Ozone Therapy in Refractory Ischemic Heart Disease.

Phase 3TerminatedNCT03660657

Bernardino Clavo, MD, PhD1 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Ischemic Heart Disease

Interventions

OzoneDRUG

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.

OxygenDRUG

Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 µg/ml (only O2); 40 sessions in 16 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

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.

Locations (1)

Dr. Negrin University Hospital

Las Palmas de Gran Canaria, Las Palmas, Spain

Outcomes

Primary Outcomes

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)

Time frame: 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).

Time frame: 16 weeks

Secondary Outcomes

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)

Time frame: 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)

Time frame: 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)

Time frame: 16 weeks

Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at the end of ozone therapy)

Data from ClinicalTrials.gov

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Serum levels of high sensitive troponin and proBNP

Time frame: 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

Time frame: 16 weeks

Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy)

Serum levels of pro-inflammatory interleukins and TNFalpha

Time frame: 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.

Time frame: 16 weeks

Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at the end of ozone therapy)

Measurement (in percentage) of LVEF

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 16 weeks

Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at 32 weeks)

Time frame: 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)

Time frame: 32 weeks

Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at 32 weeks)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 32 weeks

Change from Baseline in Biochemical parameters of inflammation (at 32 weeks)

Serum levels of pro-inflammatory interleukins and TNFalpha

Time frame: 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.

Time frame: 32 weeks

Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at 32 weeks)

Measurement (in percentage) of LVEF

Time frame: 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)

Time frame: 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)

Time frame: 32 weeks

Change from Baseline in Hyperspectral image of the supraciliary area (at 32 weeks)

Assessment of the percentage of reflectance for each wavelength

Time frame: 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)

Time frame: 32 weeks

Change from Baseline in Hyperspectral image of lower limbs (at 32 weeks)

Assessment of the percentage of reflectance for each wavelength

Time frame: 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

Time frame: 32 weeks