Clinical Trials Register

Summary
EudraCT Number:	2008-004764-39
Sponsor's Protocol Code Number:	CTBM100C2303E1
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-05-08
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

Latvia - SAM

A.2

EudraCT number

2008-004764-39

A.3

Full title of the trial

A Phase III Open-Label Extension Study to Assess the Safety and Efficacy of Tobramycin Inhalation Powder after Manufacturing Process Modifications (TIPnew) in Cystic Fibrosis (CF) Subjects Who Completed Participation in Study CTBM100C2303.

A.4.1

Sponsor's protocol code number

CTBM100C2303E1

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
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	TIP (Tobramycin inhalation powder)
D.3.2	Product code	TBM100C
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.10	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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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

Pseudomonas aeruginosa infection in cystic fibrosis patients

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10021860
E.1.2	Term	Infection pseudomonas aeruginosa

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 the safety profile of tobramycin inhalation powder after modifications in the manufacturing process (TIPnew) for the treatment of infections with P. aeruginosa in subjects suffering from cystic fibrosis, over three additional treatment cycles.

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of tobramycin inhalation powder after modifications in the manufacturing process (TIPnew) for the treatment of infections with P. aeruginosa in subjects suffering from cystic fibrosis, assessed by FEV1, FVC and FEF 25-75 profile.

• To assess the effect of tobramycin inhalation powder after modifications in the manufacturing process (TIPnew) on the density of microorganisms in sputum samples of subjects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Main inclusion criteria (refer to full protocol for comprehensive list)
• Written informed consent given by adult subjects or by the parents/legal guardian on behalf of the subject in combination with the subject’ s assent, if capable of assenting, before any assessment is performed.
• Completed all visits in study CTBM100C2303, and visit 4 of CTBM100C2303 took place not more than 5 days before enrollment into this study.
• Able to comply with all protocol requirements.
• Use of an effective means of contraception in women of childbearing potential.
• Clinically stable in the opinion of the investigator to be treated according to this protocol.
cough swab culture (or bronchoalveolar lavage [BAL]) within 6 months prior to screening and in the sputum/ deep-throat cough swab culture at the screening visit.
• Able to expectorate a sputum sample at screening.
• Use of an effective means of contraception in females of childbearing potential.
• Clinically stable in the opinion of the investigator to be treated according to this protocol.

E.4

Principal exclusion criteria

Main exclusion criteria (refer to full protocol for comprehensive list)
• Any use of inhaled anti-pseudomonal antibiotics between the termination of the core trial CTMB100C2303 and the enrollment into this study.
• Any use of systemic anti-pseudomonal antibiotics between the termination of the core trial CTMB100C2303 and the enrollment into this study.
• Serum creatinine 2 mg/dl or above, BUN 40 mg/dl or above, or an abnormal urinalysis defined as 2+ or greater proteinuria.
• Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics.
• Signs and symptoms of acute pulmonary disease, e.g., pneumonia, pneumothorax.
• Administration of any investigational drug within 30 days prior to enrollment (except for study medication in CTBM100C2303).
• Any previous exposure to tobramycin dry powder for inhalation (TIP), with the exception of study medication for study CTMB100C2303.
• Administration of loop diuretics within 7 days prior to study drug administration.
• Initiation of treatment with chronic macrolide therapy between the termination of the core trial CTMB100C2303 and the enrollment into this study (subjects may be taking chronic macrolide therapy at the time of enrollment into CTBM100C2303E1, but they must have initiated treatment more than 28 days prior to study drug administration for CTBM100C2303).
• Initiation of treatment with dornase alpha between the termination of the core trial CTMB100C2303 and the enrollment into this study (subjects may be taking dornase alpha at the time of enrollment into CTBM100C2303E1, but they must have initiated treatment more than 28 days prior to study drug administration for CTBM100C2303).
• Initiation of treatment with inhaled steroids (or increased dose) between the termination of the core trial CTMB100C2303 and the enrollment into this study (subjects may be taking inhaled steroids at the time of enrollment into CTBM100C2303E1, but they must have initiated treatment more than 28 days prior to study drug administration for CTBM100C2303).
• Initiation of treatment with inhaled hypertonic saline (HS) between the termination of the core trial CTMB100C2303 and the enrollment into this study (subjects may be inhaling hypertonic saline at the time of enrollment into CTBM100C2303E1, but they must have initiated treatment more than 28 days prior to study drug administration for CTBM100C2303 and must be on a stable regimen). In addition, patients should be instructed to inhale their HS at least 30 minutes before their pulmonary function tests (PFT). Patients should be consistent with the timing of taking their HS at home or clinic, prior to their PFT.
• Personal history of abnormal hearing or family history of abnormal hearing other than typical hearing loss associated with the aging process.
• Abnormal result from any 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).
• History of sputum culture or throat swab (or BAL) culture yielding Burkholderia cepacia (B. cepacia) within 2 years prior to screening for CTBM100C2303 and/or sputum culture yielding B. cepacia at screening for CTBM100C2303 or at enrollment into this study.
• Hemoptysis of more than 60 cc at any time within 30 days prior to study drug administration.
• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases,
• Patients with clinically significant laboratory abnormalities (unless expected under the study indication) at the termination of CTBM100C2303 / visit 4, especially if meeting the relevant criteria for premature withdrawal defined under 6.5.8.
• Subjects or caregivers with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable.
• 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 hCG laboratory test (> 5 mIU/mL).
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method (as defined per protocol).

