Clinical Trials Register

Summary
EudraCT Number:	2018-000201-24
Sponsor's Protocol Code Number:	O3Cardio
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-06-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2018-000201-24

A.3

Full title of the trial

Effectiveness and cost-effectiveness of Ozone therapy in patients with ischemic heart disease refractory to medical and surgical treatment: Randomized, triple-blind clinical trial.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Effectiveness and cost-effectiveness of Ozone therapy in patients with ischemic heart disease with unsuccessful medical and surgical treatment: Randomized, placebo-controlled, clinical trial.

Efectividad y coste-efectividad del Ozono en el manejo de pacientes con cardiopatía isquémica no candidatos a más tratamiento médico ni quirúrgico: Ensayo clínico aleatorizado, controlado con placebo, triple ciego.

A.3.2

Name or abbreviated title of the trial where available

O3Cardio

A.4.1

Sponsor's protocol code number

O3Cardio

A.5.4

Other Identifiers

Name:	FUNCANIS	Number:	PIFUN44/17
Name:	Código CEIC Negrín	Number:	170144

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bernardino Clavo - Hospital Dr. Negrín
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación Canaria de Investigación Sanitaria (FUNCANIS)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital Dr. Negrín
B.5.2	Functional name of contact point	Bernardino Clavo, Un. Investigación
B.5.3	Address:
B.5.3.1	Street Address	Barranco la ballena s/n
B.5.3.2	Town/ city	Las Palmas
B.5.3.3	Post code	35019
B.5.3.4	Country	Spain
B.5.4	Telephone number	34928449278
B.5.5	Fax number	34928449191
B.5.6	E-mail	bernardinoclavo@gmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Oxigeno Medicinal Gas Carburos Metálicos
D.2.1.1.2	Name of the Marketing Authorisation holder	S.E. de CARBUROS METÁLICOS, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxygen (Ozone)
D.3.2	Product code	O3
D.3.4	Pharmaceutical form	Rectal solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Rectal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ozone
D.3.9.1	CAS number	10028-15-6
D.3.9.3	Other descriptive name	OZONE
D.3.9.4	EV Substance Code	SUB33402
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	medicinal gas (ozone, obtained from oxygen)

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Rectal solution
D.8.4	Route of administration of the placebo	Rectal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ischemic heart disease refractory to medical and surgical treatment.

Cardiopatía isquémica refractaria a tratamiento médico y quirúrgico.

E.1.1.1

Medical condition in easily understood language

Ischemic heart disease in patients with no further medical and surgical options.

Cardiopatía isquémica no candidata a más tratamientos médicos y quirúrgicos.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10019279
E.1.2	Term	Heart failure
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10055224
E.1.2	Term	Cardiac ischemia
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1) To assess the clinical effect and impact on self-perceived health-related quality of life (HRQOL) by addition of Ozone therapy to the standard management of patients with heart failure refractory to medical and surgical treatment.

2) To estimate additional cost and the ratio of cost-effectiveness of adding Ozone therapy to standard treatment.

1) Evaluar el efecto clínico y sobre la calidad de vida relacionada con la salud (CVRS) autopercibida por los pacientes, de añadir Ozonoterapia al manejo estándar de pacientes con cardiopatía refractaria a tratamiento médico y quirúrgico.

2) Estimar los costes adicionales incurridos en la aplicación del ozono y evaluar la ratio de coste-efectividad de añadir ozonoterapia al tratamiento habitual.

E.2.2

Secondary objectives of the trial

3) To assess: a) biochemical parameters; b) cardiovascular parameters; c) adverse effects

4) To develop and evaluate the acceptability of a shared decision making (SDM) tool among professionals and patients, about ozone therapy in patients with heart failure refractory to medical and surgical treatment.

3) Evaluar la evolución de: a) parámetros bioquímicos; b) parámetros cardiovasculares; c) toxicidad del tratamiento.

