Clinical Trials Register

Summary
EudraCT Number:	2011-001255-36
Sponsor's Protocol Code Number:	GS-US-205-0162
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-10-18
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

2011-001255-36

A.3

Full title of the trial

Open-Label Phase 2 Trial to Evaluate the Safety and Efficacy of
Aztreonam 75 mg Powder and Solvent for Nebuliser
Solution/Aztreonam for Inhalation Solution (AZLI) in Pediatric
Patients with Cystic Fibrosis (CF) and New Onset Lower Respiratory
Tract Culture Positive for Pseudomonas aeruginosa (PA)

Estudio abierto en fase 2 para evaluar la seguridad y la eficacia de aztreonam 75 mg en polvo y disolvente para solución para inhalación por nebulizador / aztreonam para solución para inhalación (AZLI) en pacientes pediátricos con fibrosis quística (FQ) y nueva manifestación de resultado positivo de Pseudomonas aeruginosa (PA) en cultivo de las vías respiratorias bajas

A.3.1

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

Study of Aztreonam for Inhalation in Children with Cystic Fibrosis and New Infection of the Airways by Pseudomonas aeruginosa bacteria

Estudio de aztreonam lisina para inhalación en niños con fibrosis quística e infección nueva de las vías respiratorias por la bacteria Pseudomonas aeruginosa

A.3.2

Name or abbreviated title of the trial where available

ALPINE (Aztreonam Lysine for Pseudomonas Infection Eradication)

Estudio de aztreonam lisina para la erradicación de la infección por Pseudomonas (ALPINE)

A.4.1

Sponsor's protocol code number

GS-US-205-0162

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/117/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Gilead Sciences, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gilead Sciences, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gilead Sciences International Limited
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441223897496
B.5.5	Fax number	+441223897284
B.5.6	E-mail	clinical.trials@gilead.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	Cayston Aztreonam 75 mg polvo y disolvente para solución para inhalación por nebulizador
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/204
D.3 Description of the IMP
D.3.1	Product name	Aztreonam for Inhalation Solution
D.3.2	Product code	AZLI
D.3.4	Pharmaceutical form	Powder and solvent for nebuliser 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
D.3.9.1	CAS number	78110-38-0
D.3.9.2	Current sponsor code	AZLI
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	SUB05664MIG
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	Yes
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

Cystic fibrosis and new onset lower respiratory tract culture positive for P.aeruginosa.

Fibrosis quística y nueva infección /colonización de las vías respiratorias bajas por P.aeruginosa recién detectada

E.1.1.1

Medical condition in easily understood language

cystic fibrosis and a newly acquired lung infection with a bacterium (germ) called Pseudomonas aeruginosa

Fibrosis quística y nueva infección pulmonar por la bacteria llamada Pseudomona aeruginosa

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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10068288
E.1.2	Term	Cystic fibrosis pulmonary exacerbation
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10070608
E.1.2	Term	Infective pulmonary exacerbation of cystic fibrosis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate safety and efficacy of a 28-day course of AZLI in patients with initial PA pulmonary colonization/infection at Day 28 (end of treatment) and Days 56, 112, and 196 (1, 3, and 6 months after the end of treatment, respectively).

Evaluar la seguridad y la eficacia de un ciclo de 28 días de AZLI en pacientes con infección/colonización pulmonar inicial por PA el día 28 (fin del tratamiento) y los días 56, 112 y 196 (1, 3 y 6 meses después del fin del tratamiento respectivamente).

E.2.2

Secondary objectives of the trial

Below the age of 6 years pharmacokinetic data will be assessed.

Los datos farmacocinéticos se evaluarán hasta los 6 años de edad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Aged 3 months to less than 18 years.
? Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria: sweat chloride level ? 60 mEq/L by quantitative pilocarpine iontophoresis; or a genotype with 2 identifiable mutations consistent with CF; or an abnormal nasal transepithelial potential difference (NPD), and 1 or more
clinical features consistent with CF.
? Documented new onset of positive lower respiratory tract culture for PA within 30 days of study entry (screening visit) defined as either first lifetime documented PA-positive culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year)
? FEV1 ? 80% predicted (for patients ? 6 years of age).
? Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no chest radiograph findings at screening that would require administration of IV antipseudomonal antibiotics, oxygen supplementation, or hospitalization.