E.5 End points

E.5.1

Primary end point(s)

Safety:
A complete physical examination will be performed at visits 5, 8 and 9. Vital signs will be assessed at every visit. Single measurements will be performed at visit 9. During the other visits (visits 5 through 8), there will be assessments of vital signs before and 30 minutes after the inhalation of study medication (referred to as pre-dose and post-dose measurements, respectively).Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count will be measured at all visits (5 – 9) and in case of premature study discontinuation also at the discontinuation visit.Blood urea, creatinine, total bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, total protein, albumin, and uric acid will be measured at all visits (5 – 9) and in case of premature study discontinuation also at the discontinuation visit.Dipstick measurements for specific gravity, protein, glucose and blood will be done at all visits (5 – 9). WBC and RBC sediments will also be measured.Audiological assessments will be conducted at selected study sites at visits 5, 6 and 8, and – if findings at previous visits are abnormal and clinically significant or in case the patient is withdrawn prematurely – at visit 9.
the following safety-endpoints will also be assessed:
• Adverse events from time of first administration of study drug until study completion. Adverse events occurring before starting study treatment but after signing the informed consent form are recorded on the Medical History/Current Medical Conditions Case Report Form.
• Incidence of treatment-emergent adverse-events (AEs).
• Serious adverse events from time of consent until 4 weeks after study completion.
• Concomitant medications/Significant non-drug therapies
• Acute change in airway reactivity (FEV1 percent predicted) from pre-dose to 30 minutes after completion of first dose of study drug (where a change of 20% or more is considered clinically significant as bronchospasm).
The use of aminoglycosides in humans has been related to audiological impairment [Guthrie, 2008]. Even though no case of hearing loss has been observed in TIP or TOBI studies so far, the audiological assessment (7.5.6) has been included into this study to closely monitor the hearing ability of subjects exposed to TIP. Renal function is surveyed by clinical chemistry assessments, as nephrotoxic effects of aminoglycosides have been reported [Martinez-Saldago, 2007]. All other safety assessments selected are standard for the indication cystic fibrosis and this patient population.

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

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

Yes

E.6.13.1

Other scope of the trial description

Quality of Life

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

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.8.3

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.8.5

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

Information not present in EudraCT

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

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

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

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)

Yes

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

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 : written informed consent given by adult subjects or by the parents/legal guardian on behalf of the subject in combination with the subject’s assent, if capable of assenting, before any assessment is performed

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

100

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

2009-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-05-13

P. End of Trial
P.	End of Trial Status	Completed

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