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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2004-003675-36
    Sponsor's Protocol Code Number:COLO/DPI/02/06
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2004-12-06
    Trial 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 ConcernedDenmark - DHMA
    A.2EudraCT number2004-003675-36
    A.3Full title of the trial
    A randomised, open label study to compare the efficacy and safety of a dry powder formulation of inhaled Colistimethate Sodium and nebulised TNSFI (Tobramycin nebuliser solution for inhalation, TOBI®) in cystic fibrosis patients with pseudomonas aeruginosa lung infection
    A.4.1Sponsor's protocol code numberCOLO/DPI/02/06
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorForest Laboratories UK Ltd
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    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/3/02/088
    D.3 Description of the IMP
    D.3.1Product nameColobreathe
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 sodium
    D.3.9.1CAS number 8068-28-8
    D.3.9.3Other descriptive nameColomycin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 Information not present in EudraCT
    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®
    D.3.4Pharmaceutical form Nebuliser solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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.3.9.3Other descriptive nameTOBI®
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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
    Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis.
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To quantify any change in % predicted FEV1 compared to baseline on entry to the study at visit 1 (study day 1). The primary efficacy variable will be FEV1 % predicted measured at Visit 6 (week 24). Success will be judged by showing non inferiority in change of FEV1 for patients treated with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.

    It is assumed that non-inferiority exists when the lower limit of the 95% confidence interval of the outcome is not more than 3.0% worse than the control group.
    E.2.2Secondary objectives of the trial
    To quantify the comparative changes in microbiological sensitivity of P. aeruginosa in each treatment group as measured by in-vitro MIC.

    To compare quality of life on each treatment regime to establish superior ease of administration

    To assess the clinical and laboratory safety of 24 weeks treatment with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.

    Nutritional status. To compare weight (and BMI) change in each group.

    To compare each group for time to first acute respiratory exacerbation and time to first use (and duration of use) of additional anti-pseudomonal intravenous or oral antibiotics administered for the management of acute respiratory exacerbation.

    Other pulmonary function tests

    Use of concomitant medication including bronchodilators or rescue medication at time of study medication administration.

    To assess and compare the drop-out rate in each group using sensitivity analyses.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    a) Male or female aged 6 years and above.

    b) Patients who are receiving Tobi® in a cycle of 28 days active therapy followed by 28 days of rest from treatment.

    c) Patients who, on the first day of trial medication administration (Visit 1), will have received a minimum of 2 Tobi® on/off cycles immediately prior to randomisation.

    d) If the patient is female and post-menarche/ pre-menopausal and heterosexually active, the patient must be using adequate effective contraceptive methods.

    e) Patients are required to be non-smokers or a past smoker who has not smoked within the past 12 months prior to the first day of trial medication administration (Visit 1).

    f) Each patient or parent/ guardian must be capable of reading and understanding informed consent (assent for those under the legal contractual age of consent) and the clinical trial information leaflet.

    g) Each patient or parent/ guardian must have granted his or her written informed consent (with assent from those under the legal contractual age of consent) before any trial procedure is carried out.

    h) Patient must have a documented diagnosis of CF from a specialist CF Unit (genotype and/ or positive sweat tests).

    i) Current CF condition must be clinically stable in the investigator’s opinion i.e. there must be no evidence of a current acute respiratory exacerbation at Visit 1. A diagnosis of an acute respiratory exacerbation (which may not necessarily precipitate the need for immediate hospitalisation) is defined as the presence of at least four of the following:
    (i)Change in appearance of sputum (i.e. increased purulence or volume).
    (ii) Increased productive cough, dyspnoea or respiratory rate.
    (iii) Progressive physical findings (crackles, rhonchi and air exchange) on chest auscultation.
    (iv) New (infiltrates) intrusion on chest X-ray.
    (v) Lassitude and decreased exercise tolerance.
    (vi) Fever (≥38oC).
    (vii) Deterioration of 10% of highest FEV1 score obtained in the last 6 months.
    (viii) Decreased appetite.
    (ix) Emergence of new pathogen in sputum i.e. a pathogen that causes clinical disease.

    j) FEV1 must be at least 25% but no more than 75% of predicted value (see Appendix VI for predicted values).

    k) Patients with Pseudomonas aeruginosa infection (including colonisation), defined as either:
    (i) ≥ 50% samples (minimum of 3 samples: sputum samples or throat swabs) positive for PA over the previous 12 months prior to the first day of trial medication administration (Visit 1) OR
    (ii) two samples (sputum samples or throat swabs) positive for PA over the previous 6 months prior to the first day of trial medication administration (Visit 1).

