Clinical Trials Register

Summary
EudraCT Number:	2011-003697-93
Sponsor's Protocol Code Number:	OXITIB2011
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:	2011-11-04
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

2011-003697-93

A.3

Full title of the trial

Effectiveness of hyperbaric oxygen therapy in the treatment of the open tibial fractures. Open clinical trial, randomized, prospective and controlled.

Efectividad de la oxigenoterapia hiperbárica en el tratamiento de las facturas abiertas de tibia. Ensayo clínico abierto, randomizado, prospectivo y controlado.

A.3.1

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

Effectiveness of hyperbaric oxygen therapy in the treatment of the open tibial fractures. Open clinical trial, randomized, prospective and controlled.

Efectividad de la oxigenoterapia hiperbárica en el tratamiento de las facturas abiertas de tibia. Ensayo clínico abierto, randomizado, prospectivo y controlado.

A.3.2

Name or abbreviated title of the trial where available

OXITIB2011

A.4.1

Sponsor's protocol code number

OXITIB2011

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	Hospital Universitario de Canarias
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	IMETISA
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Johnson and Johnson
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 Canarias
B.5.2	Functional name of contact point	Mario Herrera
B.5.3	Address:
B.5.3.1	Street Address	Ofra s/n. La cuesta.
B.5.3.2	Town/ city	La Laguna
B.5.3.3	Post code	38320
B.5.3.4	Country	Spain
B.5.4	Telephone number	34600557657
B.5.5	Fax number	34922647112
B.5.6	E-mail	herrera42@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	oxígeno medicinal
D.2.1.1.2	Name of the Marketing Authorisation holder	AIR LIQUIDE Santé INTERNATIONAL
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	oxígeno
D.3.4	Pharmaceutical form	Inhalation gas
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	OXYGEN
D.3.9.4	EV Substance Code	SUB14733MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (V/V) percent volume/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Open tibial fractures

Fractura abierta de tibia

E.1.1.1

Medical condition in easily understood language

Open tibial fractures

Fractura abierta de tibia

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10030647
E.1.2	Term	Open fracture of unspecified part of tibia
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

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 investigate whether hyperbaric oxygen therapy in patients with open fracture of tibia grade II and III decreases the rate of surgical complications (necrosis, dehiscence, infection).

Investigar si la terapia con oxígeno hiperbárico en el paciente con fractura abierta grado II y III de tibia disminuye la tasa de complicación de la herida quirúrgica (necrosis, dehiscencia, infección).

E.2.2

Secondary objectives of the trial

1. To investigate whether hyperbaric oxygen increases the partial pressure of oxygen in the traumatized member.
2. To investigate whether hyperbaric oxygen reduces infection rates of fracture focus (deep infection).
3. To investigate whether this therapy reduces the rates of delayed union or nonunion.
4. To investigate whether this therapy reduces the number of amputations.
5. To investigate whether reducing the number of secondary procedures (soft tissue coverage, actions on the bone healing process).
6. To investigate whether decreases the overall average hospital stay

1. Investigar si la oxigenoterapia hiperbárica aumenta la presión parcial de oxígeno en el miembro traumatizado.
2. Investigar si la oxigenoterapia hiperbárica disminuye los índices de infección del foco fracturario (infección profunda).
3. Investigar si esta terapia disminuye los índices de retardo de consolidación o pseudoartrosis.
4. Investigar si esta terapia disminuye el número de amputaciones.
5. Investigar si disminuye el número de procedimientos secundarios (coberturas de partes blandas, actuaciones sobre el proceso de consolidación ósea).
6. Investigar si disminuye la estancia media global hospitalaria

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Subjects of both sexes between 18 and 55.
? Open fracture grade II or III of warm Gustilo classification (Table 1).
? Less than 24 hours of the accident.
? Signing the informed consent of study.
Is not permitted the inclusion of the same patient more than once

? Sujetos de ambos sexos entre 18 y 55 años.
? Fractura abierta grado II o III de tibia de la clasificación de Gustilo (TABLA 1).
? Menos de 24 horas del accidente.
? Firma del consentimiento informado del estudio.
No está permitida la inclusión del mismo paciente más de una vez.

E.4

Principal exclusion criteria

? Contraindications to oxygen therapy (page 8)
? unstable polytrauma.
? chronic peripheral arterial ischemia in the limb after effect.
? Pregnancy (beta HCG determination of blood to all female patients)
? Neoplastic disease.
? Previous fracture of the tibia affects.
? Past infection affects the tibia.
? Refusal of the patient to participate in the study.

? Contraindicaciones a la oxigenoterapia (página 8)
? Politraumatizado inestable.
? Isquemia arterial periférica crónica previa en el miembro efecto.
? Embarazo (determinación de beta HCG en sangre a todas las pacientes femeninas)
? Enfermedad neoplásica.
? Fractura previa de la tibia afecta.
? Infección previa en la tibia afecta.
? Negativa del paciente a participar en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Decreased rates of surgical complications (necrosis, dehiscence, infection): necrosis or dehiscence are easy to measure. Describe the criteria for surgical site infection.