4) Desarrollar y evaluar la aceptabilidad de una herramienta de ayuda para la toma de decisiones compartidas (HATDC), entre profesionales y pacientes, sobre la ozonoterapia en pacientes con cardiopatía isquémica severa, rebelde y refractaria al tratamiento médico y quirúrgico.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Effectiveness and cost-effectiveness of Ozone therapy in patients with ischemic heart disease refractory to medical and surgical treatment: Randomized, triple-blind clinical trial. Sub-study of biochemical parameters

Effectiveness and cost-effectiveness of Ozone therapy in patients with ischemic heart disease refractory to medical and surgical treatment: Randomized, triple-blind clinical trial. Sub-study of cardiovascular parameters.

Efectividad y coste-efectividad del Ozono en el manejo de pacientes con cardiopatía isquémica refractaria a tratamiento médico y quirúrgico: Ensayo clínico controlado, aleatorizado, triple ciego. Sub-estudio de parámetros bioquímicos.

Efectividad y coste-efectividad del Ozono en el manejo de pacientes con cardiopatía isquémica refractaria a tratamiento médico y quirúrgico: Ensayo clínico controlado, aleatorizado, triple ciego. Sub-estudio de parámetros de función cardiovascular.

E.3

Principal 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.
- Age: 18 to 80 years old
- It should be required clinical diagnosis by 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.
- Pregnant women can not participate in the clinical trial.
- 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.

- Adultos con cardiopatía isquémica sintomática, Grado 3 y 4 de la clasificación de la New York Heart Association (NYHA), a pesar de tratamiento farmacológico máximo, y no subsidiarios revascularización coronaria percutánea o quirúrgica de bypass coronario, así como sin indicación o posibilidad de trasplante cardiaco.
- Edad entre 18 y 80 años
- Se precisará diagnóstico clínico por Servicio de Cardiología y confirmación mediante cateterismo cardiaco con coronariografía.
- Fracción de eyección < 35%.
- Aceptar y firmar el consentimiento informado.
- No podrán participar en el ensayo las pacientes embarazadas
- Las mujeres en edad fértil deberán obtener un resultado negativo en la prueba de embarazo en suero o en orina en la visita de selección, y aceptar el empleo de métodos anticonceptivos adecuados al menos desde los 14 días previos a la primera dosis del fármaco de estudio hasta los 14 días siguientes a la última.

E.4

Principal exclusion criteria

- Pregnancy at the time of enrollment.
- Age < 18 or > 80 years old.
- Limited walking ability due to neurologic or orthopedic impairments of the legs
- Those who are uncapable to fill in the scales used to measure 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.

- Embarazo.
- Edad < 18 años ó > 80 años.
- Imposibilidad para caminar/bipedestación por motivos distintos a su patología cardiaca (encamamiento o afectación física severa permanente por patología osteo-articular, neurológica, etc.)
- Incapacidad para rellenar los cuestionarios de calidad de vida: diagnóstico (por neurólogo) de deterioro cognitivo importante (demencia, enfermedad Alzheimer), patología psiquiátrica reciente, dependencia a drogas o alcohol.
- Ictus (permanente o transitorio) en los 3 meses anteriores al reclutamiento o diagnóstico previo de estenosis carotídea > 80%.
- Síndrome coronario agudo o requerimiento de intervención coronaria percutánea o resvascularización transmiocárdica en los 3 meses previos.
- Pacientes hemodinámica o clínicamente inestables, o que precisen medidas intervencionistas urgentes.
- Existencia de patología pulmonar severa y limitante.
- Elevación por encima de 5 veces el límite máximo de la normalidad de enzimas hepáticas (ALT, AST)
- Elevación de creatinina por encima de 3 veces el límite máximo de la normalidad y/o aclaramiento < 25ml/min y/o que estén en diálisis.
- Patología vascular periférica severa, con dolor en reposo o con ulceración crónica significativa.
- Presencia de neoplasia activa, infección sistémica grave activa o HIV.
- Esperanza de vida (por cualquier causa) inferior a 4 meses.
- Contraindicaciones o imposibilidad para administración de ozonoterapia rectal o para acudir a realizar el tratamiento.
- Alergia conocida al ozono
- No cumplir todos y cada uno de los criterios de inclusión.

