Clinical Trials Register

Summary
EudraCT Number:	2019-000821-37
Sponsor's Protocol Code Number:	O3NPIQ
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:	2019-07-04
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

2019-000821-37

A.3

Full title of the trial

Effectiveness and cost-effectiveness of Ozone therapy in patients with pain secondary to chemotherapy-induced peripheral neuropathy. Randomized, triple-blind clinical trial.

Efectividad y coste-efectividad del Ozono en el manejo de pacientes con dolor por neuropatía periférica inducida por quimioterapia. Ensayo clínico aleatorizado, triple ciego.

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 pain secondary to peripheral neuropathy induced by chemotherapy. Randomized, placebo-controlled, clinical trial.

Efectividad y relación coste-efectividad del Ozono en el manejo de pacientes con dolor por neuropatía secundaria a tratamiento con quimioterapia. Ensayo clínico aleatorizado, controlado con placebo, triple ciego.

A.3.2

Name or abbreviated title of the trial where available

O3NPIQ

A.4.1

Sponsor's protocol code number

O3NPIQ

A.5.4

Other Identifiers

Name:

CEI/CEIm Hospital Universitario de G. C. Dr Negrín

Number:

2018-156-1

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 Universitario de G. C. 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	Hospital Universitario de G. C. Dr. Negrín
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Fundación Española de Dolor
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 Universitario de G. C. 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 de 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

Pain secondary to chemotherapy-induced peripheral neuropathy.

Dolor secundario a neuropatía periférica inducida por quimioterapia.

E.1.1.1

Medical condition in easily understood language

Painful neuropathy secondary to chemotherapy

Dolor por neuropatía secundaria a quimioterapia

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10079545
E.1.2	Term	Chemotherapy induced peripheral neuropathy
E.1.2	System Organ Class	100000004852

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 cancer of colon and rectum, treated with oxaliplatin and suffering painful chemotherapy-induced peripheral neuropathy Grade > = 2 for > 3 months.

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

1. Evaluar el efecto clínico en el nivel del dolor y sobre la calidad de vida relacionada con la salud (CVRS) autopercibida por los pacientes, de añadir Ozonoterapia al manejo habitual de pacientes con cáncer de colon y recto, tratados con oxaliplatino, que presenten desde hace más de 3 meses NPIQ de Grado > = 2 (síntomas moderados y/o limitación en las actividades instrumentales de la vida diaria) o superior.

2. Estimar los costes adicionales incurridos en la aplicación del ozono y evaluar el coste-efectividad de añadir ozonoterapia en pacientes con NPIQ, en comparación con el tratamiento habitual exclusivo.

E.2.2

Secondary objectives of the trial

1. To evaluate changes in Quality of Life (QOL) according to the “EQ-5D-5L” questionnaire.
2. To evaluate changes in Quality of Life (QOL) according to the “SF-36v2, 1 week” questionnaire.
3. To evaluate changes in biochemical parameters of oxidative stress.
4. To evaluate changes in biochemical parameters of inflammation.
5. To assess the diagnostic and predictive value of hiperespectral imaging in these patients.
6. To evaluate changes in the level of anxiety and depression according to the Hamilton scale.
7. To evaluate changes in nerve conduction studies in the painful area.
8. To evaluate the toxicity of rectal ozone therapy in these patients.
9. To evaluate the acceptability of a shared decision making (SDM) tool among professionals and patients

1. Evaluar la evolución de la calidad de vida según el cuestionario de calidad de vida “EQ-5D-5L”.
2. Evaluar la evolución de la calidad de vida según el cuestionario de calidad de vida “SF-36v2, 1 semana”.
3. Evaluar la evolución de parámetros bioquímicos de estrés oxidativo.
4. Evaluar la evolución de parámetros bioquímicos de inflamación.
5. Analizar el valor diagnóstico y pronóstico de la imagen hiperespectral en estos pacientes.
6. Evaluar la evolución de la ansiedad y la depresión en estos pacientes.
7. Evaluar la evolución la alteración y evolución de la conducción nerviosa en estos pacientes.
8. Evaluar los posibles efectos adversos
9. Evaluar la aceptabilidad de los pacientes hacia la herramienta de ayuda para la toma de decisiones compartidas HATDC

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adults > = 18 years old.
2. Cancer of colon and rectum in any stage, with treatment including oxaliplatin, chemotherapy finished > 3 months before and life expectancy > 6 months.
3. Clinical diagnosis painful chemotherapy-induced peripheral neuropathy, toxicity Grade > 2 according to the Common Toxicity Criteria for Adverse Events (CTCAE) del National Cancer Institute de EEUU, v.5.0, for > 3 months and without inclusion of new treatments for pain and/or neuropathy for > 1 month.
4. “Average pain” > 4/10 according to the Brief Pain Inventory-Short Form (BPI-SF) > 3 months beyond chemotherapy completion.
5. Pregnant women can not participate in the clinical trial.
6. 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 ozone therapy session up to 14 days after the last one.
7. Patients who have signed and dated the study ʼs specific informed consent.

1. Adultos > = 18 años de edad.
2. Cáncer de colon y recto en cualquier estadio, que hayan sido tratados con oxaliplatino, hayan acabado la QT hace > 3 meses antes y tengan una esperanza de vida > 6 meses.
3. Diagnóstico clínico de NPIQ Grado > 2 según la escala de toxicidad de Common Toxicity Criteria for Adverse Events (CTCAE) del National Cancer Institute de EEUU, v.5.0, con > 3 meses de duración, y sin incorporación de nuevos tratamientos analgésicos o para la neuropatía durante el último mes.
4. “Dolor promedio” de > 4/10 en el Brief Pain Inventory-Short Form (BPI-SF) tras > 3 meses de acabada la Quimioterapia.
5. No podrán participar en el ensayo las pacientes embarazadas.
6. 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 sesión de ozonoterapia hasta los 14 días siguientes a la sesión.
7. Aceptar y firmar el consentimiento informado.

