COVIDPhase 2PROBIOZOVIDNCT04366089
Oxygen-Ozone as Adjuvant Treatment in Early Control of COVID-19 Progression and Modulation of the Gut Microbial Flora
A Phase 2 study testing SivoMixx (200 billion), Azithromycin and hydroxychloroquine in people with COVID and SARS-CoV 2, run by Roberto Poscia MD, PhD at 1 site in Italy.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- COVID, SARS-CoV 2, Pneumonia, Viral
- What is being tested?
- SivoMixx (200 billion), Azithromycin and hydroxychloroquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 152 participants
- Where
- 1 siteItaly
- Study dates
- 26 Mar 2020to 31 Dec 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 18 years
- Nasopharyngeal swab positive for COVID-19
- COVID-19 stages I - II - III (*1)
- Hospitalization in the Department of Infectious Diseases
Who cannot join
- 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
Show all 27Show fewer
- 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)"
Trial locations and contacts
1 site in 1 country.
Fabio Araimo, MD contact
Italy1 site, 1 recruiting
- Recruiting
Francesco Pugliese
Rome, RM, 00161
Francesco Pugliese, MD PhD, 00390649978024, f.pugliese@uniroma1.it
Fabio Araimo, MD
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- COVID, SARS-CoV 2, Pneumonia, Viral, Coronavirus Infection
- Being tested
- Oxygen-ozone therapy, probiotic supplementation and Standard of care, SivoMixx (200 billion), Azithromycin, hydroxychloroquine
- Keywords
- Oxygen-ozone therapy, gut microbiota
- Medical subject headings
- Pneumonia, Viral, Coronavirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oxygen-ozone therapy, probiotic supplementation and Standard of careOther
- systemic autohemotherapy with Ozone 30 mcg / ml 250ml 2 times / day for 7 days
SivoMixx (200 billion)Dietary supplement
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)
AzithromycinDrug
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)
dose: 200 mg, 1 cp x 2 / day
| Study group | Role | What they receive |
|---|---|---|
| Standard of care | Active comparator | 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. Receives: Drug: Azithromycin; Drug: hydroxychloroquine |
| Oxygen-ozone and probiotic | Experimental | 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). Receives: Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care; Dietary Supplement: SivoMixx (200 billion); Drug: Azithromycin; Drug: hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Delta in the number of patients requiring orotracheal intubation despite treatment
Comparison between the two groups
Measured: 21 days
Secondary outcomes (12)
Delta of crude mortality
Comparison between the two groups
Measured: 21 days
Delta of length of stay for patients in hospital
Comparison between the two groups
Measured: 90 days
delta in the value of interleukin (IL)-1
Comparison between the two groups
Measured: 21 days
delta in the value of IL-6
Comparison between the two groups
Measured: 21 days
delta in the value of IL-10
Comparison between the two groups
Measured: 21 days
delta in the value of Tumor Necrosis Factor (TNF)-alpha
Comparison between the two groups
Measured: 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
Measured: 21 days
delta in the value of CD8+ CD38/ HLA-DR
Comparison between the two groups
Measured: 21 days
delta in the value of fecal calprotectin
Comparison between the two groups
Measured: 21 days
delta in the value of lipopolysaccharide (LPS)
Comparison between the two groups
Measured: 21 days
delta in the value of zonulin
Comparison between the two groups
Measured: 21 days
delta in the value of alpha1-antitrypsin
Comparison between the two groups
Measured: 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Apr 2020
- Study start26 Mar 2020
- Primary completion30 Oct 2020 (estimated)
- Study completion31 Dec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for COVIDStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 152 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Roberto Poscia MD, PhD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Roberto Poscia MD, PhD, Azienda Policlinico Umberto I
- Investigators
- Francesco Pugliese, MD, PhD, Principal investigator, University of Rome Sapienza - Policlinico Umberto I Rome (Italy)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04366089
- Sponsor's protocol ID
- 110/2020
- Acronym
- PROBIOZOVID
- Status last verified
- Apr 2020
- First submitted
- 22 Apr 2020
- Last updated
- 28 Apr 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 32303365Conti 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.
