Clinical Trials Register

Summary
EudraCT Number:	2015-003040-39
Sponsor's Protocol Code Number:	CTBM100G2202
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:	2016-08-30
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

2015-003040-39

A.3

Full title of the trial

A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non-Cystic Fibrosis Bronchiectasis and pulmonary P. aeruginosa infection

Estudio aleatorizado, con enmascaramiento y grupos paralelos, multicéntrico, de búsqueda de dosis, para evaluar la eficacia, la seguridad y la tolerabilidad de diferentes dosis de tobramicina en polvo para inhalación en pacientes con bronquiectasia no debida a fibrosis quística e infección pulmonar por P. aeruginosa

A.3.1

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

Dose-finding Study to Assess the Efficacy, Safety and Tolerability of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection

Estudio de búsqueda de dosis para evaluar la eficacia, la seguridad y la tolerabilidad de la tobramicina en polvo para inhalación en pacientes con bronquiectasia no debida a FQ e infección pulmonar por P. aeruginosa

A.4.1

Sponsor's protocol code number

CTBM100G2202

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Queen's University of Belfast
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico Oncología
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34900353036
B.5.5	Fax number	34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	TOBI Podhaler
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tobramycin inhalation powder
D.3.2	Product code	TBM100
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
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.3.9.1	CAS number	32986-56-4
D.3.9.2	Current sponsor code	TBM100
D.3.9.3	Other descriptive name	TOBRAMYCIN
D.3.9.4	EV Substance Code	SUB11134MIG
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	28
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation powder, hard capsule
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

Pseudomonas aeruginosa infection in patients with non-cystic fibrosis bronchiectasis

Infección por Pseudomonas aeruginosa en pacientes con bronquiectasia no debida a fibrosis quística.

E.1.1.1

Medical condition in easily understood language

Non-cystic Fibrosis Bronchiectasis

Bronquiectasia no debida a fibrosis quística.

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10006445
E.1.2	Term	Bronchiectasis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10070295
E.1.2	Term	Infective exacerbation of bronchiectasis
E.1.2	System Organ Class	10021881 - Infections and infestations

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 the effect of different doses of TIP administered o.d. and one b.i.d. dose on the change in P. aeruginosa bacterial load in sputum as assessed by the change in colony forming units (CFUs) from baseline to Day 29 of treatment, each compared to placebo.
- To assess the safety and tolerability with different doses of TIP administered o.d. and b.i.d. and different regimens (TIP and TIP/placebo cyclical) during the treatment epoch (112 days) and during the follow-up epoch (56 days) for each as compared to placebo.

- Evaluar el efecto de diferentes dosis de TPI en la variación de la carga bacteriana de P. aeruginosa en el esputo, según la variación en las unidades formadoras de colonias (UFC) desde el período basal hasta el día 29 de tratamiento, en cada caso comparado con el placebo.
- Evaluar la seguridad y la tolerabilidad de diferentes dosis de TPI y de diferentes pautas posológicas, tanto durante el tratamiento como durante el período de seguimiento, en comparación con el placebo.

E.2.2

Secondary objectives of the trial

Key secondary objectives (for the full list please refer to the protocol):

- To assess the effect of different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP and TIP/placebo cyclical) on the frequency, rate (by patient- months), severity and time to onset of pulmonary exacerbations at the end of the treatment epoch and over the entire study, each compared to placebo.
- To assess the efficacy profile of different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP and TIP/placebo cyclical), as measured by the time to first use, proportion of patients requiring anti-pseudomonal antibiotics (overall, oral, intravenous) and the duration of treatment, each compared to placebo.
- To assess the time to first hospitalization, proportion of patients requiring hospitalization and the duration of hospitalization due to serious respiratory-related AEs.

Objetivos secundarios:
-Evaluar el efecto de diferentes dosis de TIP administradas 1 vez al día y de 1 dosis 2 veces al día, así como de las diferentes pautas posológicas (TIP y TIP/placebo cíclico), sobre la frecuencia, la tasa (meses/paciente), la gravedad y el tiempo hasta la aparición de las reagudizaciones de la infección pulmonar al final del periodo de tto. y a lo largo de todo el estudio, cada pauta en comparación con placebo.
-Evaluar el perfil de eficacia de diferentes dosis de TIP administradas 1 vez al día y de 1 dosis 2 veces al día, así como de las diferentes pautas (TIP y TIP/placebo cíclico), según el momento del 1er uso, el % de pacientes que requiere la admón. de atbs. para la infección por P. aeruginosa (generalizada, oral, iv) y la duración del tto. , cada pauta en comparación con placebo.
-Evaluar el momento de la 1ª hospitalización, el % de pacientes que requieren hospitalización y la duración de la misma debido a AAG relacionados con el ap. respiratorio.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Optional 'serum PK' sub-study:

