Clinical Trials Register

Summary
EudraCT Number:	2009-016590-15
Sponsor's Protocol Code Number:	CTBM100C2304
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-14
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2009-016590-15

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Crossover Multi-Center Study to Assess the Efficacy and Safety of Inhaled Tobramycin Nebuliser Solution (TOBI) for the Treatment of Early Infections of P. aeruginosa in Cystic Fibrosis Subjects Aged from 3 Months to less than 7 years.

Studio cross-over, multicentrico, randomizzato in doppio cieco, controllato verso placebo, per valutare l'efficacia e la sicurezza di Tobramicina soluzione inalatoria (TOBI) per il trattamento della prima infezione da P. aeruginosa in pazienti affetti da Fibrosi Cistica di eta' superiore ai 3 Mesi e inferiore ai 7 anni.

A.3.1

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

Evaluation of the efficacy and safety of tobramycin for the treatment of early infections of P. aeruginosa in cystic fibrosis subjects aged from 3 months to less than 7 years.

Valutazione dell’efficacia e della sicurezza di Tobramicina per il trattamento della prima infezione da P. aeruginosa in pazienti affetti da fibrosi cistica di eta' superiore ai 3 mesi e inferiore ai 7 anni.

A.4.1

Sponsor's protocol code number

CTBM100C2304

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS FARMA
B.1.3.4	Country	Italy
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	NOVARTIS FARMA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NOVARTIS FARMA
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	ORIGGIO
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 9654 1
B.5.5	Fax number	+39 9659066
B.5.6	E-mail	info.studiclinici@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*NEBUL 56F 1D 300MG/5ML
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
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	TOBRAMYCIN
D.3.9.1	CAS number	32986-56-4
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
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	60
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	Nebuliser 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

Lung colonisation of Pseudomonas aeruginosa in cystic fibrosis patients.

Infezione polmonare di Pseudomonas aeruginosa in pazienti affetti da fibrosi cistica.

E.1.1.1

Medical condition in easily understood language

Lung colonisation of the bacterium Pseudomonas aeruginosa in cystic fibrosis patients.

Infezione polmonare causata dal batterio Pseudomonas aeruginosa in pazienti con fibrosi cistica.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10021860
E.1.2	Term	Infection pseudomonas aeruginosa
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 estimate the proportion of subjects free from any strain of P. aeruginosa assessed by sputum / swab culture at Day 29, i.e. after completion of a 28-day treatment period with either TOBI or placebo solution inhaled twice daily.

Stimare la percentuale di pazienti che risulta libera da qualsiasi ceppo di P. Aeruginosa, valutata tramite la coltura dell’espettorato/tampone orofaringeo al giorno 29, cioè dopo il completamento di un periodo di 28 giorni di trattamento con soluzione inalatoria di TOBI o placebo due volte al giorno.

E.2.2

Secondary objectives of the trial

-To assess the safety profile of TOBI inhaled twice daily or placebo throughout the treatment period in subjects in this age group; -To estimate the proportion of subjects free from any strain of P. aeruginosa assessed by sputum / swab culture 28 days after termination of the 2nd treatment cycle (day 91) with either TOBI inhaled twice daily for 28 days or placebo; -To estimate the proportion of subjects free from any strain of P. aeruginosa assessed by sputum / swab culture 28 days after termination of treatment with either TOBI inhaled twice daily for 28 days or placebo; -To assess the pharmacokinetics of TOBI in this age group; -To assess lung function in the subset of subjects able to reliably perform spirometry.

