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.

• Register: EUCTR
• Last refreshed on: 15 May 2012
• Main ID: EUCTR2008-004764-39-LV
• Date of registration: 08/05/2009
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: 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.
• Scientific title: 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.
• Date of first enrolment: 19/06/2009
• Target sample size: 100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-004764-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Bulgaria, Estonia, Latvia, Lithuania

Key inclusion & exclusion criteria

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.

Are the trial subjects under 18? yes
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) no
F.1.3.1 Number of subjects for this age range

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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pseudomonas aeruginosa infection in cystic fibrosis patients
MedDRA version: 9.1 Level: LLT Classification code 10021860 Term: Infection pseudomonas aeruginosa

Intervention(s)

Product Name: TIP (Tobramycin inhalation powder)
Product Code: TBM100C
Pharmaceutical Form: Inhalation powder, hard capsule
INN or Proposed INN: tobramycin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 28-

Primary Outcome(s)

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.

Main Objective: 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.

Secondary Objective: • 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.

Secondary ID(s)

2008-004764-39-LT

CTBM100C2303E1