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Ozone Therapy in Refractory Ischemic Heart Disease. (O3Cardio)

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ClinicalTrials.gov Identifier: NCT03660657
Recruitment Status : Not yet recruiting
First Posted : September 6, 2018
Last Update Posted : September 6, 2018
Sponsor:
Collaborators:
Servicio Canario de Salud
Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC)
Fundación Canaria de Investigación Sanitaria
Information provided by (Responsible Party):
Bernardino Clavo, MD, PhD, Dr. Negrin University Hospital

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.

Condition or disease Intervention/treatment Phase
Ischemic Heart Disease Drug: Ozone Drug: Oxygen Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Standard treatment + ozone therapy (O3/O2) versus Standard treatment + oxygen (O2) as placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Masking of: patients, cardiologist and cardiac surgeons (clinical assessment), investigators obtaining other parameters (quality of life, biochemical and clinical parameters), investigators for statistical analysis
Primary Purpose: Treatment
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
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


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 Name: 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 Name: O2




Primary Outcome Measures :
  1. Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at the end of ozone therapy) [ Time Frame: 16 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)

  2. Direct Hospital Cost (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros).


Secondary Outcome Measures :
  1. Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy) [ Time Frame: 16 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)

  2. Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)

  3. Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Assessment of 8 types of cognitive abilities by a total 30-point test (0 = worst, 30 = best)

  4. Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Serum levels of high sensitive troponin and proBNP

  5. Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals

  6. Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Serum levels of pro-inflammatory interleukins and TNFalpha

  7. 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) [ Time Frame: 16 weeks ]
    Measurement of volume (in ml) of LVEDV and LVESV.

  8. Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Measurement (in percentage) of LVEF

  9. Change from Baseline in Six-minute walk test (6MWT) (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Assessment of functional exercise capacity according to the walking distance covered over a time of 6 minutes (in meters)

  10. Change from Baseline in cerebral blood flow by Transcranial doppler (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Doppler ultrasound evaluation of systolic and diastolic velocity in middle cerebral arteries (in cm/s)

  11. Change from Baseline in Hyperspectral image of the supraciliary area (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Assessment of the percentage of reflectance for each wavelength

  12. Change from Baseline in lower limb blood flow by Doppler ultrasound (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Doppler ultrasound evaluation of systolic and diastolic velocity in lower limbs (in cm/s)

  13. Change from Baseline in Hyperspectral image of lower limbs (at the end of ozone therapy) [ Time Frame: 16 weeks ]
    Assessment of the percentage of reflectance for each wavelength

  14. 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) [ Time Frame: 16 weeks ]
    Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability

  15. Quality of Life (QoL) measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (at 32 weeks) [ Time Frame: 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)

  16. Direct Hospital Cost (at 32 weeks) [ Time Frame: 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)

  17. 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 ]
    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)

  18. Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36) questionnaire (at 32 weeks) [ Time Frame: 32 weeks ]
    Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)

  19. Change from Baseline in Montreal Cognitive Assessment (MOCA) questionnaire (at 32 weeks) [ Time Frame: 32 weeks ]
    Assessment of 8 types of cognitive abilities by a total 30-point test (0 = worst, 30 = best)

  20. Change from Baseline in Biochemical cardiac parameters (High sensitive troponin, pro-brain natriuretic peptide (proBNP)) (at 32 weeks) [ Time Frame: 32 weeks ]
    Serum levels of high sensitive troponin and proBNP

  21. Change from Baseline in Biochemical parameters of oxidative stress (at 32 weeks) [ Time Frame: 32 weeks ]
    Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals

  22. Change from Baseline in Biochemical parameters of inflammation (at 32 weeks) [ Time Frame: 32 weeks ]
    Serum levels of pro-inflammatory interleukins and TNFalpha

  23. Change from Baseline (by Echocardiograpy) of: left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (at 32 weeks) [ Time Frame: 32 weeks ]
    Measurement of volume (in ml) of LVEDV and LVESV.

