Clinical Trials Register

Summary
EudraCT Number:	2015-001109-15
Sponsor's Protocol Code Number:	BIOTOB
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:	2015-11-18
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

2015-001109-15

A.3

Full title of the trial

A Phase III clinical trial randomized and blinded on the use of inhaled tobramycin compared with placebo in patients undergoing mechanical ventilation and colonized by Gram negative bacteria for effectiveness in reducing the time mecánica.mechanical ventilation ventilation in patients Undergoing mechanical ventilation and colonized by Gram Negative

Ensayo clínico fase III aleatorizado y ciego sobre el uso de tobramicina inhalada comparada con placebo en pacientes sometidos a ventilación mecánica y colonizados por bacterias Gram negativas para comprobar su eficacia en la reducción del tiempo de ventilación mecánica.mechanical ventilation in patients undergoing mechanical ventilation and colonized by Gram Negative

A.3.1

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

Study the efficacy on the use of inhaled tobramycin in the reduction of the time to mechanical ventilation in patients undergoing mechanical ventilation and colonized by Gram Negative

Estudio de la eficacia en el uso de tobramicina inhalada en la reducción del tiempo para la ventilación mecánica en pacientes sometidos a ventilación mecánica y colonizado por bacterias Gram negativo

A.4.1

Sponsor's protocol code number

BIOTOB

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	INSTITUTO DE INVESTIGACION SANITARIA LA FE
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	INSTITUTO DE INVESTIGACION SANITARIA LA FE
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	INSTITUTO DE INVESTIGACION SANITARIA LA FE
B.5.2	Functional name of contact point	UREC
B.5.3	Address:
B.5.3.1	Street Address	Avenida Fernando Abril Martorell, 106
B.5.3.2	Town/ city	VALENCIA
B.5.3.3	Post code	46026
B.5.3.4	Country	Spain
B.5.4	Telephone number	34961246611
B.5.5	Fax number	34961246620
B.5.6	E-mail	investigacion_clinica@iislafe.es

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	Tobramycin
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.3.4	Pharmaceutical form	Inhalation solution
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.3.8	INN - Proposed INN	TOBRAMYCIN
D.3.9.3	Other descriptive name	TOBRAMYCIN INHALATE
D.3.9.4	EV Substance Code	SUB11134MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Inhalation solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

critically ill patients undergoing mechanical ventilation

Pacientes críticos sometidos a ventilación mecánica

E.1.1.1

Medical condition in easily understood language

critically ill patients undergoing mechanical ventilation

Pacientes críticos sometidos a ventilación mecánica

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10066821
E.1.2	Term	Mechanical ventilation complication
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

Reduce by 10% the duration of mechanical ventilation in patients treated with inhaled tobramycin compared to patients treated with placebo.

Reducir en un 10% el tiempo de ventilación mecánica en los pacientes tratados con tobramicina inhalada en comparación con los pacientes tratados con placebo.

E.2.2

Secondary objectives of the trial

Reduce by 10% the time of artificial airway in patients treated with inhaled tobramycin compared to patients treated with placebo
- Evaluate the clinical and microbiological response in patients treated with inhaled tobramycin compared to patients treated with placebo.
- Analyze the formation of biofilm and the persistence of viable microorganisms on the surface of the endotracheal tube or tracheostomy tube removed after treatment with inhaled tobramycin vs. placebo.
- Analyze the occurrence of respiratory infections until day 28 after the last dose of treatment in patients treated with inhaled tobramycin compared to patients treated with placebo.
- Evaluate the emergence of resistance to tobramycin in respiratory samples and microbiological samples from other sources in patients treated with inhaled tobramycin compared to patients treated with placebo.
- Analyze the pharmacokinetic behavior of inhaled tobramycin in the study population.

Reducir en un 10% el tiempo de vía aérea artificial en los pacientes tratado con tobramicina inhalada en comparación con los pacientes tratados con placebo
- Evaluar la respuesta clínica y microbiológica en los pacientes tratados con tobramicina inhalada en comparación con los pacientes tratados con placebo.
- Analizar la formación de biofilm y la persistencia de microorganismos sobre la superficie del tubo endotraqueal o la cánula de traqueostomía retirados tras el tratamiento con tobramicina inhalada vs. placebo.
- Analizar la aparición de infecciones respiratorias hasta el día 28 tras la última dosis de tratamiento en los pacientes tratados con tobramicina inhalada en comparación con los pacientes tratados con placebo.
- Evaluar la aparición de resistencia a la tobramicina en muestras respiratorias y microbiológicas de otras procedencias en los pacientes tratados con tobramicina inhalada vs pacientes tratados con placebo.
- Analizar el comportamiento farmacocinético

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients older than 18 years, admitted to the ICU, undergoing mechanical ventilation and carriers artificial airway (endotracheal tube or tracheostomy) for at least 7 days and meet the following requirements:
a. Persistent colonization of the airway sensitive to tobramycin Gram negative bacteria. Persistent define as the isolation of the same organism in at least two respiratory samples with minimal time separation of 72h.
b. Abundant and / or purulent Bronchorrhea that the judgment of the attending physician may interfere with the patient's respiratory process

