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    Summary
    EudraCT Number:2012-003621-21
    Sponsor's Protocol Code Number:CTBM100DDE04T
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-06
    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 ConcernedGermany - BfArM
    A.2EudraCT number2012-003621-21
    A.3Full title of the trial
    Prospective phase IIA multicenter double-blinded randomized placebo-controlled clinical trial evaluating the efficacy and safety of inhaled, aerosolized Tobramycin (TOBI®) b.i.d. in patients with ventilator-associated pneumonia (VAP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Inhaled, aerosolized Tobramycin in patients with ventilator-associated pneumonia (VAP)
    A.3.2Name or abbreviated title of the trial where available
    iTO-VAP (inhaled TOBI® in patients with VAP)
    A.4.1Sponsor's protocol code numberCTBM100DDE04T
    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 SponsorCharité University Hospital Berlin
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité University Hospital Berlin
    B.5.2Functional name of contact pointDr. Carsten Schwarz
    B.5.3 Address:
    B.5.3.1Street AddressAugustenburger Platz 1
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13353
    B.5.3.4CountryGermany
    B.5.4Telephone number4930450556552
    B.5.5Fax number4930450566951
    B.5.6E-mailcarsten.schwarz@charite.de
    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®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.1Product nameTobramycin
    D.3.2Product code TBM100B
    D.3.4Pharmaceutical form 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 INNTobramycin
    D.3.9.1CAS number 32986-56-4
    D.3.9.2Current sponsor codeTobi
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboNebuliser solution
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Intensive care unit patients with ventilation-associated pneumonia.
    E.1.1.1Medical condition in easily understood language
    Intensive care unit patients with ventilation-associated pneumonia.
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10065153
    E.1.2Term Ventilator associated pneumonia
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is the reduction and eradication of the endobronchial gram-negative bacteria in the pulmonal system, assessed as eradication of the pathogen at day 6 measured by the decrease in gram-negative pathogen-load in pulmonary infiltrate (either by gram-staining of the pathogen, by measurement of copies of DNA per ml in end-point PCR analysis or by kinetic laser measurement of turbidity increase of particles).
    E.2.2Secondary objectives of the trial
    The safety of the therapy with TOBI® or aerosolized sodium chloride solution will be assessed each day of the study by physical examination, vital signs, laboratory tests and evaluation of adverse events. Furthermore, the patient will be monitored for spontaneous complaints after treatment with TOBI® or aerosolized sodium chloride solution (control group).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - male or female subjects aged ≥ 18 and ≤ 85 years at the time of screening
    - legal care by an appropriate legal guardian has been set prior
    any study related procedure unless the patient can give his own
    written informed consent
    - written informed consent form signed by patient and if appropriate by parent/legal guardians, prior to any study-related procedure
    - ventilated patient with ventilator-associated pneumonia (VAP; definition VAP according to Luna et al., 2003 and Dalhoff et al. 2012)
    - reasonable suspicion of gram-negative bacteria in pulmonary infiltrate (gram-negativity diagnosed by gram stain preparation, PCR technologies or kinetic laser measurement of turbidity increase of particles (diagnosis is made within 24 hours)
    - patient must be able to receive either one of the two arms of treatment defined for the study
    - patient was treated shorter than 48 hours with standard systemic antibiotic therapy before the diagnosis of VAP
    - enrolment of patients with therapy-refractive VAP possible (within 6 days after start of new systemic antibiotic therapy)
    E.4Principal exclusion criteria
    - patients do not match the criteria for inclusion
    - chronic colonisation with non-fermenting organisms which was known before hospitalization of the patient and which was verified at least twice at an interval of 4 weeks
    - known local or systemic hypersensitivity to aminoglycosides, inhaled antibiotics, to drugs with similar chemical structures or other ingredients of the trial medication
    - patients who are pregnant or breast feeding (pregnancy 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))
    - history of severe clinical relevant bronchospasm
    - severe active hemoptysis of more than 60 cc (60 ml) at any time within 30 days prior to study drug administration
    - tinnitus treated in the last 3 months before enrollment
    - treatment with mannitol in the last 24 h before enrollment
    - treatment with drugs5 that might unfavorably interact with TOBI®
    - patients with cystic fibrosis, acquired immune deficiency syndrome (AIDS), neutropenia, active tuberculosis, or patients taking immunosuppressive therapy in preparation for or following an organ transplant
    - antibiotic treatment (except surgical antibiotic prophylaxis following national guidelines) according to the following terms:
    o systemic antibiotics against VAP that helped to treat this VAP successfully
    o use of antibiotics not authorized in the study (all inhalative antibiotics including off-label use of antibiotics: e.g. amphotericin b, colistin, ciprofloxacin, levofloxacin, ceftazidime, meropenem)
    - patients who are included in another intervention study or who have been part of another intervention study 30 days before entry into this study
    - lack of written informed consent by the patient or his legal guardian
    - patients with other underlying conditions6 that may have a significant effect on the target variables and would make it difficult to interpret response to study drug
    - patients with deteriorating general condition (maximal survival expectance < 6 weeks)
    - persons held or being hospitalized in an institution by legal or official order (according to AMG § 40(1)
    E.5 End points
    E.5.1Primary end point(s)
    Eradication of the gram-negative pathogen (two days after termination of inhalation treatment, day 6)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 6
    E.5.2Secondary end point(s)
    A) eradication of the gram-negative pathogen
    B) length of stay in ICU (at final visit)
    C) clinical cure of pneumonia
    D) duration of systemic antibiotic treatment for pneumonia
    E) systemic antibiotic-free days
    F) duration of ventilation for pneumonia
    G) ventilator-free days
    H) reinfection3 of pneumonia caused by the same verified pathogen (at discharge from ICU)
    E.5.2.1Timepoint(s) of evaluation of this end point
    For secondary endpoint A) - two days after termination of systemic antibiotic treatment
    For secondary endpoint B) - at final visit (at maximum day 90 after enrollment)
    For secondary endpoint C) - each day until two days after termination of systemic antibiotic treatment
    For secondary endpoint D) - at discharge from ICU
    For secondary endpoint E) - at discharge from ICU
    For secondary endpoint F) - at discharge from ICU
    For secondary endpoint G) - at discharge from ICU
    For secondary endpoint H) - at discharge from ICU
    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 Yes
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    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 Yes
    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
    As patients are under intensive care, informed consent will be signed by legal representative.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    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 Decision2013-10-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-30
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