Ozone Therapy in Refractory Ischemic Heart Disease. (O3Cardio)

Effectiveness and Cost-effectiveness of Ozone Therapy in Patients With Ischemic Heart Disease Refractory to Medical and Surgical Treatment: Randomized, Triple-blind Clinical Trial

The main objective of this clinical trial is to evaluate the effectiveness and cost-effectiveness of adding ozone therapy to standard management of patients with advanced ischemic heart disease refractory to medical and surgical treatment.

Study Overview

• Status: Terminated
• Conditions: Ischemic Heart Disease
• Intervention / Treatment: Drug: Ozone; Drug: Oxygen

Detailed Description

This study will evaluate the potential role of ozone therapy added to the standard management of patients with symptomatic refractory ischemic heart disease, III-IV functional class of the classification of the New York Heart Association (NYHA).

MAIN OBJECTIVES: 1) to evaluate clinical effect and quality of life related to health (HRQOL) of adding O3 to the standard treatment of these patients. 2) to estimate the additional costs of adding O3 to the standard treatment and to evaluate the cost-effectiveness ratio.

SECONDARY OBJECTIVES: 3) To evaluate the evolution of a) biochemical parameters; b) cardiovascular parameters; c) toxicity of O3. 4) Develop and evaluate the acceptability of a shared decision-making (SDM) tool between professionals and patients.

METHODOLOGY: Phase II-III clinical trial, randomized, triple-blind. Sample size: 18 patients.

TREATMENT: All patients will receive their standard treatment + 40 sessions of rectal insufflation:

1. Ozone-Group (n = 9): O3/O2 concentration progressively increased from 10 to 30 µg/ml.
2. Control-placebo-Group (n = 9): O3/O2 Concentration = 0 µg/ml (only O2).

Main Variables: 1) changes in the self-perceived quality of life (Minnesota scale). 2) Direct costs.

Secondary Variables: 1) biochemical parameters; 2) Cardiovascular parameters; 3) Side effects. 4) acceptability of patients to a shared decision-making (SDM) tool.

Length of treatment: 16 weeks.

Follow-up: 16 weeks after completion of O3.

Assessments: 1) Pre-O3 (basal), 2) pos-O3 (end of O3), 3) 4 months pos-O3.

Planned length of clinical trial: 36 months.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Spain
  • Las Palmas
    • Las Palmas De Gran Canaria, Las Palmas, Spain, 35019
      • Dr. Negrin University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults with ischemic heart disease, Functional Class III-IV from the NYHA, with symptoms in spite of maximal conventional medical treatment and no suitable to further percutaneous or surgical procedures.
• It should be required clinical diagnosis by the Cardiology Department and confirmation by cardiac catheterization with coronary angiography.
• Ejection Fraction < 40%
• Patients who have signed and dated the study 's specific informed consent.
• Before enrollment, women of childbearing potential should obtain a negative result in the serum or urine pregnancy test at the screening visit, and accept the use of appropriate contraceptive methods at least from the 14 days prior to the first dose of the study drug. up to 14 days after the last one.

Exclusion Criteria:

• Age < 18 or > 85 years old.
• Severe valve disease and/or dynamic left ventricular outflow tract obstruction.
• Pregnancy at the time of enrollment.
• Limited walking ability due to neurologic or orthopedic impairments of the legs
• Those who are incapable to fill in the scales used to measure the quality of life variables
• Cerebral vascular accident (CVA or Transient Ischemic Attack (TIA) within the previous 3 months or carotid stenosis > 80%.
• Acute myocardial infarction (AMI), Percutaneous coronary intervention (PCI) or transmyocardial laser revascularization (TMR or PMR) within the previous 3 months.
• Hemodynamically or clinically unstable patients.
• Severe or limiting pulmonary diseases.
• Specific liver enzymes [Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) > 5 times the upper limit of normal
• Increased creatinine > 3 times the upper limit of normal or Glomerular Filtration Rate (GFR) < 25 ml/min or who are on chronic renal dialysis.
• Severe peripheral vascular disease with rest pain or significant chronic wounds.

Uncontrolled cancer disease or severe active systemic infection or HIV.

