Clinical Trials Register

Summary
EudraCT Number:	2021-002744-74
Sponsor's Protocol Code Number:	F3-IROzono-COVID-19
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-31
Trial 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

2021-002744-74

A.3

Full title of the trial

Effect of rectal ozone therapy on the clinical progress of hospitalized patients with mild-moderate covid19 infection: A triple- blind, randomized controlled trial.

Evaluación del efecto del ozono rectal en la evolución de los pacientes hospitalizados con afectación leve/moderada por Covid-19. Ensayo clínico controlado aleatorizado, triple ciego.

A.3.1

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

Effect of rectal ozone therapy in hospitalized patients with mild-moderate COVID-19

Evaluación del efecto del ozono rectal en la evolución de pacientes hospitalizados con afectación leve/moderada por Covid-19

A.4.1

Sponsor's protocol code number

F3-IROzono-COVID-19

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	Sociedad Española de Ozonoterapia - SEOT
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	Sociedad Española de Ozonoterapia - SEOT
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	Sociedad Española de Ozonoterapia - SEOT
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Av. de la Plata, 34
B.5.3.2	Town/ city	Valencia
B.5.3.3	Post code	46013
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034689255019
B.5.6	E-mail	presidente@seot.es
B.Sponsor: 2
B.1.1	Name of Sponsor	Cátedra de Ozonoterapia y Dolor Crónico de la Universidad Católica San Antonio de Murcia - UCAM
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	Cátedra de Ozonoterapia y Dolor Crónico de la Universidad Católica San Antonio de Murcia - UCAM
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	Cátedra de Ozonoterapia y Dolor Crónico de la Universidad Católica San Antonio de Murcia - UCAM
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Campus de los Jerónimos, Guadalupe
B.5.3.2	Town/ city	Murcia
B.5.3.3	Post code	30107
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034627836562
B.5.6	E-mail	jhidalgo@ucam.edu

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	equal
D.3.10.3	Concentration number	40
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	No

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

COVID-19 infection requiring hospitalization

Infección COVID-19 que precisa de hospitalización

E.1.1.1

Medical condition in easily understood language

COVID-19 infection requiring hospitalization

Infección COVID-19 que precisa hospitalización

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.1
E.1.2	Level	LLT
E.1.2	Classification code	10084401
E.1.2	Term	COVID-19 respiratory infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To asses, using controls, the need for oxygen therapy from the onset of ozone treatment until the 15th day of treatment, or until hospital discharge if that occurs earlier, counting the number of days with a SaO2/FiO2 ratio less than 445 (SaO2 = Arterial oxygen saturation; FiO2 = Inspired oxygen fraction).

Evaluar en la población descrita frente a controles el efecto del ozono IR en la necesidad de oxigenoterapia desde el inicio del tratamiento con ozono hasta el día 15 del ensayo o al alta hospitalaria si fuera anterior, contabilizando el número de días con un cociente SaO2/FiO2 menor de 445 (SaO2 = Saturación arterial de oxígeno; FiO2 = Fracción inspirada de oxígeno).

E.2.2

Secondary objectives of the trial

- To compare the number of patients shifting to lower scores (<5) of the WHO ordinal scale.
- To compare the number of patients shifting to higher scores (≥6) of the WHO ordinal scale.
- To compare differences in the length of hospital stay.
- To compare the timeframe until a negative COVID19 PCR test result.
- To compare the number of patients in need for intubation.
- To compare differences in the number of deaths.
- To assess the impact of IR ozone therapy on the basis of the following parameters: Vital signs, blood count and basic biochemistry, electrocardiogram, brain natriuretic peptide N-terminal prohormon, venous gasometry, interleukin 6, lactate dehydrogenase, procalcitonin, amylase, C-reactive protein, ferritin and dimer D.
- To compare bilateral thoracic radiology evolution.
- To compare patterns of medication.
- To assess the global clinical progress of tpatients.
- To record possible adverse events.

- Comparar el número de pacientes que evolucionan a estadios inferiores (<5) de la Escala Numérica de la OMS.
- Comparar el número de pacientes que evolucionan a estadios superiores (≥6) de la Escala Numérica de la OMS.
- Comparar los días de estancia hospitalaria.
- Comparar los días transcurridos hasta el registro de una PCR negativa.
- Comparar el número de pacientes que han necesitado ser intubados.
- Comparar el número de defunciones.
- Evaluar el impacto del tratamiento sobre los parámetros: Constantes vitales, hemograma y bioquímica básica, electrocardiograma, Prohormona N-terminal del péptido natriurético cerebral, gasometría venosa, interleuquina 6, lactato deshidrogenasa, procalcitonina, proteína C reactiva, ferritina y dímero D.
- Evaluar la evolución radiológica torácica bilateral.
- Evaluar el consumo y las pautas de medicación.
- Evaluar la mejoría clínica global de los pacientes.
- Registrar los efectos adversos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnosed patients with COVID-19, confirmed with nasopharyngeal PCR, in a clinical stage that score 5 according to the WHO ordinal scale.
- Patients of legal age, who have given their written informed consent to participate in the trial and to be treated with IR medical ozone.

