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    Summary
    EudraCT Number:2012-001565-33
    Sponsor's Protocol Code Number:CTBM100C2403
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-11
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2012-001565-33
    A.3Full title of the trial
    An open-label, crossover, interventional Phase IV study to compare the ease of use of tobramycin inhalation powder with tobramycin inhalation solution and nebulized colistimethate for the treatment of pulmonary Pseudomonas aeruginosa in patients with cystic fibrosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label clinical trial that compares how long it takes in total for a patient with cystic fibrosis to take a daily dose of tobramycin dry power versus nebulised forms of tobramycin or colistin
    A.4.1Sponsor's protocol code numberCTBM100C2403
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationfilled by CPO
    B.5.2Functional name of contact pointfilled by CPO
    B.5.3 Address:
    B.5.3.1Street Addressfilled by CPO
    B.5.3.2Town/ cityfilled by CPO
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TOBI Podhaler
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/03/140
    D.3 Description of the IMP
    D.3.1Product nameTOBI Podhaler
    D.3.2Product code TBM100C
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTobramycin
    D.3.9.1CAS number 32986-56-4
    D.3.9.2Current sponsor codeTBM100
    D.3.9.3Other descriptive nameTOBRAMYCIN
    D.3.9.4EV Substance CodeSUB11134MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number28
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Nebulisation solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTobramycin
    D.3.9.1CAS number 3232986-56-4
    D.3.9.2Current sponsor codeTBM100
    D.3.9.3Other descriptive nameTOBRAMYCIN
    D.3.9.4EV Substance CodeSUB11134MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder and solvent for nebuliser solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNColistimethate
    D.3.9.1CAS number 30387-39-4
    D.3.9.3Other descriptive nameCOLISTIMETHATE
    D.3.9.4EV Substance CodeSUB23213
    D.3.10 Strength
    D.3.10.1Concentration unit million IU million international units
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Chronic lung infection with Pseudomonas aeruginosa in cystic fibrosis
    patients
    E.1.1.1Medical condition in easily understood language
    Bacterial infection in cystic fibrosis patients
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10011762
    E.1.2Term Cystic fibrosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10021860
    E.1.2Term Infection Pseudomonas aeruginosa
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare as a primary indicator for ease of use the mean cumulative time required to set-up the delivery device (including preparation of the treatment), administer the drug, and clean the delivery device for TIP administered with the T 326 Inhaler with the cumulative time to perform the same activities (including disinfection of the device, where applicable) for the patient’s usual (pre-study prescribed) nebulized, antibiotic treatment for P. aeruginosa.
    E.2.2Secondary objectives of the trial
    To assess:
    -the absolute change in the number of P.aeruginosa colony-forming units in sputum after up to a period of 28days of treatment in each treatment arm
    -the frequency and type of microbial contamination of the T-326 Inhaler used to administer TIP after lifetime use(7days of treatment) compared with the contamination of the nebulizer used for the ent’s usual nebulized antibiotic treatment for P.aeruginosa or for any other nebulized medication at baseline(Visit2)and at each visit.
    - tolerability and safety of TIPvsTISvscolistimethate over both the on-treatment and off-treatment periods of the study by comparison of adverse event rates, severity, and discontinuation rates
    To evaluate:
    -the change in the minimum inhibitory concentration of the relevant antibiotic for P. aeruginosa after a period of up to 28days of treatment of TIPvsTISvscolistimethate
    -the safety profile of TIPvsTISvscolistimethate in terms of clinical laboratory results and postinhalational bronchospasm
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Provide written informed consent, Health Insurance Portability and Accountability Act (HIPAA) authorization (where applicable), 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):
    •quantitative pilocarpine iontophoresis sweat chloride test of greater than 60 mmol/L or 60 mEq/L
    •genotype with identifiable CF-causing mutations on both chromosomes
    •a positive newborn screening for CF
    •an abnormal nasal transepithelial potential difference characteristic of CF
    3.Male and female patients 6 years of age or older at screening (Visit 1)
    4.FEV1 at screening (Visit 1) must be at least 25% and less than or equal to 90% of normal predicted values for age, sex, and height based on the NHANES III values (Hankinson et al 1999) for patients 18 years of age or greater, and based on values from Wang (Wang et al 1993) for patients less than 18 years of age. Please refer to Appendix 4 for the relevant equations.