-Valutare il profilo di sicurezza di TOBI o placebo per via inalatoria 2volte al giorno durante tutto il periodo di trattamento in soggetti appartenenti a questa fascia di età;-Stimare la percentuale di pazienti che risulta libera da qualsiasi ceppo di P. Aeruginosa,valutata tramite la coltura dell’espettorato/tampone orofaringeo 28giorni dopo il completamento del secondo ciclo di trattamento(giorno 91),con soluzione inalatoria di TOBI o placebo 2volte al giorno; -Stimare la percentuale di pazienti che risulta libera da qualsiasi ceppo di P. Aeruginosa, valutata tramite la coltura dell’espettorato/tampone orofaringeo 28giorni dopo il completamento del trattamento con soluzione inalatoria di TOBI o placebo 2volte al giorno; -Valutare la farmacocinetica di TOBI in questa fascia di età; -Valutare la funzionalità polmonare nel sottogruppo di pazienti in grado di eseguire la spirometria.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent given by the parent/legal guardian on behalf of the subject; 2.Diagnosis of CF by one or more clinical features of CF: a documented sweat chloride test of > 60 mEq/L by quantitative pilocarpine iontophoresis; genotype with two identifiable CF-causing mutations; a positive newborn screening for CF; 3.Male and female subjects aged 3 months to less than 7 years of age at the time of screening; 4.Early lower respiratory tract infection with P. aeruginosa, defined by either of the following: infection defined as the first time P. aeruginosa is isolated from sputum or deep throat cough swab culture Or isolation of P. aeruginosa from sputum or deep-throat cough-swab culture after at least 1 year of negative cultures (documented with at least two negative cultures during the latter 1-year period, with no positive culture during that period), no antipseudomonal treatment by any route of administration during this one-year period; 5.Able to comply with all protocol requirements (except spirometry where not applicable); 6.Clinically stable in the opinion of the investigator.

1.Consenso informato scritto dato dal genitore/tutore legale per conto del soggetto; 2.Diagnosi di fibrosi cistica acertata da una o più caratteristiche cliniche: test del sudore documentato con valori > 60 mEq/L tramite ionoforesi quantitativa con pilocarpina; genotipo con 2 mutazioni identificabili che causano la fibrosi cistica; screening neonatale positivo per la fibrosi cistica; 3.Soggetti di entrambi i sessi di età superiore ai 3 mesi ed inferiore ai 7 anni al momento dello screening; 4.Prima infezione delle basse vie respiratorie con P. aeruginosa, definita da una delle seguenti caratteristiche: infezione definita come prima acquisizione di P. aeruginosa isolata tramite coltura dell’espettorato/tampone orofaringeo oppure isolamento di P. aeruginosa tramite coltura dell’espettorato/tampone orofaringeo dopo almeno un anno di colture negative (accertate attraverso almeno due colture negative nell’ultimo anno e in assenza di colture positive durante questo periodo), in assenza di trattamento anti pseudomonas somministrato attraverso qualunque via durante questo periodo di un anno; 5.Soggetti in grado di soddisfare tutti i requisiti del protocollo (eccetto la spirometria dove non applicabile); 6.Soggetti clinicamente stabili a giudizio del medico responsabile dello studio.

E.4

Principal exclusion criteria

1. Serum creatinine above the upper limit of the normal range for age; 2.Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics; 3.Signs and symptoms of acute pulmonary disease, e.g., pneumonia, pneumothorax; 4.Administration of any investigational drug within 30 days or 5 half-lives prior to enrollment, whichever is longer; 5.Administration of loop diuretics within 7 days prior to study drug administration; 6.Personal/family history of abnormal hearing; 7.Current (continuing, present at screening) or persisting abnormal result from audiology testing (defined as either a unilateral pure-tone audiometry test showing a threshold elevation > 20 dB at any frequency across the frequency range 0.25 kHz to 8 kHz or the absence of emission at the evoked otoacoustic emission test); 8.History of sputum culture, throat swab, or lower respiratory specimen culture yielding Burkholderia cepacia (B. cepacia) within 2 years prior to screening and/or sputum culture yielding B. cepacia at screening; 9.Hemoptysis which is clinically significant based on the subjects age and clinical status within 30 days prior to study drug administration; 10.History of malignancy of any organ system treated or untreated, regardless of whether there is evidence of local recurrence or metastases; 11.Subjects with clinically significant laboratory abnormalities including congenital diseases other than CF (not associated with the study indication) at screening; 12.Subjects with other clinically significant conditions (not associated with the study indication) at screening which might interfere with the assessment of this study; 13.Subjects or caregivers with a history of noncompliance to medical regimens and subjects or caregivers who are considered potentially unreliable.