To evaluate serum PK in approximately 16 patients on active treatment, at least 20-22 patients from each cohort (at least 60 total patients) will participate in a PK sub-study. All patients will be asked to participate in the sub-study until enrollment is fulfilled for each cohort. Patients in this PK subset (20-22 patients/ cohort) will instead provide one serum specimen per specified interval at Visits 101 and 103: pre-dose, 0-1, 1-2, 3-4 and 5-6 h.

Subestudio FC en plasma opcional:
Evaluar la FC en plasma en aproximadamente 16 pacientes con tratamiento activo; al menos 20-22 pacientes de cada cohorte (un mínimo de 60 pacientes en total) participarán en un estudio FC. A todos los pacientes se les preguntará si desean participar en el subestudio hasta que se alcance el número de pacientes inscritos requeridos para cada cohorte. Los pacientes incluidos en este subgrupo FC (20-22 pacientes de cada cohorte) proporcionarán una muestra
de suero por intervalo especificado en las visitas 101 y 103: antes de la dosis y a las 0-1, 1-2, 3-4 y 5-6 horas.

E.3

Principal inclusion criteria

• Written informed consent must be obtained before any assessment is performed.
• Male and female patients of ≥ 18 years of age at screening (Visit 1).
• Proven diagnosis of non-CF BE as documented by computed tomography or high-resolution computed tomography
• At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring intravenous antibiotic treatment within 12 months prior
to screening.
• FEV1 ≥ 30% predicted at screening (Visit 1).
• P. aeruginosa, must be documented in a respiratory sample at least 1 time within 12 months and also present in the expectorated sputum culture at Visit 1.

• Debe obtenerse el consentimiento informado por escrito antes de realizar ninguna evaluación.
• Pacientes de ambos sexos que tengan al menos 18 años en el momento de la selección (visita 1).
• Diagnóstico probado de BE no debida a FQ, documentado mediante tomografía axial computarizada o tomografía axial computarizada de alta resolución
• Al menos 2 reagudizaciones que hayan sido tratadas con antibióticos por vía oral O al menos 1 reagudización que haya requerido tratamiento antibiótico por vía intravenosa, en el transcurso de los 12 meses anteriores a la selección.
• VEMS ≥ 30 % del previsto en la selección (visita 1).
• Debe haberse documentado la presencia de P. aeruginosa en una muestra del aparato respiratorio al menos en 1 ocasión en el transcurso de los últimos 12 meses y en el cultivo del esputo expectorado en la visita 1.

E.4

Principal exclusion criteria

• Patients with a history of cystic fibrosis.
• Patients with a primary diagnosis of bronchial asthma.
• Patients with a primary diagnosis of COPD associated with at least a 20 pack year smoking history.
• Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that in the opinion of the investigator makes participation in the trial against the patients’ best interests.
• History of hearing loss or chronic tinnitus deemed clinically significant by the investigator.
• Patients with active pulmonary tuberculosis.
• Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease.
• Patients who are regularly receiving inhaled antipseudomonal antibiotic (during the study inhaled antipseudomonal antibiotics are not allowed other than the study drug).

• Pacientes con antecedentes de fibrosis quística.
• Pacientes con diagnóstico principal de asma bronquial.
• Pacientes con diagnóstico principal de EPOC asociada a antecedentes de tabaquismo de al menos un índice de consumo de cigarrillos de 20.
• Cualquier enfermedad importante que se haya diagnosticado recientemente o no se haya mantenido estable durante los últimos 3 meses (salvo las reagudizaciones pulmonares) y que, en opinión del investigador, haga que la participación en el ensayo no constituya la mejor opción para el paciente.
• Antecedentes de sordera parcial o acúfenos crónicos que el investigador considere clínicamente significativos.
• Pacientes con tuberculosis pulmonar activa.
• Pacientes que en la actualidad reciban tratamiento para enfermedad pulmonar micobacteriana no tuberculosa (MNT).
• Pacientes que reciban antibióticos antipseudomona por vía inhalatoria con frecuencia (durante el estudio no se permite la administración de antibióticos antipseudomona por vía inhalatoria, salvo el fármaco del estudio).

E.5 End points

E.5.1

Primary end point(s)

P. aeruginosa density in sputum: change in P. aeruginosa bacterial load in sputum as
assessed by the change in log10 colony forming units (CFUs) from baseline.