• Life expectancy < 4 months
• Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
• Known allergy to ozone.
• Patients who do not meet all the inclusion criteria.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ozone Group: Standard treatment + Ozone therapy (O3/O2)	Drug: Ozone; Ozone Group: Standard treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 µg/ml; 40 sessions in 16 weeks.; Other Names: O3
Placebo Comparator: Control Group: Standard treatment + Oxygen (O2)	Drug: Oxygen; Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 µg/ml (only O2); 40 sessions in 16 weeks.; Other Names: O2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Direct Hospital Cost (at the end of ozone therapy)	The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros).	16 weeks
Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at the end of ozone therapy)	Self-reported evaluation of 21 physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. Each item is scored from 0 (no affected) to 5 (very much affected). Total range from 0 (best) to 105 (worst)	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy)	Self-reported evaluation of: a) 5 physical and emotional items scored in five levels, from 1 (best: I have no problem) to 5 (worst: I have extreme problem or I am unable to…) and b) additional self-assessment of health by a visual analogue scale (0 = worst health patient can imagine, 100 = best health patient can imagine)	16 weeks
Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy)	Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals	16 weeks
Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy)	Serum levels of pro-inflammatory interleukins and TNFalpha	16 weeks
Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at the end of ozone therapy)	Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability	16 weeks
Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at the end of ozone therapy)	Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)	16 weeks
Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at the end of ozone therapy)	Assessment of 8 types of cognitive abilities by a total 30-point test (0 = worst, 30 = best)	16 weeks
Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at the end of ozone therapy)	Serum levels of high sensitive troponin and proBNP	16 weeks
Change from Baseline (by Echocardiograpy) of: left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (at the end of ozone therapy)	Measurement of volume (in ml) of LVEDV and LVESV.	16 weeks
Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at the end of ozone therapy)	Measurement (in percentage) of LVEF	16 weeks
Change from Baseline in Six-minute walk test (6MWT) (at the end of ozone therapy)	Assessment of functional exercise capacity according to the walking distance covered over a time of 6 minutes (in meters)	16 weeks
Change from Baseline in cerebral blood flow by Transcranial doppler (at the end of ozone therapy)	Doppler ultrasound evaluation of systolic and diastolic velocity in middle cerebral arteries (in cm/s)	16 weeks
Change from Baseline in Hyperspectral image of the supraciliary area (at the end of ozone therapy)	Assessment of the percentage of reflectance for each wavelength	16 weeks
Change from Baseline in lower limb blood flow by Doppler ultrasound (at the end of ozone therapy)	Doppler ultrasound evaluation of systolic and diastolic velocity in lower limbs (in cm/s)	16 weeks
Change from Baseline in Hyperspectral image of lower limbs (at the end of ozone therapy)	Assessment of the percentage of reflectance for each wavelength	16 weeks
Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at 32 weeks)	Self-reported evaluation of 21 physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. Each item is scored from 0 (no affected) to 5 (very much affected). Total range from 0 (best) to 105 (worst)	32 weeks
Direct Hospital Cost (at 32 weeks)	The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros)	32 weeks
Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at 32 weeks)	Self-reported evaluation of: a) 5 physical and emotional items scored in five levels, from 1 (best: I have no problem) to 5 (worst: I have extreme problem or I am unable to…) and b) additional self-assessment of health by a visual analogue scale (0 = worst health patient can imagine, 100 = best health patient can imagine)	32 weeks
Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at 32 weeks)	Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)	32 weeks
Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at 32 weeks)	Assessment of 8 types of cognitive abilities by a total 30-point test (0 = worst, 30 = best)	32 weeks
Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at 32 weeks)	Serum levels of high sensitive troponin and proBNP	32 weeks
Change from Baseline in Biochemical parameters of oxidative stress (at 32 weeks)	Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals	32 weeks
Change from Baseline in Biochemical parameters of inflammation (at 32 weeks)	Serum levels of pro-inflammatory interleukins and TNFalpha	32 weeks
Change from Baseline (by Echocardiograpy) of: left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (at 32 weeks)	Measurement of volume (in ml) of LVEDV and LVESV.	32 weeks
Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at 32 weeks)	Measurement (in percentage) of LVEF	32 weeks
Change from Baseline in Six-minute walk test (6MWT) (at 32 weeks)	Assessment of functional exercise capacity according to the walking distance covered over a time of 6 minutes (in meters)	32 weeks
Change from Baseline in cerebral blood flow by Transcranial doppler (at 32 weeks)	Doppler ultrasound evaluation of systolic and diastolic velocity in middle cerebral arteries (in cm/s)	32 weeks
Change from Baseline in Hyperspectral image of the supraciliary area (at 32 weeks)	Assessment of the percentage of reflectance for each wavelength	32 weeks
Change from Baseline in lower limb blood flow by Doppler ultrasound (at 32 weeks)	Doppler ultrasound evaluation of systolic and diastolic velocity in lower limbs (in cm/s)	32 weeks
Change from Baseline in Hyperspectral image of lower limbs (at 32 weeks)	Assessment of the percentage of reflectance for each wavelength	32 weeks
Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at 32 weeks)	Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability	32 weeks

