Clinical trial NCT03660657: Ozone Therapy in Refractory Ischemic Heart Disease.
Official title: Effectiveness and Cost-effectiveness of Ozone Therapy in Patients With Ischemic Heart Disease Refractory to Medical and Surgical Treatment: Randomized, Triple-blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Ischemic Heart Disease
Keywords: complementary and integrative medicine
cost-effectiveness ratio
ischemic heart disease
heart failure
ozone therapy
quality of life related to health
shared decision-making tool
Lead sponsor: Dr. Negrin University Hospital
Sponsor class: OTHER
Collaborators: name: Servicio Canario de Salud
name: Red de Investigación en Servicios de Salud en Enfermedades Crónicas
name: Fundación Canaria de Investigación Sanitaria
name: Colegio Oficial de Médicos de Las Palmas
name: Fundación MAPFRE Guanarteme
First posted: 2018-09-06
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Standard treatment + ozone therapy (O3/O2) versus Standard treatment + oxygen (O2) as placebo
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Direct Hospital Cost (at the end of ozone therapy)
timeFrame: 16 weeks
Secondary outcomes:
measure: Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy)
timeFrame: 16 weeks
measure: 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)
timeFrame: 16 weeks
measure: Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Six-minute walk test (6MWT) (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in cerebral blood flow by Transcranial doppler (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Hyperspectral image of the supraciliary area (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in lower limb blood flow by Doppler ultrasound (at the end of ozone therapy)
timeFrame: 16 weeks
measure: Change from Baseline in Hyperspectral image of lower limbs (at the end of ozone therapy)
timeFrame: 16 weeks
measure: 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)
timeFrame: 16 weeks
measure: Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at 32 weeks)
timeFrame: 32 weeks
measure: Direct Hospital Cost (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Biochemical parameters of oxidative stress (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Biochemical parameters of inflammation (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline (by Echocardiograpy) of: left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Six-minute walk test (6MWT) (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in cerebral blood flow by Transcranial doppler (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Hyperspectral image of the supraciliary area (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in lower limb blood flow by Doppler ultrasound (at 32 weeks)
timeFrame: 32 weeks
measure: Change from Baseline in Hyperspectral image of lower limbs (at 32 weeks)
timeFrame: 32 weeks
measure: Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at 32 weeks)
timeFrame: 32 weeks
Other outcomes:
Locations:
city: Las Palmas De Gran Canaria
country: Spain
facility: Dr. Negrin University Hospital
state: Las Palmas
Study officials:
affiliation: Dr. Negrín University Hospital, Las Palmas, Spain
name: Bernardino Clavo, MD, PhD
role: STUDY_CHAIR
affiliation: Servicio de Evaluación. Servicio Canario de Salud. Spain
name: Pedro G Serrano-Aguilar, MD, PhD
role: STUDY_DIRECTOR
affiliation: Servicio de Evaluación. Servicio Canario de Salud. Spain
name: Renata Linertová, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dr. Negrín University Hospital, Las Palmas, Spain
name: Bernardino Clavo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dr. Negrín University Hospital, Las Palmas, Spain
name: Celestina Amador, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dr. Negrín University Hospital, Las Palmas, Spain
name: Francisco Rodríguez-Esparragón, BSc, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia
name: Norberto Santana-Rodríguez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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citation: 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.
citation: 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.
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