E.5 End points

E.5.1

Primary end point(s)

1. Main variable will be the punctuation in Quality of Life (QoL) measured by the Minnesota Living with Heart Failure questionnaire.

2. Direct Hospital Cost: hospital resources (medication, tests, medical visits...) and non-health cost (non-sanitary transport, social services...).

1. La variable principal será la puntuación en la escala de Minnesota (Minnesota Living with Heart Failure Questionnaire) específica para valorar calidad de vida en pacientes con fracaso cardiaco.

2. Costes directos. Se recogerá el uso de recursos hospitalarios (medicación, pruebas, visitas médicas, material sanitario, etc.) y el coste no sanitario (transporte no sanitario, servicios sociales, etc.).

E.5.1.1

Timepoint(s) of evaluation of this end point

These 2 "Primary end points" will be evaluated at 3 timepoints:
1) Basal,
2) at the end of the treatment,
3) at 16 weeks after the end of treatment

Estos 2 “Primary end points” se evaluarán en 3 momentos:

1) Basal,
2) al finalizar el tratamiento,
3) a las 16 semanas de finalizar el tratamiento

E.5.2

Secondary end point(s)

1. Quality of life questionnaire: EQ-5D-5L.
2. Quality of life questionnaire: SF-36
3. Montreal Cognitive Assessment (MOCA) questionnaire
4. Biochemical cardiac parameters
5. Biochemical parameters of oxidative stress
6. Biochemical parameters of inflammation
7. Echocardiographic parameters
8. Ischemia tests
9. Six minute walk test (SMWT)
10. Transcranial doppler
11. Hyperspectral image of supraciliary area.
12. Doppler ultrasound of lower limbs arteries
13. Hyperspectral image of lower limbs.
14. To evaluate the toxicity of rectal ozone therapy in these patients.
15. To evaluate the acceptability of a shared decision making (SDM) tool among professionals and patients.

1. Cuestionario de calidad de vida EQ-5D-5L.
2. Cuestionario de calidad de vida SF-36
3. Valoración neurocognitiva mediante el cuestionario Montreal Cognitive Assessment (MOCA).
4. Parámetros bioquímicos cardiacos
5. Parámetros bioquímicos de estrés oxidativo
6. Parámetros bioquímicos de inflamación
7. Parámetros ecocardiográficos
8. Tests de isquemia,
9. Test de la marcha de 6 minutos,
10. ECO-doppler arterial transcraneal
11. Imagen hiperespectral de región supraciliar.
12. ECO-doppler arterial de miembros inferiores
13. Imagen hiperespectral de miembros inferiores.
14. Evaluar la toxicidad del tratamiento con ozonoterapia vía rectal en estos pacientes.
15. Evaluar la aceptabilidad de los pacientes hacia la herramienta de ayuda para la toma de decisiones compartidas HATDC

E.5.2.1

Timepoint(s) of evaluation of this end point

The "Secondary end points" 1 to 13 will be evaluated at 3 timepoints:
1) Basal,
2) at the end of the treatment,
3) at 16 weeks after the end of treatment

The "Secondary end points" 14 and 15 will be evaluated at the end of follow-up (16 weeks after the end of treatment).

Los “Secondary end points” 1 a 13 se evaluarán en 3 momentos:
1) Basal,
2) al finalizar el tratamiento,
3) a las 16 semanas de finalizar el tratamiento

Los “Secondary end points” 14 y 15 se evaluarán al final del seguimiento (16 semanas tras el fin del tratamiento)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of the last subject (LVLS)

El estudio finalizará con la última visita del último sujeto participante.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	REDISSEC (Red de Investigación en Servicios de Salud en Enfermedades Crónicas)
G.4.3.4	Network Country	Spain

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-11-30

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Orphan Designation Number:
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