MD
      • Sub-Investigator: Paolo Tordiglione, MD PhD
      • Sub-Investigator: Claudio M Mastroianni, MD PhD
      • Sub-Investigator: Gabriella d'Ettorre, MD PhD
      • Sub-Investigator: Giancarlo Ceccarelli, MD PhD MSc
      • Sub-Investigator: Andrea Calò, MD
      • Sub-Investigator: Vera MAuro, MD
      • Sub-Investigator: Serena Zancla, MD
      • Sub-Investigator: Gregorio Egidio Recchia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)"

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care; 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; 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); Drug: hydroxychloroquine; dose: 200 mg, 1 cp x 2 / day
Experimental: Oxygen-ozone and probiotic; 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).	Drug: Azithromycin; 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); Drug: hydroxychloroquine; dose: 200 mg, 1 cp x 2 / day; Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care; - systemic autohemotherapy with Ozone 30 mcg / ml 250ml 2 times / day for 7 days; Dietary supplement: SivoMixx (200 billion); 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Roberto Poscia MD, PhD
• Investigators: Principal Investigator: Francesco Pugliese, MD, PhD, University of Rome Sapienza - Policlinico Umberto I Rome (Italy)

Publications and helpful links

General Publications

• Hernandez A, Papadakos PJ, Torres A, Gonzalez DA, Vives M, Ferrando C, Baeza J. Two known therapies could be useful as adjuvant therapy in critical patients infected by COVID-19. Rev Esp Anestesiol Reanim (Engl Ed). 2020 May;67(5):245-252. doi: 10.1016/j.redar.2020.03.004. Epub 2020 Apr 14. English, Spanish.
• Conti P, Gallenga CE, Tete G, Caraffa A, Ronconi G, Younes A, Toniato E, Ross R, Kritas SK. How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1. J Biol Regul Homeost Agents. 2020 March-April,;34(2):333-338. doi: 10.23812/Editorial-Conti-2.
• Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2022 Oct 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2020
• Primary Completion (Anticipated): October 30, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: April 22, 2020
• First Submitted That Met QC Criteria: April 27, 2020
• First Posted (Actual): April 28, 2020

Study Record Updates

• Last Update Posted (Actual): April 28, 2020
• Last Update Submitted That Met QC Criteria: April 27, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: gut microbiota; Oxygen-ozone therapy
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia; Lung Diseases; Coronavirus Infections; Pneumonia, Viral; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Azithromycin; Hydroxychloroquine
• Other Study ID Numbers: 110/2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No