Pacientes mayores de 18 años, ingresados en UCI, sometidos a ventilación mecánica y portadores de vía aérea artificial (tubo endotraqueal o traqueostomía) durante al menos 7 días y que cumplan los siguientes requisitos:
a. Colonización persistente de la vía aérea por bacterias Gram negativas sensibles a tobramicina. Definiremos persistente como el aislamiento del mismo microorganismo en al menos dos muestras respiratorias obtenidas con un tiempo de separación mínimo de 72h.
b. Broncorrea abundante y/o purulenta que a juicio del médico asistencial podría interferir en el proceso respiratorio del paciente

E.4

Principal exclusion criteria

- Allergy to aminoglycosides.
- Refusal of informed consent.
- Renal insufficiency, creatinine clearance <60 ml / min or use of renal replacement
- Pregnant or lactating women.
- Data suggestive of respiratory infection associated with mechanical ventilation (pneumonia or tracheobronchitis) at the time of inclusion in the study.
Respiratory colonization by bacteria resistant to tobramycin.
- Limitation of therapeutic effort.
- Participation in another clinical trial within the previous 30 days.
- Bronchiectasis or cystic fibrosis. - Patients being treated with furosemide, urea or mannitol

- Alergia a aminoglucósidos.
- Denegación del consentimiento informado.
- Insuficiencia renal, aclaramiento creatinina <60 ml/min o uso de depuración extrarrenal
- Mujeres embarazadas o en periodo de lactancia.
- Datos sugestivos de infección respiratoria asociada a la ventilación mecánica (neumonía o traqueobronquitis) en el momento de inclusión en el estudio.
Colonización respiratoria por bacterias resistentes a la tobramicina.
- Limitación del esfuerzo terapéutico.
- Participación en otro ensayo clínico en los 30 días previos.
- Bronquiectasias o fibrosis quística. - Pacientes que estén siendo tratados con furosemida, urea o manitol

E.5 End points

E.5.1

Primary end point(s)

Duration of mechanical ventilation

Tiempo de ventilación mecánica

E.5.1.1

Timepoint(s) of evaluation of this end point

Time measured in hours from the onset of mechanical ventilation to successful cessation of mechanical ventilation.

Tiempo medido en horas desde el inicio de la ventilación mecánica hasta el cese con éxito de la ventilación mecánica.

E.5.2

Secondary end point(s)

Artificial airway time
Clinical response
Microbiological response.
Microbiological Elimination
Respiratory infection associated with mechanical ventilation: The diagnosis of pneumonia associated with mechanical ventilation (VAP) will be in accordance with established criteria. Presence of pulmonary infiltrates or progression of preexisting condensation on chest radiograph plus two of the following three clinical variables: fever> 38 °, leukocytosis (> 12,000 / mm3) or leukopenia (<4,000 / mm3) and purulent respiratory secretions.

Tiempo de vía aérea artificial
Respuesta clínica
Respuesta microbiológica.
Erradicación microbiológica
Infección respiratoria asociada a la ventilación mecánica: El diagnóstico de neumonía asociada a la ventilación mecánica (NAVM) se realizará de acuerdo con los criterios establecidos . Presencia de infiltrados pulmonares o progresión de condensación preexistente en la radiografía de tórax más dos de las tres variables clínicas siguientes: fiebre >38º, leucocitosis (>12.000/mm3) o leucopenia (<4.000/mm3) y secreciones respiratorias purulentas.

E.5.2.1

Timepoint(s) of evaluation of this end point

Time artificial airway: part time in hours from the insertion of the artificial airway to the successful withdrawal thereof
Clinical response: Measured as the improvement of gas exchange and the disappearance of purulent secretions.
Microbiological response: Positive if there is a reduction of at least 50% in quantitative microbiological culture of respiratory specimens after initiation of treatment.
Microbiological eradication: when the initial bacteria can not isolate the corresponding crops.
Respiratory infection associated with mechanical ventilation Diagnostic confirmation will be by quantitative culture of respiratory sample with the cutoff established by the Spanish Society of Infectious Diseases and Clinical Microbiology

Tiempo de vía aérea artificial: Tiempo 1/2 en horas desde la inserción de la vía aérea artificial hasta la retirada con éxito de la misma
Respuesta clínica: Medida como, la mejoría del intercambio gaseoso y la desaparición de las secreciones purulentas.
Respuesta microbiológica: Será positiva si hay una reducción de al menos el 50% en cultivo microbiológico cuantitativo de muestras respiratorias tras el inicio del tratamiento.
Erradicación microbiológica: cuando no se aíslen las bacterias iniciales en los cultivos correspondientes.
Infección respiratoria asociada a la ventilación mecánica: La confirmación diagnóstica será por cultivo cuantitativo de muestra respiratoria, con el punto de corte establecido por la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

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

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

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

Yes

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients admitted to the ICU, incapable of giving informed consent

Pacientes ingresados en la UMI, incapaces de otorgar el consentimiento informado

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-02-18

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