  24. Change from Baseline (by Echocardiograpy) of left ventricular ejection fraction (LVEF) (at 32 weeks) [ Time Frame: 32 weeks ]
    Measurement (in percentage) of LVEF

  25. Change from Baseline in Six-minute walk test (6MWT) (at 32 weeks) [ Time Frame: 32 weeks ]
    Assessment of functional exercise capacity according to the walking distance covered over a time of 6 minutes (in meters)

  26. Change from Baseline in cerebral blood flow by Transcranial doppler (at 32 weeks) [ Time Frame: 32 weeks ]
    Doppler ultrasound evaluation of systolic and diastolic velocity in middle cerebral arteries (in cm/s)

  27. Change from Baseline in Hyperspectral image of the supraciliary area (at 32 weeks) [ Time Frame: 32 weeks ]
    Assessment of the percentage of reflectance for each wavelength

  28. Change from Baseline in lower limb blood flow by Doppler ultrasound (at 32 weeks) [ Time Frame: 32 weeks ]
    Doppler ultrasound evaluation of systolic and diastolic velocity in lower limbs (in cm/s)

  29. Change from Baseline in Hyperspectral image of lower limbs (at 32 weeks) [ Time Frame: 32 weeks ]
    Assessment of the percentage of reflectance for each wavelength

  30. Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at 32 weeks) [ Time Frame: 32 weeks ]
    Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults with chronic heart failure 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 < 35%
  • Patients who have signed and dated the study ʼs 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 > 80 years old.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03660657


Contacts
Layout table for location contacts
Contact: Bernardino Clavo, MD, PhD (34)928449278 bernardinoclavo@gmail.com
Contact: Celestina Amador, MD, PhD (34)928450513 celesamador@gmail.com

Locations
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Spain
Dr. Negrin University Hospital Not yet recruiting
Las Palmas De Gran Canaria, Las Palmas, Spain, 35019
Contact: Bernardino Clavo, MD, PhD    (+34)928449278    bernardinoclavo@gmail.com   
Contact: Celestina Amador, MD, PhD    (+34)928450513    celesamador@gmail.com   
Sub-Investigator: Cipriano C Abad, MD, PhD         
Sub-Investigator: Miguel A Caramés, MD         
Sub-Investigator: Ruth Martín, MD         
Sub-Investigator: Gustavo I Marrero, PhD         
Sub-Investigator: Leandro F Fernández, MD, PhD         
Sponsors and Collaborators
Bernardino Clavo, MD, PhD
Servicio Canario de Salud
Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC)
Fundación Canaria de Investigación Sanitaria
Investigators
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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: Renata Linertová, PhD Servicio de Evaluación. Servicio Canario de Salud. Spain
Principal Investigator: Bernardino Clavo, MD, PhD Dr. Negrín University Hospital, Las Palmas, Spain
Principal Investigator: Celestina Amador, MD, PhD Dr. Negrín University Hospital, Las Palmas, Spain
Principal Investigator: Francisco Rodríguez-Esparragón, BSc, 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

Additional Information:
Publications:

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Responsible Party: Bernardino Clavo, MD, PhD, MD, PhD, Head of Research Unit, Dr. Negrin University Hospital
ClinicalTrials.gov Identifier: NCT03660657     History of Changes
Other Study ID Numbers: O3Cardio
2018-000201-24 ( EudraCT Number )
2018-000201-24 ( Other Identifier: Registro Español de Ensayos Clínicos (REec) )
PIFUN44/17 ( Other Grant/Funding Number: Fundación Canaria de Investigación Sanitaria (FUNCANIS) )
First Posted: September 6, 2018    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Bernardino Clavo, MD, PhD, Dr. Negrin University Hospital:
complementary and integrative medicine
cost-effectiveness ratio
ischemic heart disease
heart failure
ozone therapy
quality of life related to health
shared decision-making tool

Additional relevant MeSH terms:
Layout table for MeSH terms
Ischemia
Heart Diseases
Myocardial Ischemia
Coronary Artery Disease
Pathologic Processes
Cardiovascular Diseases
Vascular Diseases
Coronary Disease
Arteriosclerosis
Arterial Occlusive Diseases