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    Summary
    EudraCT Number:2010-023529-39
    Sponsor's Protocol Code Number:RHM CHI 0548
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-12-31
    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 ConcernedUK - MHRA
    A.2EudraCT number2010-023529-39
    A.3Full title of the trial
    Reducing antibiotic tolerance using low dose nitric oxide in
    cystic fibrosis – a phase 2 pilot study
    A.3.2Name or abbreviated title of the trial where available
    RATNO (Reducing Antibiotic Tolerance using Nitric Oxide in CF) v 1.0
    A.4.1Sponsor's protocol code numberRHM CHI 0548
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) Numbern/a
    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 SponsorSouthampton University Hopsitals NHS Trust
    B.1.3.4CountryUnited Kingdom
    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 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 Yes
    D.2.1.1.1Trade name INOmax 400ppm mol/mol inhalation gas
    D.2.1.1.2Name of the Marketing Authorisation holderINO Therapeutics AB, SE-181 81 Lidingo, Sweden
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 nameNitric Oxide
    D.3.2Product code NO
    D.3.4Pharmaceutical form Inhalation gas
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPInhalation use
    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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 No
    D.3.11.8Extractive medicinal product No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInhalation gas
    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
    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
    The primary objective of this pilot study is to see whether giving low dose inhaled nitric oxide in addition to standard intravenous antibiotic therapy (during a pulmonary exacerbation in patients with cystic fibrosis) will increase the effectiveness of the antibiotic therapy due to the disruption and killing of microcolonies of Pseudomonas aeruginosa (PA) bacteria.
    E.2.2Secondary objectives of the trial
    Laboratory

    1. To compare the effect of low dose inhaled nitric oxide and placebo on the amount of PA bacteria in sputum.

    2. To estimate the effect of low dose inhaled nitric oxide given with standard antibiotic therapy on the whole community of bacteria within the CF lung.

    3. To estimate the NO levels in sputum in each group.

    4. To look at the types and variety of bacteria in the wider community of bacteria found in the CF lung during an exacerbation and to compare this between the two groups.

    Clinical

    1. To assess the effect of inhaled NO on lung function measured by FEV1.

    2. To assess the effect of low dose inhaled nitric oxide on exhaled nitric oxide levels.

    3. To assess the effect of low dose inhaled nitric oxide on Health Related Quality Of Life using the CFQ-UK?

    4. To determine the appropriate clinical endpoints for a future larger trial of nitric oxide in participants with CF undergoing IV antibiotic therapy for an exacerbation?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adolescents and young adults with cystic fibrosis aged 12 or above
    • Colonised with Pseudomonas aeruginosa (50% or more of all cultures in the last 12 months positive for Pseudomonas aeruginosa)

    Criteria for randomisation:
    • Requiring antibiotic therapy for a pulmonary exacerbation:

    A pulmonary exacerbation will be defined according to the criteria published by the 1994 cystic fibrosis foundation microbiology and infectious disease consensus and used in recent large clinical trials.

    The presence of 3 of the following 11 criteria:
     Increased cough
     Increased sputum production, change in appearance of expectorated sputum production, or both
     Fever (greater than or equal to 38°C for at least 4 hrs in a 24 hrs period) on more than one occasion in the previous week
     Weight loss greater than or equal to 1kg or 5% of bodyweight associated with anorexia and decreased dietary intake
     School or work absenteeism (due to illness) in the previous week
     Increased respiratory rate, increased work of breathing, or both
     New findings on chest examination (e.g. rales, wheezing, crackles)
     Decreased exercise tolerance
     Decrease in FEV1 of greater than or equal to 10% from previous baseline study within the past 3 months
     Decrease in haemoglobin saturation (as measured by oximetry) from baseline value within past 3 months of greater than or equal to 10%
     New finding on chest radiograph
    E.4Principal exclusion criteria
    • Colonisation with Burkholderia Cepacia
    • Known hypersensitivity to the antibiotics used in the study
    • Other known contraindications to the antibiotics to be used in the study including known aminoglycoside related hearing/renal damage
    • Patients requiring non-invasive ventilation (NIV)
    • Patients who have a pneumothorax
    • Patients who are admitted for specific treatment of nontuberculous mycobacteria (NTM)
    • Patients who cannot tolerate nasal canula e.g. those who cannot breathe through their nose
    • Patients who have nasal polyposis that is causing significant blockage of the nasal passages
    • Adolescents who are not Gillick competent (and therefore not able to give their own assent in addition to parental consent)
    • Patients not likely to survive the time period of the study washout period (4 months from enrolment)
    • Treatment with an investigational drug or device within the last 3 months prior to enrolment
    • Patients who are pregnant (a pregnancy test will be carried out for females of 11 years and above as is standard practice for clinical trials)
    • Immediate families of investigators or site personnel directly affiliated with the study. Immediate family is defined as child or sibling, whether biological or legally adopted.
    E.5 End points
    E.5.1Primary end point(s)
    Between group differences in proportion of bacteria in biofilms (as determined by live/dead staining, direct visualisation of the biofilm and image analysis) between T0 and T20-25.
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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 Information not present in EudraCT
    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
    The end of the trial is the last visit (follow-up at T20-25) of the last subject randomised in the trial.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    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 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 2010-12-31. Yes
    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
    Children aged 12-17. Parents will be asked to give consent and children will be asked for their assent to take part.

    Women of childbearing age will have to take a pregnancy test before randomisation as they cannot receive NO if they are pregnant.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    There is no treatment available after the trial as this is a pilot to establish the basis for a large randomised controlled trial.
    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 Decision2011-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-09-26
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