Collaborators and Investigators

• Sponsor: Bernardino Clavo, MD, PhD
• Collaborators: Servicio Canario de Salud; Red de Investigación en Servicios de Salud en Enfermedades Crónicas; Fundación Canaria de Investigación Sanitaria; Colegio Oficial de Médicos de Las Palmas; Fundación MAPFRE Guanarteme
• Investigators: Study Chair: Bernardino Clavo, MD, PhD, Dr. Negrín University Hospital, Las Palmas, Spain; Study Director: Pedro G Serrano-Aguilar, MD, PhD, Servicio de Evaluación. Servicio Canario de Salud. Spain; Principal Investigator: Francisco Rodríguez-Esparragón, BSc, PhD, Dr. Negrín University Hospital, Las Palmas, Spain; Principal Investigator: Bernardino Clavo, MD, PhD, Dr. Negrín University Hospital, Las Palmas, Spain; Principal Investigator: Renata Linertová, PhD, Servicio de Evaluación. Servicio Canario de Salud. Spain; Principal Investigator: Celestina Amador, MD, PhD, Dr. Negrín University Hospital, Las Palmas, Spain; Principal Investigator: Norberto Santana-Rodríguez, MD, PhD, King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia

Publications and helpful links

General Publications

• Bocci V, Zanardi I, Travagli V. Ozone: a new therapeutic agent in vascular diseases. Am J Cardiovasc Drugs. 2011;11(2):73-82. doi: 10.2165/11539890-000000000-00000.
• Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Front Chem. 2015 Feb 2;3:4. doi: 10.3389/fchem.2015.00004. eCollection 2015.
• Bocci VA, Zanardi I, Travagli V. Ozone acting on human blood yields a hormetic dose-response relationship. J Transl Med. 2011 May 17;9:66. doi: 10.1186/1479-5876-9-66.
• Buyuklu M, Kandemir FM, Set T, Bakirci EM, Degirmenci H, Hamur H, Topal E, Kucukler S, Turkmen K. Beneficial Effects of Ozone Therapy on Oxidative Stress, Cardiac Functions and Clinical Findings in Patients with Heart Failure Reduced Ejection Fraction. Cardiovasc Toxicol. 2017 Oct;17(4):426-433. doi: 10.1007/s12012-017-9400-8.
• Bocci V, Borrelli E, Travagli V, Zanardi I. The ozone paradox: ozone is a strong oxidant as well as a medical drug. Med Res Rev. 2009 Jul;29(4):646-82. doi: 10.1002/med.20150.
• Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Rodriguez V, Macias D, Santana M, Morera J, Fiuza D, Robaina F, Gunderoth M. Effect of ozone therapy on muscle oxygenation. J Altern Complement Med. 2003 Apr;9(2):251-6. doi: 10.1089/10755530360623365.
• Clavo B, Catala L, Perez JL, Rodriguez V, Robaina F. Ozone Therapy on Cerebral Blood Flow: A Preliminary Report. Evid Based Complement Alternat Med. 2004 Dec;1(3):315-319. doi: 10.1093/ecam/neh039. Epub 2004 Oct 6.
• Clavo B, Eltobgy K, Caballero E, Abad C, Rodriguez-Esparragon F, Santana-Rodriguez N. Is There a Place for Ozone Therapy in Patients with Heart Failure? Cardiovasc Toxicol. 2017 Oct;17(4):496-497. doi: 10.1007/s12012-017-9423-1. No abstract available.
• Di Filippo C, Marfella R, Capodanno P, Ferraraccio F, Coppola L, Luongo M, Mascolo L, Luongo C, Capuano A, Rossi F, D'Amico M. Acute oxygen-ozone administration to rats protects the heart from ischemia reperfusion infarct. Inflamm Res. 2008 Oct;57(10):445-9. doi: 10.1007/s00011-008-7237-0.
• Giunta R, Coppola A, Luongo C, Sammartino A, Guastafierro S, Grassia A, Giunta L, Mascolo L, Tirelli A, Coppola L. Ozonized autohemotransfusion improves hemorheological parameters and oxygen delivery to tissues in patients with peripheral occlusive arterial disease. Ann Hematol. 2001 Dec;80(12):745-8. doi: 10.1007/s002770100377. Epub 2001 Oct 13.
• Martinez-Sanchez G, Delgado-Roche L, Diaz-Batista A, Perez-Davison G, Re L. Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease. Eur J Pharmacol. 2012 Sep 15;691(1-3):156-62. doi: 10.1016/j.ejphar.2012.07.010. Epub 2012 Jul 13.

Helpful Links

• EU Clinical Trials Register (European Union Clinical Trials Register)
• Spanish Clinical Studies Registry

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2020
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 30, 2020

Study Registration Dates

• First Submitted: August 23, 2018
• First Submitted That Met QC Criteria: September 4, 2018
• First Posted (Actual): September 6, 2018

Study Record Updates

• Last Update Posted (Actual): April 4, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: ischemic heart disease; heart failure; complementary and integrative medicine; cost-effectiveness ratio; ozone therapy; quality of life related to health; shared decision-making tool
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Ischemia
• Other Study ID Numbers: O3Cardio; 2018-000201-24 (Other Identifier: Registro Español de Ensayos Clínicos (REec)); PIFUN44/17 (Other Grant/Funding Number: Fundación Canaria de Investigación Sanitaria (FUNCANIS))

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