? Edad: 3 meses a menos de 18 años
? Diagnóstico de fibrosis quística establecido de acuerdo con los criterios de la Conferencia de Consenso sobre la Fibrosis Quística de 1997: concentración de cloruro en sudor ? 60 mEq/L, evaluada mediante prueba cuantitativa de iontoforesis con pilocarpina; o bien un genotipo con 2 mutaciones identificables que concuerden con la fibrosis quística; o bien una diferencia potencial transepitelial (DPT) nasal anómala, y 1 o más características clínicas que concuerden con la fibrosis quística.
? Nueva manifestación documentada de un cultivo positivo del aparato respiratorio inferior para la PA en los 30 días previos a la incorporación al estudio (visita de selección) definido como un primer cultivo positivo para la PA o bien la reaparición de la PA tras al menos 2 años con cultivos respiratorios negativos para PA (al menos 2 cultivos al año)
? VEF1 ? 80 % del valor predicho (para pacientes ? 6 años de edad).
? Clínicamente estable y sin evidencias de síntomas respiratorios significativos o, si se obtiene para una evaluación clínica, ausencia de hallazgos radiológicos durante la selección que requiriesen la administración de antibióticos i.v. contra Pseudomonas, suplementación con oxígeno u hospitalización.

E.4

Principal exclusion criteria

? Use of IV or inhaled antipseudomonal antibiotics within 2 years of study entry (screening visit).
? Use of oral antipseudomonal antibiotics within 30 days of study entry (screening visit).
? History of hypersensitivity/adverse reaction to aztreonam, or beta-agonists.
? Use of any investigational drug, or device within 28 days of study entry (screening visit).
? Presence of a condition or abnormality that would compromise the patient?s safety or the quality of study data, in the opinion of the investigator.

? Uso de antibióticos i.v. contra Pseudomonas o inhalados durante los 2 años anteriores a la entrada en el estudio (visita de selección).
? Uso de antibióticos contra Pseudomonas orales durante los 30 días anteriores a la entrada en el estudio (visita de selección).
? Historia de hipersensibilidad / reacción adversa al aztreonam o a los agonistas beta.
? Uso de cualquier fármaco o dispositivo en investigación durante los 28 días anteriores a la entrada en el estudio (visita de selección).
? Presencia de un trastorno o anomalía que, en opinión del investigador, ponga en peligro la seguridad del paciente o la calidad de los datos del estudio.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is to evaluate the proportion of patients with PA-negative cultures at all time points during a 6-month monitoring period (through Day 196) after cessation of active treatment; microbiological cultures will be obtained at Baseline, Day 28 (end of treatment), Day 56 (1 month after
completing AZLI), Day 112 (3 months after completing AZLI), and Day 196 (6 months after completing AZLI). PA-specific antibody titers will be obtained at Baseline, Day 28, and Day 196. Safety endpoints will include adverse events, airway reactivity (study drug-induced bronchspasm), vital signs, blood biochemistry
and hematology.

El objetivo principal de este estudio es evaluar la proporción de pacientes con cultivos negativos para PA en todos los momentos temporales durante un periodo de monitorización de 6 meses (hasta el día 196) tras el cese del tratamiento activo. Se realizarán cultivos microbiológicos al inicio, el día 28 (fin del tratamiento), el día 56 (1 mes después de finalizar AZLI), el día 112 (3 meses después de finalizar AZLI) y el día 196 (6 meses después de finalizar AZLI).Se obtendrán las titulaciones de anticuerpos específicos contra PA al inicio, el día 28 y el día 196.Los criterios de valoración de seguridad incluirán los acontecimientos adversos, la reactividad de las vías respiratorias (incluidos broncoespasmos inducidos por el fármaco del estudio), las constantes vitales, la bioquímica sanguínea y la hematología.

E.5.1.1

Timepoint(s) of evaluation of this end point

Microbiological cultures will be obtained at Baseline (Day 1), Day 28 (end of treatment), Day 56 (1 month after completing AZLI), Day 112 (3 months after completing AZLI), and Day 196 (6 months after completing AZLI). PA-specific antibody titers will be obtained at Baseline, Day 28, and Day 196. Airway reactivity (study drug-induced bronchospasm) will be assessed at Baseline and Day 28. Blood biochemistry and hematology will be assessed at Screening, Baseline, Day 28 and Day 196. Adverse events and vital signs will be assessed at Screening, Baseline, Day 28, Day 56, Day 112 and Day 196.

Se realizarán cultivos microbiológicos al inicio, el día 28 (fin del tratamiento), el día 56 (1 mes después de finalizar AZLI), el día 112 (3 meses después de finalizar AZLI) y el día 196 (6 meses después de finalizar AZLI).Se obtendrán las titulaciones de anticuerpos específicos contra PA al inicio, el día 28 y el día 196.Se evaluará la reactividad de las vías respiratorias (broncoespasmo inducido por el fármaco del estudio) al inicio en el día 28. Se valorará la bioquímica se´rica y la hematologái en al visita de selección, en la visita basal, el día 28 y el dái 196. Los efectos adversos y constantes vitales se evaluarán en la visita de selección, en la visita basal, el día 28, el día 56, el día 112 y el día 196.

