Clinical Trials Register

Summary
EudraCT Number:	2014-001401-41
Sponsor's Protocol Code Number:	TAPAS-2014
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2021-09-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001401-41

A.3

Full title of the trial

Targeting Antibiotics to Pseudomonas aeruginosa in Small airways (TAPAS) study in patients with Cystic Fibrosis

A.3.1

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

Targeting Antibiotics to Pseudomonas aeruginosa in Small airways study in patients with Cystic Fibrosis

trattamento antibiotico dell’infezione cronica da Pseudomonas aeruginosa in pazienti con Fibrosi Cistica

A.3.2

Name or abbreviated title of the trial where available

TAPAS study in patients with CF

A.4.1

Sponsor's protocol code number

TAPAS-2014

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	ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM
B.1.3.4	Country	Netherlands
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	ERASMUS MC
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC- Sophia Children's Hospital
B.5.2	Functional name of contact point	Principal Investigator Netheralnds
B.5.3	Address:
B.5.3.1	Street Address	Wytemaweg 80, Sp 3456
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015CN
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31107037980
B.5.5	Fax number	NA
B.5.6	E-mail	h.janssens@erasmusmc.nl

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	BRAMITOB - 300 MG/4 ML SOLUZIONE DA NEBULIZZARE 56 CONTENITORI MONODOSE 4 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	CHIESI FARMACEUTICI S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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/3/09/613
D.3 Description of the IMP
D.3.1	Product name	Bramitob
D.3.4	Pharmaceutical form	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	TOBRAMICINA
D.3.9.1	CAS number	32986-56-4
D.3.9.2	Current sponsor code	BRAMITOB
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	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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 chronic infection with Pseudomonas aeuroginosa

Fibrosi Cistica associata ad infezione cronica da Pseudomonas aeuroginosa

E.1.1.1

Medical condition in easily understood language

Mucoviscidosis and crhonic lung infection

Fibrosi cistica e infezione polmonare cronica

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	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10057582
E.1.2	Term	Lung infection pseudomonal
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 compare the change in small airways obstruction (FEF75%) in patients with CF when inhaling one ampule of 300 mg of inhaled tobramycin with the Akita® compared to standard of treatment (twice daily nebulization of one ampule of 300 mg using standard nebulizer equipment)

Confrontare il cambiamento di ostruzione delle piccole vie aeree (FEF75%) nei pazienti con fibrosi cistica trattati con una fiala di 300 mg di tobramicina per inalazione con Akita® rispetto al trattamento standard (nebulizzazione di una fiala da 300 mg con nebulizzatore standard due volte al giorno)

E.2.2

Secondary objectives of the trial

1. To compare changes in lung function parameters (FEV1, FVC, FEF25-75%, MMEF25-75) and LCI.
2. To compare changes in bacterial CFUs of Pseudomonas aeruginosa in sputum between both treatment arms.
3. To compare the effect on ‘trapped air’ between both treatment arms as depicted by spirometer controlled expiratory chest Magnetic Resonance Imaging (MRI).
4. To assess safety of Akita® tobramycin inhalation therapy in CF-patients by monitoring trough levels of tobramycine, ototoxicity and nephrotoxicity.

1. confrontare alterazioni dei parametri di funzionalità polmonare (FEV1, FVC, FEF25-75%, MMEF25-75) e LCI.
2. confrontare le modifiche in CFU di Pseudomonas aeruginosa nell'espettorato tra i due bracci di trattamento.
3. confrontare gli effetti sull 'aria intrappolata su MRI tra i due bracci di trattamento.
4. valutare la sicurezza della terapia inalatoria di tobramicina con Akita® nei pazienti con CF controllando i livelli di tobramicina, ototossicità e nefrotossicità.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Age = 12 years
•Clinical diagnosis of CF and a positive sweat test or two CF-related mutations;
•Chronic Pa colonization requiring maintenance therapy with inhaled tobramycin, defined according to the Leeds criteria (>50% Pa positive airway cultures over last 12 months) 22;
•Small airways obstruction present on spirometry (defined as follows: dissociation between FVC and FEF75 values (i.e. FEF75 at least 20% (absolute percent predicted) less than FVC);
•Ability to breathe through a mouthpiece and to use the inhaler;
•Ability to perform lung function tests;
•Written informed consent (12-18 years: child and parents; = 18 years: patient).