    5.Documented use of any of the inhaled antibiotics to treat chronic P. aeruginosa infection based on local practice:
    •TIS, colistimethate, or TIP for at least 1 cycle (4 weeks on treatment followed by 4 weeks off treatment) within the last 6 months or
    •colistimethate continuous use for at least 8 weeks within the last 6 months
    This cycle of treatment (or continuous colistimethate treatment period) is in addition to the treatment cycle during which the subject is being screened.
    6.P. aeruginosa must be present in a sputum or deep cough throat swab culture or bronchoalveolar lavage (BAL) (only for BAL a threshold level of 10^3 CFU/mL is required) within 6 months prior to screening and in the sputum or deep cough throat swab culture at screening or rescreening (Visit 1)
    7.Judged by the investigator to be able to use the dry powder inhaler successfully
    8.Clinically stable in the opinion of the investigator
    E.4Principal 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 or sputum culture yielding B. cenocepacia complex at screening (Visit 1)
    2.Hemoptysis more than approx. 60 mL at any time within 30 days prior to screening
    3.History of hearing loss or chronic tinnitus deemed clinically significant by the investigator
    4.Serum creatinine 176.8 μmol/L (2 mg/dL) or greater, blood urea nitrogen (BUN) 14.28 μmol/L (40 mg/dL) or greater or an abnormal urinalysis defined as 2+ or greater proteinuria at screening (Visit 1)
    5.Known local or systemic hypersensitivity to aminoglycosides
    6.Regularly receiving more than 1 class of inhaled antipseudomonal antibiotic. During the study, inhaled antipseudomonal antibiotics are not allowed other than the antipseudomonal antibiotic the patient is using at the time of entrance into the study.
    7.Use of systemic antipseudomonal antibiotics within 28 days prior to study medication administration (Visit 2)
    8.For patients on colistimethate: current use of cautioned concomitant medications as indicated in the prescribing information, including aminoglycosides, polymixins, curariform muscle relaxants (e.g. tubocurarine), ether, succinylcholine, gallamine, decamethonium, and sodium citrate, at screening
    9.Use of loop diuretics within 7 days prior to study medication administration (Visit 2)
    10.Use 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
    14.Clinically significant laboratory abnormalities (not associated with the study indication) at screening (Visit 1)
    15.Clinically significant conditions or findings at screening (Visit 1) that might interfere with the accurate and valid assessment of this study
    16.Patients or caregivers who are considered potentially unreliable or considered unlikely to be compliant within the trial
    17.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
    18.Women of childbearing 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.
    •Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge, or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
    •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during study treatment. Effective contraception methods are defined in the full protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Time required to administer study treatment including device set-up, administration, and device breakdown and cleaning
    E.5.1.1Timepoint(s) of evaluation of this end point
    Daily (e-Diary)
    E.5.2Secondary end point(s)
    * Microbial contamination of delivery device: P. aeruginosa and other pathogens
    * Adverse event (AE) rates, severity, and discontinuation rates
    * MIC of antibiotics from patients’ specimens (specific for P. aeruginosa)
    * Hospitalizations for respiratory-related AE
    * Clinical laboratory results and post-inhalational bronchospasm
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to assess schedule in full protocol for the timepoint for each assessment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Ease of use / time spent on treatment
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Nebulised tobramycin, nebulised colistin
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Spain
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days20
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days20
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 37
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients under 18 years of age.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 52
    F.4.2.2In the whole clinical trial 67
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-10-20
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