Clinical Trials Register

Summary
EudraCT Number:	2018-003865-32
Sponsor's Protocol Code Number:	AZLI-2018-AR
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2018-11-16
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

2018-003865-32

A.3

Full title of the trial

Efficacy, safety and pharmacokinetics profile of nebulized Aztreonam Lysine (AZLI) for prevention of Gram negative pneumonia in heavily colonized mechanically ventilated patients: AZLIS

Perfil de eficacia, seguridad y farmacocinética de Aztreonam lisina nebulizada (AZLI) para la prevención de la neumonía gram negativo en pacientes con ventilación mecánica altamente colonizados: AZLIS

A.3.1

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

Clinical trial to evaluate the efficacy, safety and pharmacokinetics profile of nebulized Aztreonam Lysine (AZLI) for prevention of Gram negative pneumonia in heavily colonized mechanically ventilated patients

Ensayo clínico para valorar el perfil de eficacia, seguridad y farmacocinética de Aztreonam lisina nebulizada (AZLI) para la prevención de la neumonía gram negativo en pacientes con ventilación mecánica altamente colonizados

A.3.2

Name or abbreviated title of the trial where available

AZLIS

A.4.1

Sponsor's protocol code number

AZLI-2018-AR

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	Alejandro Rodriguez Oviedo ‐ Critical Care Department – Hospital Universitario de Tarragona Joan XXIII
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	Institut d'Investigació Sanitària Pere Virgili (IISPV)
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	Critical Care Department – Hospital Universitario de Tarragona Joan XXIII
B.5.2	Functional name of contact point	Alejandro Rodríguez Oviedo
B.5.3	Address:
B.5.3.1	Street Address	C/ Mallafré Guasch, 4
B.5.3.2	Town/ city	Tarragona
B.5.3.3	Post code	43007
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34-977295818
B.5.5	Fax number	+34-977214768
B.5.6	E-mail	arodri.hj23.ics@gencat.cat

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	Cayston
D.2.1.1.2	Name of the Marketing Authorisation holder	Cayston
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	AZTREONAM LYSINE
D.3.9.1	CAS number	827611-49-4
D.3.9.2	Current sponsor code	Cayston
D.3.9.3	Other descriptive name	AZTREONAM LYSINE
D.3.9.4	EV Substance Code	SUB30777
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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

Gram negative pneumonia in heavily colonized mechanically ventilated patients

Neumonia gram negativo en pacientes con alta colonización y ventilación mecánica.

E.1.1.1

Medical condition in easily understood language

Gram negative pneumonia in heavily colonized mechanically ventilated patients.

Neumonia gram negativo en pacientes con alta colonización y 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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10035725
E.1.2	Term	Pneumonia NOS
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 evaluate efficacy (microbiological cure) of nebulized AZLI for the prevention of Gram-negative IVAC after 5 day of treatment.

Evaluar la eficacia (cura microbiológica) de AZLI nebulizado para la prevención de IVAC gramnegativos después de 5 días de tratamiento.

E.2.2

Secondary objectives of the trial

- To determine safety and tolerability of nebulized AZLI in ventilated patients
- To determine the pharmacokinetics profile of AZLI in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) in patients who received AZLI nebulized by a novel ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer at baseline, and 10 minutes, 2 hours and 4 hourss post-treatment . Determinations AZLI in respiratory samples will be made at day 1 and at day 2 of treatment.
- To determine plasma Aztreonam levels at 9 time points on day 3 of treatment: before treatment, immediately post-treatment and at 0.5, 1, 2, 4 ,5, 6 and 8 hours post-treatment

- Determinar la seguridad y tolerabilidad de AZLI nebulizado en pacientes ventilados.
- Determinar el perfil farmacocinético de AZLI en aspirado traqueal (EA) o lavado broncoalveolar (BAL) en pacientes que recibieron AZLI nebulizado por un nuevo nebulizador ultrasónico (Aeroneb solo®) más Combihaler® spacer en tiempo basal, y 10 minutos, 2 horas y 4 horas de postratamiento. Las determinaciones de AZLI en muestras respiratorias se realizarán en el día 1 y en el día 2 de tratamiento.
- Para determinar los niveles plasmáticos de Aztreonam en 9 puntos de tiempo el día 3 del tratamiento: antes del tratamiento, inmediatamente después del tratamiento y a las 0,5, 1, 2, 4, 5, 6 y 8 horas después del tratamiento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years.
2. Patients under mechanical ventilation for more than 5 day
3. Patient with heavy colonization by Gram-negative microorganisms
4. No clinical suspicion of infections-related ventilator-associated complications (IVAC) according CDC criteria
5. Patients with ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments.
6. Informed consent signed