Disminución de los índices de complicación de la herida quirúrgica (necrosis, dehiscencia, infección): La necrosis o dehiscencia son fácilmente objetivables. Describiremos los criterios de infección del sitio quirúrgico.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

30 días

E.5.2

Secondary end point(s)

Increased partial pressure of oxygen in the affected limb. We will evaluate whether hyperbaric oxygen actually produces an increase in oxygen delivery to traumatized tissue , for this, following Bouachour et al (19) will be measured partial pressure of oxygen by pulse oximetry in the affected limb in both patient groups at 2, 4 and 7 days of treatment. On the other hand, pulse oximetry would be conducted before and after hyperbaric oxygen therapy in the treatment group 2 (see Section 6.4).
Deep infection rate (focus of fracture): The deep infection of the surgical site is one that affects the muscle fascia and subfascial tissues (muscle, bone, etc.).. If the infection affects both the surface and at depth, must be labeled as deep. A deep infection must meet at least one of the following requirements:
a. Purulent drainage below the fascia.
b. A deep incision that is open spontaneously or by the surgeon when the patient has at least one of the following signs or symptoms: fever (> 38 º C), or localized pain or tenderness, unless the culture of the incision is negative.
c. An abscess or other evidence of infection affecting the deep incision is at the direct examination of the wound or during reoperation, or by histopathological or radiological study.
d. Diagnosis of deep surgical site infection by the surgeon or physician.
Rate of fracture healing at 3, 6 and 9 months: radiological consolidation of the fracture is defined as evidence of bone trabeculae pass or consolidation of all cortical least two orthogonal projections (anteroposterior and lateral in our trial). The clinical healing was defined as the carrying capacity without pain at the fracture site. The definition of nonunion of the fracture of the tibia is surprisingly difficult. The mean union time of the open fracture of the tibia is significantly higher than the closed fracture. Following authors like Court-Brown et al. (23), the average times vary depending on the degree open fracture and have:
? Level I: 15 weeks
? Level II: 24 weeks
? Grade IIIa: 27 weeks
? Grade IIIb: 38 weeks
? Grade IIIc: 56 weeks

The signs of delayed union or nonunion are: persistent pain in the fracture focus and abnormal mobility, local inflammation and increased local temperature, the fracture line continued in at least one radiographic projection (anteroposterior and lateral).
Reduction of hospital days and number of repeat or secondary interventions.

Aumento de la presión parcial de oxígeno en el miembro afecto. Valoraremos si la oxigenoterapia hiperbárica produce realmente un aumento de la llegada de oxígeno a los tejidos traumatizados, para este, siguiendo a Bouachour y cols (19) se realizará medición de la presión parcial de oxígeno mediante pulsioximetría en el miembro afecto en ambos grupos de pacientes al 2º, 4º y 7º días de tratamiento. Por otro lado, la pulsioximetría se realizaría antes y después de la oxigenoterapia en cámara hiperbárica en el grupo 2 de tratamiento (ver apartado 6.4).
Tasa de infección profunda (foco fracturario): La infección profunda del sitio quirúrgico es aquella que afecta a la fascia muscular y tejidos subfasciales (músculo, hueso, etc.). Si la infección afecta tanto a la superficie como a la profundidad, debe etiquetarse como profunda. Una infección profunda debe cumplir al menos uno de los siguientes requisitos:
a. Drenaje purulento por debajo de la fascia.
b. Una incisión profunda que es abierta espontáneamente o por el cirujano cuando el paciente tiene al menos uno de los siguientes signos o síntomas: fiebre (>38ºC), o dolor localizado o aumento de sensibilidad, a menos que el cultivo de la incisión sea negativo.
c. Un absceso u otra evidencia de infección que afecte a la incisión profunda se encuentre a la exploración directa de la herida o durante la reintervención, o mediante el estudio histopatológico o radiológico.
d. Diagnóstico de infección profunda del sitio quirúrgico por el cirujano o el médico responsable.
Tasa de consolidación de las fracturas a los 3, 6 y 9 meses: La consolidación radiológica de la fractura se define como la evidencia de paso de trabéculas óseas o consolidación de todas las corticales en por lo menos dos proyecciones ortogonales (anteroposterior y lateral en nuestro ensayo). La consolidación clínica se define como la capacidad de carga sin dolor en el foco de fractura. La definición de ausencia de consolidación de la fractura de tibia es sorprendentemente dificultosa. El tiempo promedio de consolidación de la fractura abierta de tibia es notablemente superior al de la fractura cerrada. Siguiendo a autores como Court-Brown y cols. (23), los tiempos promedios varían según el grado de fractura abierta, así tendríamos:
? Grado I: 15 semanas
? Grado II: 24 semanas
? Grado IIIa:27 semanas
? Grado IIIb:38 semanas
? Grado IIIc: 56 semanas

Los signos de retardo de consolidación o pseudoartrosis son: dolor persistente en el foco fracturario y movilidad anormal, inflamación local y aumento de temperatura local, persistencia de la línea fracturaria en al menos una proyección radiológica (anteroposterior y lateral).
Disminución de días de hospitalización y número de reintervenciones o intervenciones secundarias.

E.5.2.1

Timepoint(s) of evaluation of this end point

2,4 and 7 days

2,4 y 7 días

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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.8.4.1

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

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)

After the last visit, the visits will be made according to clinical practice - Detection and evaluation of adverse events, if applicable.

Después de la última visita, se realizarán las visitas según la práctica clínica habitual - Detección y evaluación de Acontecimientos adversos, si procede.

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

2011-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-31

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

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