La variación de la carga bacteriana de P. aeruginosa en el esputo, según la variación en las unidades formadoras de colonias (UFC) desde el período basal hasta el día 29 de tratamiento

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to Day 29

Desde el período basal hasta el día 29 de tratamiento

E.5.2

Secondary end point(s)

1) Frequency of pulmonary exacerbations (compared to placebo)
2) Time to first use of antipseudomonal antibiotics (compared to placebo)
3) Serum tobramycin concentration
4) Sputum tobramycin concentration
5) P. aeruginosa density in sputum over the entire study duration: Change in P. aeruginosa bacterial load in sputum from baseline as assessed by the change in
colony forming units (CFUs) of P. aeruginosa.
6) Respiratory Symptom Scale Quality of Life Questionnaire for Bronchiectasis (QOL-B): Change from baseline on the Respiratory Symptom Scale QOL-B. Respiratory Symptoms is 1 out of 8 domains of the QOL-B instrument and is graded on a 4-point Likert scale.
7) Rate of pulmonary Exacerbations (compared to placebo)
8) Severity of pulmonary exacerbations (compared to placebo)
9) Time to onset of pulmonary exacerbations (compared to placebo)
10) Proportion of patients requiring antipseudomonal antibiotics (compared to placebo)
11) Duration of antipseudomonal antibiotic treatment (compared to placebo)

1) Frecuencia de las reagudizaciones de la infección pulmonar (en comparación con placebo).
2) Momento del primer uso de los antibióticos para la infección por P. aeruginosa (en comparación con placebo).
3) Concentración de tobramicina en suero.
4) Concentración de tobramicina en el esputo.
5) Densidad de P. aeruginosa en el esputo a lo largo de todo el estudio:
Cambio en el grado de contaminación bacteriana de P. aeruginosa en el esputo respecto al inicio evaluado según la modificación en las unidades formadoras de colonias (CFU) de P. aeruginosa.
6) Escala de síntomas respiratorios. Cuestionario de calidad de vida para bronquiectasia (QOL-B): Cambio en la escala de síntomas respiratorios QOL-B respecto al inicio. Los síntomas respiratorios constituyen 1 de los 8 campos del instrumento QOL-B y se puntúan del 1 al 4 en la escala de Likert.
7) Tasa de las reagudizaciones de la infección pulmonar (en comparación con placebo).
8) Gravedad de las reagudizaciones de la infección pulmonar (en comparación con placebo).
9) Tiempo hasta las reagudizaciones de la infección pulmonar (en comparación con placebo).
10) Porcentaje de pacientes que requiere la administración de antibióticos para la infección por P. aeruginosa (en comparación con placebo).
11) Duración del tratamiento con antibióticos para la infección por P. aeruginosa (en comparación con placebo).

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 112 days of treatment and 56 days of follow-up
2) 112 days of treatment and 56 days of follow-up
3) Day 29
4) Day 85
5) 112 days of treatment and 56 days of follow-up
6) 112 days of treatment and 56 days of follow-up
7) 112 days of treatment and 56 days of follow-up
8) 112 days of treatment and 56 days of follow-up
9) 112 days of treatment and 56 days of follow-up
10) 112 days of treatment and 56 days of follow-up
11) 112 days of treatment and 56 days of follow-up

1) 112 días de tratamiento y 56 días de seguimiento.
2) 112 días de tratamiento y 56 días de seguimiento.
3) Día 29
4) Día 85
5) 112 días de tratamiento y 56 días de seguimiento.
6) 112 días de tratamiento y 56 días de seguimiento.
7) 112 días de tratamiento y 56 días de seguimiento.
8) 112 días de tratamiento y 56 días de seguimiento.
9) 112 días de tratamiento y 56 días de seguimiento.
10) 112 días de tratamiento y 56 días de seguimiento.
11) 112 días de tratamiento y 56 días de seguimiento.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

E.8.1.3

Single blind

Yes

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)

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

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

Belgium

France

Germany

Ireland

Italy

Netherlands

Spain

Switzerland

United Kingdom

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

Last patient last visit

Última visita del ultimo 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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

178

F.4.2.2

In the whole clinical trial

180

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	Combacte Lab-Net
G.4.3.4	Network Country	Belgium
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	EMBARC
G.4.3.4	Network Country	United Kingdom
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	ECFS-Clinical Trial Network (ECFS-CTN)
G.4.3.4	Network Country	Denmark

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-03-20

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