E.4

Principal exclusion criteria

1. Age < 18 years old.
2. Pregnancy at the time of enrollment.
3. Women with childbearing potential who are unwilling to perform a pregnancy test and/or employ adequate contraception from the 14 days prior to the first ozone therapy session up to 14 days after the last one.
4. History or symptoms of peripheral neuropathy (compressive or diabetic neuropathy) in the same area prior to receiving neurotoxic chemotherapy.
5. Psychiatric illness or social situations that would limit compliance with study requirements.
6. Those who are uncapable to fill in the scales used to measure quality of life variables
7. Specific liver enzymes [Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) > 5 times the upper limit of normal
8. Increased creatinine > 3 times the upper limit of normal.
9. Hemodynamically or clinically unstable patients or uncontrolled severe illness.
10. Uncontrolled cancer disease requiring chemotherapy treatment.
11. Leptomeningeal carcinomatosis.
12. Life expectancy < 6 months
13. Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
14. Known allergy to ozone.
15. Patients who do not meet all the inclusion criteria.

1. Edad < 18 años.
2. Mujer embarazada o con sospecha de estarlo.
3. Mujeres en edad fértil que no estén dispuestas a realizarse un test de embarazo y/o emplear medidas anticonceptivas adecuadas desde 14 días antes de la primera sesión hasta 14 días después de la última sesión.
4. Neuropatía diabética o compresiva con afectación previa del área de los síntomas: síndrome del túnel del carpo/tarso, radiculopatía, estenosis de canal, plexopatía braquial.
5. Trastornos psiquiátricos severos (ideación de autolisis, enfermedad bipolar, depresión severa, trastorno mayor de la ingesta, abuso de alcohol u otras drogas) o situación social que pudiera limitar la adecuada cumplimentación del protocolo y/o los cuestionarios de calidad de vida.
6. Incapacidad para rellenar los cuestionarios de calidad de vida: diagnóstico (por neurólogo) de deterioro cognitivo importante (demencia, enfermedad Alzheimer).
7. Elevación por encima de 5 veces el límite máximo de la normalidad de enzimas hepáticas (ALT, AST)
8. Creatinina > 3 veces el límite alto de la normalidad.
9. Paciente hemodinámica o clínicamente inestable, o que precise medidas intervencionistas urgentes o a corto plazo o con enfermedad severa no controlada.
10. Neoplasia en progresión precisando Quimioterapia.
11. Carcinomatosis leptomeningea
12. Esperanza de vida (por cualquier causa) < 6 meses.
13. Contraindicaciones o imposibilidad para ttº con ozono rectal o para acudir a realizar el ttº.
14. Alergia conocida al ozono.
15. No cumplir todos y cada uno de los criterios de inclusión

E.5 End points

E.5.1

Primary end point(s)

1. The most relevant main variable will be the “average pain” according to the Brief Pain Inventory-Short Form (BPI-SF).
2. Direct Hospital Cost: hospital resources (medication, tests, medical visits...) and associated costs.

1. La variable principal más importante será el nivel de “dolor promedio” según el Brief Pain Inventory-Short Form (BPI-SF).
2. Costes hospitalarios directos. Se recogerá el uso de recursos hospitalarios (medicación, pruebas, visitas médicas, material sanitario, etc.) y el coste asociado (a partir de la información generada en los Servicios de Admisión, Gestión Contable y Contabilidad Analítica de nuestro Hospital).

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 12 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 12 semanas de finalizar el tratamiento

E.5.2

Secondary end point(s)

1. Quality of Life (QOL) measured by “EQ-5D-5L” questionnaire.
2. Quality of Life (QOL) measured by “SF-36v2, 1 week” questionnaire.
3. Biochemical parameters of oxidative stress
4. Biochemical parameters of inflammation
5. Hyperspectral image of painful area.
6. Levels of anxiety and depression according to the Hamilton scale.
7. Nerve conduction studies in the painful area.
8. Toxicity of rectal ozone therapy in these patients.
9. 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-36v2, 1 semana.
3. Parámetros bioquímicos de estrés oxidativo.
4. Parámetros bioquímicos de inflamación.
5. Imagen hiperespectral de la zona afecta.
6. Grado de ansiedad y depresión mediante la escala de Hamilton.
7. Estudios de conducción nerviosa en la región afecta.
8. Toxicidad del tratamiento con ozonoterapia vía rectal en estos pacientes.
9. 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 6 will be evaluated at 3 timepoints:
1. Basal,
2. at the end of the treatment,
3. at 12 weeks after the end of treatment

The "Secondary end point" 7 will be evaluated at 2 timepoints:
1. Basal,
2. al finalizar el tratamiento,

The "Secondary end points" 8 and 9 will be evaluated at the end of follow-up (12 weeks after the end of treatment).

Los "Secondary end points" 1 a 6 se evaluarán en 3 momentos:
1. Basal,
2. al finalizar el tratamiento,
3. a las 12 semanas de finalizar el tratamiento

El "Secondary end point" 7 se evaluará en 2 momentos:
1. Basal,
2. al finalizar el tratamiento,

Los "Secondary end points" 8 y 9 se evaluarán al final del seguimiento (12 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

The 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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

2019-12-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-03

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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