1.Creatinina sierica al di sopra del limite superiore del range di normalità per età; 2.Nota ipersensibilità locale o sistemica agli aminoglicosidi o antibiotici per via inalatoria;3.Segni e sintomi di malattia polmonare acuta, i.e., polmonite, pneumotorace; 4.Somministrazione di qualsiasi farmaco sperimentale entro 30 giorni o 5 emivite prima dell’arruolamento, qualunque sia la durata; 5.Somministrazione di diuretici dell’ansa nei 7 giorni precedenti la somministrazione del farmaco in studio; 6.Storia personale/familiare di capacità uditiva anormale; 7.Recenti (attuali o presenti allo screening) risultati anomali dei test audiometrici (definiti come innalzamento > 20 dB a qualsiasi frequenza nel range 0.25 kHz to 8 kHz del test audiometrico tonale a toni puri; o l’assenza di emissioni al test delle emissioni otoacustiche evocate); 8.Storia di coltura dell’espettorato, tampone orofaringeo o coltura di un campione delle basse vie respiratorie, positivo per Burkholderia cepacia (B. cepacia) nei due anni che precedono lo screening e/o coltura dell’espettorato positivo per B. cepacia al momento dello screening; 9.Emottisi, clinicamente significativa in base all'età e allo stato clinico dei soggetti nei 30 giorni precedenti la somministrazione del farmaco di studio; 10.Storia di neoplasie malinge per qualsiasi sistema d’organo, trattate o non trattate, indipendentemente dal fatto che non vi è prova della ricorrenza locale o di metastasi; 11.Pazienti con anomalie di laboratorio clinicamente significative (non associate con l'indicazione di studio) al momento dello screening; 12.pazienti con altre condizioni clinicamente significative, comprese malattie congenite diverse dalla fibrosi cistica (non associate con l'indicazione di studio) al momento dello screening che potrebbero interferire con le valutazioni di questo studio; 13.Soggetti o caregiver con una storia di non conformità a regimi medici e pazienti o caregiver che sono considerati potenzialmente inaffidabili.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with negative P. aeruginosa culture at day 29 in each treatment group.

Percentuale di pazienti per ogni gruppo di trattamento con coltura di P. aeruginosa negativa al giorno 29.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 29

Giorno 29

E.5.2

Secondary end point(s)

-Valutare il profilo di sicurezza di TOBI o placebo per via inalatoria due volte al giorno durante tutto il periodo di trattamento in soggetti appartenenti a questa fascia di età; -Stimare la percentuale di pazienti che risulta libera da qualsiasi ceppo di P. Aeruginosa, valutata tramite la coltura dell’espettorato/tampone orofaringeo 28 giorni dopo il completamento del secondo ciclo di trattamento (giorno 91), con soluzione inalatoria di TOBI o placebo due volte al giorno; -Stimare la percentuale di pazienti che risulta libera da qualsiasi ceppo di P. Aeruginosa, valutata tramite la coltura dell’espettorato/tampone orofaringeo 28 giorni dopo il completamento del trattamento con soluzione inalatoria di TOBI o placebo due volte al giorno; -Valutare la farmacocinetica di TOBI in questa fascia di età; -Valutare la funzionalità polmonare nel sottogruppo di pazienti in grado di eseguire la spirometria.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 29

Giorno 29

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

Yes

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

In aperto se cultura positiva a Pa al giorno29

Open label active if Pa positive culture at day29

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

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

Canada

Russian Federation

Switzerland

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

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)

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

Children aged 3 months to less than 7 years

Bambini di età superiore ai 3 Mesi e inferiore ai 7 anni

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)

A 12-month follow-up period is included in the protocol after the 3-month randomised period. During this follow-up patients are tested quarterly for Pa culture receive 28-day TOBI treatment upon recurrence of Pa colonisation.

Successivamente al periodo di randomizzazione di 3 mesi è previsto un periodo di follow-up di 12 mesi. Durante il periodo di follow-up i pazienti saranno testati trimestralmente e nel caso in cui ci sia ricomparsa di P. aeruginosa, i pazienti riceveranno il trattamento con TOBI per ulteriori 28 giorni.

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

2011-07-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-24

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