PubMed 32228825Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2023 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/
PubMed 32150360
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxygen-Ozone as Adjuvant Treatment in Early Control of Disease Progression in Patients With COVID-19 Associated With Modulation of the Gut Microbial Flora
- ClinicalTrials.gov ID
- NCT04366089
- Acronym / sponsor ID
- PROBIOZOVID / 110/2020
- Conditions
- COVID, SARS-CoV 2, Pneumonia, Viral, Coronavirus Infection
- Keywords
- Oxygen-ozone therapy, gut microbiota
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 152 participants (estimated)
- Lead sponsor
- Roberto Poscia MD, PhDUniversity, hospital or other
- Study start
- 26 Mar 2020 (actual)
- Primary completion
- 30 Oct 2020 (estimated)
- Study completion
- 31 Dec 2020 (estimated)
- First posted
- 28 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard of care | Active comparator | Drug: Azithromycin, Drug: hydroxychloroquineAzithromycin 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. |
| Oxygen-ozone and probiotic | Experimental | Other: Oxygen-ozone therapy, probiotic supplementation and Standard of care, Dietary Supplement: SivoMixx (200 billion), Drug: Azithromycin, Drug: hydroxychloroquineOxygen-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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age > 18 years
- Nasopharyngeal swab positive for COVID-19
- COVID-19 stages I - II - III (*1)
- Hospitalization in the Department of Infectious Diseases
Key exclusion criteria (27 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oxygen-ozone therapy, probiotic supplementation and Standard of care- systemic autohemotherapy with Ozone 30 mcg / ml 250ml 2 times / day for 7 days | Other | Oxygen-ozone and probiotic |
| 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) | Dietary supplement | Oxygen-ozone and probiotic |
| Azithromycindose: 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 | Oxygen-ozone and probiotic, Standard of care |
| hydroxychloroquinedose: 200 mg, 1 cp x 2 / day | Drug | Oxygen-ozone and probiotic, Standard of care |
Primary outcome
Delta in the number of patients requiring orotracheal intubation despite treatment
Time frame: 21 days
Comparison between the two groups
12 secondary outcomes
Delta of crude mortality
Time frame: 21 days
Delta of length of stay for patients in hospital
Time frame: 90 days
delta in the value of interleukin (IL)-1
Time frame: 21 days
delta in the value of IL-6
Time frame: 21 days
delta in the value of IL-10
Time frame: 21 days
delta in the value of Tumor Necrosis Factor (TNF)-alpha
Time frame: 21 days
delta in the value of cluster of differentiation (CD)4+ CD38/ Human Leukocyte Antigen-DR isotype (HLA-DR)
Time frame: 21 days
delta in the value of CD8+ CD38/ HLA-DR
Time frame: 21 days
delta in the value of fecal calprotectin
Time frame: 21 days
delta in the value of lipopolysaccharide (LPS)
Time frame: 21 days
delta in the value of zonulin
Time frame: 21 days
delta in the value of alpha1-antitrypsin
Time frame: 21 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2020.
- Results publication: PubMed 32303365Hernandez 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.
- Results publication: PubMed 32228825Conti 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.
- Results publication: PubMed 32150360Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2023 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/
- Clinical study for ozonated autohemotherapy in the treatment of Novel Coronavirus Pneumonia (COVID-19)Link provided by the sponsor.
- A randomized controlled trial for the efficacy of ozonated autohemotherapy in the treatment of Novel Coronavirus Pneumonia (COVID-19)Link provided by the sponsor.
- A multicenter randomized controlled trial for ozone autohemotherapy in the treatment of novel coronavirus pneumonia (COVID-19)Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fabio Araimo, MD contact
Francesco Pugliese, MD, PhD principal investigator
University of Rome Sapienza - Policlinico Umberto I Rome (Italy)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing SivoMixx (200 billion), Azithromycin and hydroxychloroquine in people with COVID and SARS-CoV 2, run by Roberto Poscia MD, PhD at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Francesco Pugliese, MD, PhD (00390649978024, f.pugliese@uniroma1.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Delta in the number of patients requiring orotracheal intubation despite treatment (time frame: 21 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04366089, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2020.