Blood Ozonization in Patients With SARS-CoV-2 Respiratory Failure (CORMOR)

• ClinicalTrials.gov Identifier: NCT04388514
• Recruitment Status: Unknown
• First Posted: May 14, 2020
• Last Update Posted: May 14, 2020
• Sponsor: Azienda Sanitaria-Universitaria Integrata di Udine
• Collaborators: Fondazione Toscana Gabriele Monasterio; Policlinico Militare, Roma - Italy; Ospedale San Liberatore di Atri; Ospedale Umberto I di Torino; Università di Siena; Ospedale Civile di Lucca; Ospedale di Siracusa; Azienda Sanitaria Locale di Vercelli
• Information provided by (Responsible Party): Carlo Tascini, Azienda Sanitaria-Universitaria Integrata di Udine

Study Description

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.

Condition or disease	Intervention/treatment	Phase
SARS-CoV-2 Respiratory Failure	Procedure: Medical Ozone procedure	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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 (Investigator)
• Masking Description: Randomization, 1:1 ratio
• Primary Purpose: Treatment
• Official Title: Blood Ozonization in Patients With SARS-CoV-2 Respiratory Failure
• Actual Study Start Date: April 8, 2020
• Estimated Primary Completion Date: October 8, 2020
• Estimated Study Completion Date: October 8, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Blood ozonization; Blood ozonization plus BAT	Procedure: Medical Ozone procedure; 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.
No Intervention: Standard of Care; 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.

Outcome Measures

Primary Outcome Measures :

1. Time of respiratory improvement and earlier weaning from oxygen support [ Time Frame: 3 days ]
   Evaluation of ABG paramethers the day after the last blood ozonization procedure (Day 3)
2. The time of respiratory improvement and earlier weaning from oxygen support [ Time Frame: 10 days ]
   Evaluation of ABG paramethers the one week after the last blood ozonization procedure (Day 10)

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Carlo Tascini, MD; +39 0432 559355; c.tascini@gmail.com

Contact: Emanuela Sozio, MD; +39; emanuela.sozio@gmail.com

Locations

Italy

Dott. Amato De Monte; Recruiting

Udine, Italy

Contact: Amato De Monte, MD

Sponsors and Collaborators

Azienda Sanitaria-Universitaria Integrata di Udine

Fondazione Toscana Gabriele Monasterio

Policlinico Militare, Roma - Italy

Ospedale San Liberatore di Atri

Ospedale Umberto I di Torino

Università di Siena

Ospedale Civile di Lucca

Ospedale di Siracusa

Azienda Sanitaria Locale di Vercelli

Investigators

• Study Chair: Amato De Monte; Presidio Ospedaliero Universitario "Santa Maria della Misericordia", Udine - Italy

  Study Documents (Full-Text)

Documents provided by Carlo Tascini, Azienda Sanitaria-Universitaria Integrata di Udine:

Study Protocol and Statistical Analysis Plan  [PDF] April 8, 2020

More Information

Additional Information:

SIMEU Classification and Guidelines 

doi: 10.4081/ozone.2020.9014. 

Publications:

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.

Elvis AM, Ekta JS. Ozone therapy: A clinical review. J Nat Sci Biol Med. 2011 Jan;2(1):66-70. doi: 10.4103/0976-9668.82319.

Bocci VA. Scientific and medical aspects of ozone therapy. State of the art. Arch Med Res. 2006 May;37(4):425-35. doi: 10.1016/j.arcmed.2005.08.006.

Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res. 2017 Oct 17;7(3):212-219. doi: 10.4103/2045-9912.215752. eCollection 2017 Jul-Sep.

Gulmen S, Kurtoglu T, Meteoglu I, Kaya S, Okutan H. Ozone therapy as an adjunct to vancomycin enhances bacterial elimination in methicillin resistant Staphylococcus aureus mediastinitis. J Surg Res. 2013 Nov;185(1):64-9. doi: 10.1016/j.jss.2013.05.085. Epub 2013 Jun 19.

• Responsible Party: Carlo Tascini, Infectious Diseases Department, Azienda Sanitaria-Universitaria Integrata di Udine
• ClinicalTrials.gov Identifier: NCT04388514
• Other Study ID Numbers: CIG: Z7C2CA5837
• First Posted: May 14, 2020
• Last Update Posted: May 14, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: all IPD that underlie results in a publication
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: starting 6 months after publication
• Access Criteria: Contacting the Principal Investigator

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Carlo Tascini, Azienda Sanitaria-Universitaria Integrata di Udine:

SARS-CoV-2; Respiratory Failure; COVID-19; medical ozone; ozone therapy; cytokine release syndrome

Additional relevant MeSH terms:

Respiratory Insufficiency; Respiration Disorders; Respiratory Tract Diseases