    l) Patient’s lung function must be clinically stable (investigator’s decision) after completing i.v. therapy (elective or treatment for exacerbation) at Visit 1 prior to randomisation.

    m) Patient’s who, on the first day of trial medication administration (Visit 1), will have had at least 28 days but no more than 35 days off TOBI®.
    E.4Principal exclusion criteria
    a) Evidence of an acute respiratory exacerbation on the first day of trial medication administration (Visit 1).

    b) Known sensitivity (or previous intolerance) to colistimethate sodium or β2 agonists.

    c) Administration of any investigational drug within 28 days prior to first trial medication administration (Visit 1).

    d) Patients who have received treatment which has permanently reduced Pseudomonas aeruginosa infection status will not be included (e.g. effective anti-pseudomonal vaccination and gene therapy).

    e) Existence of any pre-study medical conditions which, in the judgement of the investigator, warrants exclusion from the study.

    f) Patients who are pregnant or breast-feeding, or who plan to become pregnant during the study period.

    g) Inability to communicate or co-operate with the investigator due to language problems, poor mental development or impaired cerebral function.

    h) Objection by the patient’s usual CF care-giver to their participation in the study.

    i) Inability to comply with any of the study procedures or the study regimen (including inability to use study devices i.e. Turbospin® device or PARI LC Plus® nebuliser for duration of the trial).

    j) Laboratory parameters falling outside the expected normal ranges for CF (Investigator decision).

    k) Children who in the opinion of the investigator would not be reliable in handling the devices.

    l) Patients who are or will be receiving an elective course of intravenous antibiotic therapy on the day of anticipated first administration of trial medication (i.e. Visit 1).

    m) Patients who, on the first day of trial medication administration (Visit 1), will have had less than 28 days or more than 35 days off Tobi® or less than 28 days off inhaled colistin.

    n) Patients who, on the first day of trial medication administration (Visit 1), are receiving anti-pseudomonal agents specifically for the treatment of an exacerbation or pre-scheduled prophylactic courses of oral antibiotics. [Long term use of antibiotics (e.g. ciprofloxacin) for prophylaxis or anti-inflammatories (e.g. azithromycin) is permitted, provided the regimen has been used for at least 28 days and is planned to continue throughout the study.]

    o) Patients who need to receive another anti-pseudomonal agent as part of their standard care during the off-cycle of Tobi®. [Long term use of antibiotics (e.g. ciprofloxacin) for prophylaxis or anti-inflammatories (e.g. azithromycin) is permitted, provided the regimen has been used for at least 28 days and is planned to continue throughout the study.]

    p) Patients who are infected/ colonised with Burkholderia cepacia.

    q) Patients who are complicated by symptoms related to allergic bronchopulmonary aspergillosis (ABPA).

    r) Patients who are awaiting heart-lung or lung transplantation, where the transplant is likely to take place within 6 months of the first day of trial medication administration (i.e. Visit 1).

    s) Patient’s lung function not clinically stable (investigator’s decision) after completing i.v. therapy (elective or treatment for exacerbation) at Visit 1 prior to randomisation.
    E.5 End points
    E.5.1Primary end point(s)
    To quantify any change in % predicted FEV1 compared to baseline on entry to the study at visit 1 (study day 1). The primary efficacy variable will be FEV1 % predicted measured at Visit 6 (week 24). Success will be judged by showing non inferiority in change of FEV1 for patients treated with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.

    It is assumed that non-inferiority exists when the lower limit of the 95% confidence interval of the outcome is not more than 3.0% worse than the control group.

    Assessments for primary and applicable secondary endpoints will be performed at Visit 6 (week 24/exit). As active treatment with Tobi® ceases 4 weeks prior to the end of the study, evaluations of pulmonary function testing and QoL will additionally be performed at Visit 5 (week 20). The primary analysis will be based on the Visit 6 (week 24/exit) assessments, with evaluations from Visit 5 (week 20) providing supportive data. For microbiology resistance testing, any isolate from individual patients recovered at interim and final time points exhibiting greater resistance than the baseline isolate to either colistin or tobramycin from the patient’s initial sample will be tested for cross-resistance at the end of the study to a short panel of antipseudomonal agents.

    Patients who develop an acute respiratory exacerbation will continue trial medication throughout the exacerbation and do not need to be withdrawn from the study.
    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 Information not present in EudraCT
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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 days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2004-12-06. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 360
    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 Decision2004-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-08-14
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