• Età = 12 anni
• Diagnosi clinica di CF e un test del sudore positivo o due mutazioni CF-correlate;
• colonizzazione Pa cronica che richiede una terapia di mantenimento con tobramicina per inalazione.
• ostruzione delle piccole vie aeree evidenziata dalla spirometria
• capacità di respirare attraverso un boccaglio e di utilizzare l'inalatore;
• Capacità di eseguire test di funzionalità polmonare - spirometria-;
• consenso informato scritto (12-18 anni: bambino e genitori; = 18 anni: paziente)

E.4

Principal exclusion criteria

•Severe acute exacerbation of pulmonary infection (needing intravenous treatment) within one month prior to start or during the study;
•Known impaired kidney function (estimated creatinine clearance < 60 ml/min);
•Known aminoglycoside hypersensitivity;
•Start of nephrotoxic or ototoxic drugs, e.g. aminoglycosides, within 1 month prior to start or during the study;
•Use of Tobramycin Inhalation Powder as part of the maintenance therapy

-Esacerbazione polmonare acuta grave (che necessita di un trattamento endovenoso) entro un mese prima di iniziare o durante lo studio;
-Funzionerenale compromenssa(Clearance della creatinina minore 60ml/min;
- ipersensibilità nota agli aminoglicosidi;
uso di trbamicina in polvere come parte della terapia cronica;

E.5 End points

E.5.1

Primary end point(s)

change in FEF75 (Z-score and L/s) after 4 weeks of targeted treatment.

variazione del valore di FEF75 (Z-score e L/s) dopo 4 settimane di trattamento mirato

E.5.1.1

Timepoint(s) of evaluation of this end point

Every study visit. Patients will be included for 3 months and study visit are planned at the start and end of the first andthird month. 4 study visits in total

Ogni visita dello studio. I pazienti saranno inclusi per 3 mesi e le visite per lo studio sono previste all'inizio e alla fine del primo e del terzo mese. 4 visite in totale

E.5.2

Secondary end point(s)

•Change in FEV1, FVC, FEF25, FEF50, MMEF25-75 (Z-scores and absolute values);; •Change in Lung Clearance Index (LCI) measurements as assessed by multiple breath washout;; • Change in Pa bacterial CFUs (defined as the log10 value for the number of Pa CFUs per millilitre of sputum, either expectorated or collected by suction of the oropharynx);; •Change in percentage of trapped air on MRI (% of total lung volume);; •Change in FEV1, FVC, FEF25, FEF50, MMEF25-75 (Z-scores and absolute values);
•Change in Lung Clearance Index (LCI) measurements as assessed by multiple breath washout;
•Change in Pa bacterial CFUs (defined as the log10 value for the number of Pa CFUs per millilitre of sputum, either expectorated or collected by suction of the oropharynx);
•Change in percentage of trapped air on MRI (% of total lung volume);
•Change in FEV1 before and after nebulisation (safety parameter);
•Systemic bioavailability of inhaled tobramycin, defined by trough level;
•Change in creatinine and blood urea nitrogen (BUN) values as measure of early renal toxicity;
•Change in hearing function (measured by HFPTA);
•Compliance rate;
•Patient satisfaction (use of device);
•Cystic Fibrosis questionnaire-revised (CFQ-R): respiratory symptoms scale scores and treatment burden scale scores.

•Variazione del FEV1, FVC, FEF25, FEF50, MMEF25-75 (Z-scores e valori assoluti);; •Variazione del Lung Clearance Index (LCI) ; Variazioni Delle CFU batteriche; Variazione della percentuale di aria intrappolata su MRI (% del volume polmonare totale); -Variazione dei valori di FEV1, FVC, FEF25, FEF50, MMEF25-75 (Z-scores e valori assoluti);
-Variazione dell'indice di Clearance polmonare (LCI);
-Variazioni delle Unità formanti colonia batterica;
-Variazione della percentuale di aria intrappolata in MRI (% delvolume polmonare totale);
-Variazione del valore di FEV1 prima e dopo la nebulizzazione ( paramentro di sicurezza);
-Biodisponibilità sistemica della tobramicina definita per via inalatoria;
- Variazione della creatinina e dell'azoto urico nel sangue come misura della tossicità renale precoce;
- Variazione dell'udito;
-Compliance;
-Grado di soddisfazione del paziente
-Somministrazione del questionario (CFQ-R):

E.5.2.1

Timepoint(s) of evaluation of this end point

4 weeks; 4 weeks; 4 weeks; 4 weeks; study visit 2 and 4

4 settimane; 4 settimane; 4 settimane; 4 settimane; seconda e quarta visita per lo studio

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3.1

Comparator description

trattamento standard ( nebulizzazione di 300 mg di trobamicina due volte al giorno con nebulizatore

standard of treatment (twice daily nebulization of 300 mg tobramycin using standard nebulizer

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

Yes

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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.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)

none

nessuno

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

2015-12-17

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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