Ozone Therapy in Refractory Ischemic Heart Disease.

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Ozone-Group (n = 9): O3/O2 concentration progressively increased from 10 to 30 µg/ml. 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.

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

Conditions
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Ischemic Heart Disease

Intervention / Treatment
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* Drug: Ozone
* Drug: Oxygen


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Interventional Model Description: Standard treatment + ozone therapy (O3/O2) versus Standard treatment + oxygen (O2) as placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ozone Group:<br>Standard treatment + Ozone therapy (O3/O2) | Drug: Ozone<br>* 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.<br>* Other names: O3;|
| Placebo Comparator: Control Group:<br>Standard treatment + Oxygen (O2) | Drug: Oxygen<br>* Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 µg/ml (only O2); 40 sessions in 16 weeks.<br>* Other names: O2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

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 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 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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complementary and integrative medicine, cost-effectiveness ratio, ischemic heart disease, heart failure, ozone therapy, quality of life related to health, shared decision-making tool