Clinical Trials Register

Summary
EudraCT Number:	2014-001204-21
Sponsor's Protocol Code Number:	CTBM100CDE02
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-08-22
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

Germany - BfArM

A.2

EudraCT number

2014-001204-21

A.3

Full title of the trial

An 8 week open-label interventional multicenter study to evaluate the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥ 6 years of age, chronically infected with Pseudomonas aeruginosa

A.3.1

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

An open-label clinical trial that evaluates the lung clearance index in cystic fibrosis patients ≥ 6 years of age, chronically infected with Pseudomonas aeruginosa

A.4.1

Sponsor's protocol code number

CTBM100CDE02

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 GmbH
B.1.3.4	Country	Germany
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 Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+491802232300
B.5.5	Fax number	+499112732160
B.5.6	E-mail	infoservice.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/140
D.3 Description of the IMP
D.3.1	Product name	TOBI Podhaler
D.3.2	Product code	TBM100C
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.IMP: 2
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.2.5	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	Nebulisation 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	3232986-56-4
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	300
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

Chronic lung infection with Pseudomonas aeruginosa in cystic fibrosis
patients

E.1.1.1

Medical condition in easily understood language

Bacterial infection in cystic fibrosis patients

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10011762
E.1.2	Term	Cystic fibrosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10021860
E.1.2	Term	Infection Pseudomonas aeruginosa
E.1.2	System Organ Class	100000004862

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 assess the change of LCI after 4 weeks following onset of study drug inhalation versus Baseline

E.2.2

Secondary objectives of the trial

To assess:
• Change of FEV1 after 4 weeks following onset of study drug inhalation versus Baseline.
• Change in CFU after 4 weeks following onset of study drug inhalation versus Baseline
• Change of LCI after 1 week following onset of study drug inhalation versus Baseline.
• Change of LCI, FEV1 and CFU between week 4 (end of Study drug inhalation in the current treatment cycle) and week 8 (prior to start of Study drug inhalation in the following treatment cycle).
• Correlation between the changes of LCI, FEV1 and CFU after 1 week, 4 weeks, and 8 weeks versus Baseline, respectively.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provide written informed consent and assent (as appropriate for minors) prior to the performance of any study-related procedure.
2. Confirmed diagnosis of CF by one or more of the following tests for CF (current or historic):
a. quantitative pilocarpine iontophoresis sweat chloride test of greater than 60 mmol/L or 60 mEq/L
b. genotype with 2 identifiable CF-causing mutations
c. an abnormal nasal transepithelial potential difference characteristic of CF
3. Male and female patients 6 - 50 years of age at screening (Visit 1).
4. Patients with elevated LCI of ≥ 7.5 at screening, confirmed by a central MBW specialist.
5. Patients with FEV1 of ≥ 50% predicted at screening.
6. P. aeruginosa must be present in two sputum or deep cough throat swab cultures or bronchoalveolar lavage (BAL) (only for BAL, a threshold level of 103 CFU/mL is required) within 12 months prior to screening or in one culture within 12 months prior to screening and in the sputum or deep cough throat swab culture at screening.
7. Use of inhaled Tobramycin in a 28 days on / off regimen in the past 3 months before screening, as prescribed by the treating physician.
8. Clinically stable in the opinion of the investigator and likely to be able to participate in the study until the end of the study (Visit 5).

E.4

Principal exclusion criteria

1. History of sputum culture or deep cough throat swab (or BAL) culture yielding Burkholderia cenocepacia complex within 2 years prior to screening and / or sputum culture yielding B. cenocepacia complex at screening (Visit 1).
2. Hemoptysis more than 60 mL at any time within 30 days prior to screening (Visit 1).
3. History of hearing loss or chronic tinnitus.
4. Serum creatinine 2mg/dL or greater, BUN 40 mg/dL or greater, known local or systemic hypersensitivity to aminoglycosides.
5. Patients who are regularly receiving more than 1 class of inhaled anti-pseudomonal antibiotic during the study or in the past 56 days (8 weeks) prior to baseline visit (Visit 2).
6. Patients who have used oral or intravenous anti-pseudomonal antibiotics within 28 days prior to on-phase of study drug (Visit 2). These patients may be rescreened after 1 month following stop of i.v. treatment.
7. Change in dose, formulation or strength of the study drug in the past treatment cycle before screening.
8. Patients following onset or discontinuation of therapy with macrolides, chest physiotherapy, nebulized hypertonic saline, dornase alpha, long acting bronchodilators, inhaled steroids or inhaled mannitol during the study and within 56 days (8 weeks) prior to baseline visit (V2).
9. Use of loop diuretics within 7 days prior to first study medication administration (Visit 2).
10. Administration of any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to screening (Visit 1).
11. Signs and symptoms of acute pulmonary disease, e.g. pneumonia, pneumothorax.
12. Body mass index less than 12 kg/m2.
13. History of malignancy of any organ system, treated or untreated, regardless of whether there is evidence of local recurrence or metastases.
14. Patients with known or suspected neuromuscular disorders, e. g. Parkinson´s disease, Myasthenia gravis.
15. Patients or caregivers who are considered potentially unreliable or considered unlikely to be compliant within the trial.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).
17. Women who are menstruating and capable of becoming pregnant* and either not practicing a medically approved method of contraception (Pearl Index <1**) or not practicing total abstinence (when this is in line with the preferred and usual lifestyle of the patient) during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required with sufficient lead time before inclusion
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy
**examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
• hormonal oral contraception (Combination of estrogen and gestagen, PI=0.1-0.9)
• hormonal vaginal ring (combination of estrogen and gestagen, PI=0.65 uncorr.; 0.4 corr.)
• hormonal transdermal patch (combination of estrogen and gestagen PI= 0.72 uncorr.; 0.9 corr.)
• Estrogen-free ovulation inhibitors (containing desogestrel (PI=0.14)
• Implanted hormones containing etonogestrel (PI=0-0.08)
• Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
• Intra-uterine progestine device (synthetic progestin containing IUDs,PI=0.16)
Oral contraceptive without estrogen (e.g. "mini-pills"), nonsynthetic progesterone only IUDs, female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception..
18. Study personnel or first degree relatives of investigator(s) must not be included in the study.

E.5 End points

E.5.1

Primary end point(s)

Change of LCI after 4 weeks following onset of study drug inhalation versus Baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks

E.5.2

Secondary end point(s)

1 - Change of FEV1
2 - Change in CFU
3 - Change of LCI
4 - Change of LCI, FEV1 and CFU
5 - Correlation between the changes of LCI, FEV1 and CFU

E.5.2.1

Timepoint(s) of evaluation of this end point

1- after 4 weeks following onset of study drug inhalation versus Baseline
2- after 4 weeks following onset of study drug inhalation versus Baseline
3- after 1 week following onset of study drug inhalation versus Baseline
4- between week 4 (end of Study drug inhalation in the current treatment cycle) and week 8 (prior to start of Study drug inhalation in the following treatment cycle).
5- after 1 week, 4 weeks, and 8 weeks versus Baseline, respectively.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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)

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

E.8.1.1

Randomised

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.8.2.4

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

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

last visit of the last subject

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

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)

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)

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

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.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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-04-10

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