- Pacientes diagnosticados de COVID19, confirmado con PCR en muestra nasofaríngea, con un estadio clínico que puntúe 5 según la escala numérica de la OMS
- Pacientes mayores de edad que hayan dado su consentimiento y hayan firmado los documentos de consentimiento informado para ser incluidos en el ensayo y para ser tratados con ozono médico mediante IR.

E.4

Principal exclusion criteria

- Patients diagnosed with COVID19 with a clinical stage that doesn’t score 5 according to the WHO numerical scale.
- Patients who have received any form of systemic ozone therapy six months prior to start of the trial.
- Patients who have been previously treated with ozone rectal therapy and have experienced any kind of adverse event.
- Patients with a deficiency in Glucose-6-Phosphate-Dehydrogenase.
- Patients with a chronic systemic co-morbidity classified, in the researcher’s opinion, asclinically decompensated , regardless of their COVID-19 condition.
- Patients suffering from a psychiatric disorder specified on axis I of DSM-V, other than major depression.
- Patients under the age of 60.

- Pacientes diagnosticados de COVID19 con un estadio clínico que no puntúe 5 según la escala numérica de la OMS.
- Pacientes que hayan recibido tratamiento con cualquier modalidad de ozonoterapia sistémica desde seis meses antes de ser reclutados.
- Pacientes que previamente hayan sido tratados y hayan experimentado algún tipo de reacción adversa ante la IR.
- Pacientes con déficit conocido de Glucosa-6-Fosfato-Deshidrogenasa.
- Pacientes con proceso sistémico comórbido crónico que a juicio del investigador se encuentren clínicamente descompensados, independientemente del padecimiento de COVID-19.
- Pacientes que padezcan algún trastorno psiquiátrico especificado en el eje I de la DSM-V que no sea la depresión mayor.
- Pacientes menores de 60 años.

E.5 End points

E.5.1

Primary end point(s)

SaO2/FiO2 ratio

Cociente SaO2/FiO2

E.5.1.1

Timepoint(s) of evaluation of this end point

Days 1, 4, 7, 10, 12 and 15 of the study

Días 1, 4, 7, 10, 12 y 15 del estudio

E.5.2

Secondary end point(s)

- WHO ordinal scale.
- Total dose of medical ozone administered to the patients.
- Clinical variables: temperature (degree Celsius), pulse (bpm).
- Laboratory variables: Ferritin (ng/mL), Dimer D (ng/mL), hemoglobin (g/dL), total leukocytes (10x3 microL) and leukocyte formula (%), platelets (10x3 microL), PCR (mg/dL), VSG (mm/h), ALT/AST, BNPPro, procalcitonin (ng/mL), LDH (U/L), IL-6 (pg/mL)
- Venous blood gas sample.
- Radiological variables: degree of affectation according to the Taylor’s radiological scale.
- Quantitative nasopharyngeal PCR for Covid-19 detection.
- Electrocardiogram.
- Clinical Global Impression Scale (CGI).
- Days of hospitalization.
- Stay in the intensive care unit (days)
- Outcome: discharge from hospital, éxitus.
- Days until negative RT-PCR SARS-COV-2
- Adverse events.
- Mortality, registered at days 15 and 60 of the trial.
- Satisfaction and patient status questionnaire.

- Escala Numérica de la OMS.
- Dosis recibida de ozono médico.
- Variables clínicas: temperatura (grado Celsius), pulso (lpm).
- Variables de laboratorio: Ferritina (ng/mL), Dímero D (ng/mL), hemoglobina (g/dL), leucocitos totales (10x3 microL) y fórmula leucocitaria (%) , plaquetas (10x3 microL), PCR (mg/dL), VSG (mm/h), ALT/AST, BNPPro, procalcitonina (ng/mL), LDH (U/L), IL-6 (pg/mL).
- Gasometría venosa.
- Variables radiológicas: grado de afectación según escala radiológica de Taylor.
- PCR cuantitativa nasofaríngea para COVID-19.
- ECG.
- Escala de Impresión Clínica Global (ICG).
- Estancia hospitalaria (días).
- Estancia en UCI (días).
- Desenlace: alta del hospital, éxitus.
- Negativización de RT-PCR SARS-COV-2 (días)
- Efectos secundarios.
- Mortalidad, medida a los 15 y 60 días tras el tratamiento
- Cuestionario telefónico de satisfacción y estado del paciente (CTSE).

E.5.2.1

Timepoint(s) of evaluation of this end point

Days 1-15 and 60 of the study

Días 1-15 y 60 del estudio

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

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)

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

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Triple ciego

Triple blind

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

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

LVLS

Última visita del último sujeto que participa en el ensayo clínico

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

Ninguno

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-06-14

P. End of Trial
P.	End of Trial Status	Ongoing

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