1. Edad ≥ 18 años.
2. Pacientes sometidos a ventilación mecánica durante más de 5 días.
3. Paciente con fuerte colonización por microorganismos gramnegativos.
4. No hay sospecha clínica de complicaciones relacionadas con el ventilador relacionadas con infecciones (IVAC) según los criterios de los CDC
5. Pacientes con capacidad para comprender los requisitos del estudio, proporcionar un consentimiento informado por escrito y autorización de uso y divulgación de información médica protegida, y aceptar cumplir con las restricciones del estudio y regresar para las evaluaciones requeridas.
6. Consentimiento informado firmado.

E.4

Principal exclusion criteria

1. Suspected of IVAC.
2. Patients with known hypersensitivity to Aztreonam.
3. Patients who received more than 48 hours of broad spectrum antibiotics.
4. Evidence of active mycobacterium infections, chronic pulmonary infection or bronchial obstruction.
5. Granulomatous disease, lung cancer or lung transplant.
6. Acute respiratory distress syndrome (ARDS)
7.Woman who is pregnant or breast-feeding while enrolled in this study.
8. Any medical condition which, in the opinion of the Investigator, places the patient at an unacceptable risk for toxicities if entered into the clinical study

1. Se sospecha de IVAC.
2. Pacientes con hipersensibilidad conocida al aztreonam.
3. Pacientes que recibieron más de 48 horas de antibióticos de amplio espectro.
4. Evidencia de infecciones por micobacterias activas, infección pulmonar crónica u obstrucción bronquial.
5. Enfermedad granulomatosa, cáncer de pulmón o trasplante de pulmón.
6. Síndrome de dificultad respiratoria aguda (SDRA)
7. Mujer lactante o embarazada mientras esté incluida en el estudio.
8. Cualquier condición médica la cual, en opinión del investigador, sitúe al paciente en una situación de riesgo inaceptable de toxicidad si entrara en el ensayo clínico

E.5 End points

E.5.1

Primary end point(s)

To compare the microbiological cure at day-5 of treatment and the incidence of Gram-negative IVAC between 7th and 10th days after first dose in patients heavily colonized by Gram-negative bacteria treated with nebulized AZLI vs. no treatment.

Comparar la cura microbiológica en el día 5 del tratamiento y la incidencia de IVAC gramnegativos entre los días 7 y 10 después de la primera dosis en pacientes muy colonizados por bacterias gramnegativas tratadas con AZLI nebulizado versus ningún tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

The evaluation of primary endpoint will be on days 5, 7 and 10

Se evaluaran en los días 5, 7 y 10

E.5.2

Secondary end point(s)

- Safety and tolerability of AZLI administered during 5 days in adults patients under mechanical ventilation heavily colonized by Gram-negative bacteria
- The pharmacokinetic profile in tracheal aspirate (EA) or bronchoalveolar lavage (BAL)
- The plasma levels of nebulized AZLI in patients under mechanical ventilation heavily colonized by Gram-negative bacteria.

- Seguridad y tolerabilidad de AZLI administrado durante 5 días en pacientes adultos con ventilación mecánica fuertemente colonizada por bacterias Gram-negativas
- El perfil farmacocinético en aspirado traqueal (EA) o lavado broncoalveolar (BAL)
- Los niveles plasmáticos de AZLI nebulizado en pacientes sometidos a ventilación mecánica fuertemente colonizados por bacterias gramnegativas.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Safety and tolerability from day 1 to 10
- Pharmacokinetics days 1 and 2
- Plasma leves day 3

- Seguridad y tolerabilidad desde el día 1 al 10
- Perfil farmacocinético días 1 y 2
- Niveles de plasma el día 3

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

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)

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

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

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

E.8.2.3

Other

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

LPLV

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)

According to clinical practice

Acorde a práctica clínica

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

2019-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-29

P. End of Trial
P.	End of Trial Status	Restarted

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