E.5.2

Secondary end point(s)

In patients ? 6 years of age:
? Change from baseline in FEV1 % predicted at Days 28, 56, 112, and 196;
? Change from baseline in CFQ-R Respiratory Symptoms Score (RSS) at Days 28, 56, 112, and 196.
In all patients:
? Proportion of patients with PA-negative cultures at Days 28, 56, 112 and 196;
? Use of additional (non-study) antipseudomonal antibiotics (as a marker for PA exacerbation);
? Change from baseline in weight, height, and body mass index (BMI) at Days 28, 56, 112, and 196;
In patients < 6 years of age:
? Pharmacokinetics: 1 peak plasma sample will be obtained 1 hour after the first dose of AZLI (Day 1); 1 trough plasma sample will be obtained immediately prior to the last dose of AZLI (Day 28). Plasma aztreonam concentrations at each time point will be summarized (mean, median, standard deviation [SD], minimum, maximum, and number of samples).

En pacientes ? 6 años de edad:
? Cambio respecto al nivel inicial en el % predicho del VEF1 los días 28, 56, 112 y 196
? Cambio respecto al nivel inicial en la puntuación en la escala de síntomas respiratorios de la CFQ-R los días 28, 56, 112 y 196
En todos los pacientes:
? Proporción de pacientes con cultivos negativos para PA los días 28, 56, 112 y 196
? Uso de antibióticos adicionales contra Pseudomonas (no del estudio) (como marcador de la exacerbación de PA)
? Cambio respecto al nivel inicial en el peso, la estatura y el índice de masa corporal (IMC) los días 28, 56, 112 y 196
En pacientes menores de 6 años de edad:
? Farmacocinética: Se obtendrá una muestra plasmática del valor máximo 1 hora después de la primera dosis de AZLI (día 1); asimismo, se obtendrá una muestra plasmática del valor mínimo inmediatamente antes de la última dosis de AZLI (día 28). Se resumirán las concentraciones plasmáticas de aztreonam en cada momento temporal (media, mediana, desviación estándar [DE], mínimo, máximo y número de muestras)

E.5.2.1

Timepoint(s) of evaluation of this end point

In patients ? 6 years of age at Days 28, 56, 112, and 196:
? Change from baseline in FEV1 % predicted;
? Change from baseline in CFQ-R Respiratory Symptoms Score (RSS).
In all patients at Days 28, 56, 112 and 196:
? Proportion of patients with PA-negative cultures;
? Change from baseline in weight, height, and body mass index (BMI).
In all patients at Screening and Days 1, 28, 56, 112 and 196:
? Use of additional (non-study) antipseudomonal antibiotics (as a marker for PA exacerbation).
In patients < 6 years of age:
? Pharmacokinetics: 1 peak plasma sample will be obtained 1 hour after the first dose of AZLI (Day 1); 1 trough plasma sample will be obtained immediately prior to the last dose of AZLI (Day 28).

En pacientes ? 6 años de edad (los días 28, 56, 112 y 196):
? Cambio respecto al nivel inicial en el % predicho del VEF1
? Cambio respecto al nivel inicial en la puntuación en la escala de síntomas respiratorios de la CFQ-R.
En todos los pacientes(los días 28, 56, 112 y 196):
? Proporción de pacientes con cultivos negativos para PA
? Uso de antibióticos adicionales contra Pseudomonas (no del estudio) (como marcador de la exacerbación de PA)
? Cambio respecto al nivel inicial en el peso, la estatura y el índice de masa corporal (IMC)
En pacientes menores de 6 años de edad:
? Farmacocinética: concentración plasmática máxima de 1 hora después de la primera dosis de AZLI (día 1); concentraciones plasmáticas mínimas de inmediatamente antes de la última dosis de azli(día 28)

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

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

E.8.1.2

Open

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Belgium

France

Germany

Ireland

Italy

Netherlands

Poland

Spain

United States

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

Date of last study visit of last study subject.

Fecha de la última visita del ensayo del último paciente

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Infants and young children

Bebés y niños

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

adolescent girls of childbearing potential using contraception

Chicas adolescentes potencialmente fértiles usando métodos anticonceptivos

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Upon completion of study participation, subjects will be referred back to the physician who referred them to the study for continuing care and treatment.

Al final de su participación en el ensayo, los sujetos serán remitidos de nuevo al médico qeu les recomendó el estudio para continuar con sus cuidados y tratamiento

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	European Cystic Fibrosis Society Clinical Trials Network (ECFS-CTN)
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Cystic Fibrosis Foundation Therapeutics (CFFT) Therapeutics Development Network (TDN)
G.4.3.4	Network Country	United States

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-11-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-05-29

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IMP with orphan designation in the indication
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