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    Summary
    EudraCT Number:2013-002855-13
    Sponsor's Protocol Code Number:CAP-01-102
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-29
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2013-002855-13
    A.3Full title of the trial
    A Randomized Double-Blind, Placebo-Controlled, Parallel Group, Phase 2 Study of Aerosolized Amikacin and Fosfomycin Delivered via the Investigational eFlow® Inline System in Mechanically Ventilated Patients with Gram-negative Bacterial Pneumonia (IASIS)
    Randomizált, kettős vak, placebo-kontrollos, párhuzamos csoportos, 2. fázisú vizsgálat az aeroszol formájában, a vizsgálati eFlow® vezetékbe iktatott rendszer segítségével alkalmazott amikacin és foszfomicin értékelésére, géppel lélegeztetett, Gram-negatív bakteriális tüdőgyulladásban szenvedő betegeknél (Aerosolized Amikacin and Fosfomycin Delivered via the Investigational eFlow® Inline System, IASIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Aerosolized amikacin and fosfomycin in mechanically ventilated patients with Gram-negative pneumonia
    Aerosol formában alkalmazott amikacin és foszfomicin értékelésére, géppel lélegeztetett, Gram-negatív bakteriális tüdőgyulladásban szenvedő betegeknél
    A.4.1Sponsor's protocol code numberCAP-01-102
    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 SponsorCardeas Pharma
    B.1.3.4CountryUnited States
    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 supportCardeas Pharma
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCardeas Pharma
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address2025 First Avenue, Suite 1200
    B.5.3.2Town/ citySeattle
    B.5.3.3Post codeWA 98121
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1206 973 1026
    B.5.5Fax number+1206-973-1720
    B.5.6E-mailinfo@cardeaspharma.com
    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 No
    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 nameAmikacin
    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 INNAMIKACIN
    D.3.9.1CAS number 37517-28-5
    D.3.9.4EV Substance CodeSUB05431MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 No
    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 nameFosfomycin
    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 INNFOSFOMYCIN SODIUM
    D.3.9.1CAS number 26016-99-9
    D.3.9.4EV Substance CodeSUB02262MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.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
    D.8 Placebo: 2
    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
    Gram-negative Bacterial Pneumonia in Mechanically Ventilated Patients
    Gram-negatív bakteriális tüdőgyulladás géppel lélegeztetett betegeknél
    E.1.1.1Medical condition in easily understood language
    Pneumonia
    tüdőgyulladás
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10004051
    E.1.2Term Bacterial pneumonia, unspecified
    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 purpose of this study is to demonstrate the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS).
    E.2.2Secondary objectives of the trial
    -To demonstrate that adjuvant therapy with AFIS, in conjunction with IV antibiotics, improves the clinical course of Gram-negative pneumonia in mechanically ventilated patients; and
    -To demonstrate the safety of AFIS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    OPTIONAL BACTERIAL DETECTION RESEARCH
    The purpose of this research is to develop rapid identification methods for bacteria found in patients with pneumonia. No patient identifying information will be provided to the lab conducting this research.
    E.3Principal inclusion criteria
    1. Males and non-pregnant, non-lactating females, ? 18 years and ? 80 years of age
    2. Intubated and mechanically-ventilated
    3. Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on the most recent chest radiograph prior to screening, as determined by the treating physician
    4. Signs of infection (within 24 hours prior to screening):
    -Fever (> 38ºC or > 100.4ºF); or
    -Leukopenia (< 4,000 white blood cells [WBC]/mm3) or leukocytosis (? 12,000 WBC/mm3)
    5. Impaired oxygenation (within 24 hours prior to screening):
    -PaO2/FiO2 ? 350 mmHg
    6. Acute Physiology and Chronic Health Evaluation (APACHE) II score > 10 (within 24 hours prior to screening)
    7. Presence, or high suspicion, of Gram-negative organism(s) by either Gram stain or culture of respiratory secretions from a sample obtained within the previous 7 days (enrollment can occur before culture results are available)
    E.4Principal exclusion criteria
    1. History of hypersensitivity to amikacin, other aminoglycosides, fosfomycin, imipenem, meropenem, or colistin
    2. Received systemic antibiotic therapy for this episode of Gram-negative pneumonia for greater than 72 hours at the time of randomization
    3. PaO2/FiO2 ? 100 mmHg plus diffuse infiltrates on Chest X-ray
    4. Refractory septic shock (severe sepsis plus unstable hypotension, in spite of adequate fluid resuscitation and vasopressors)
    5. Any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy:
    a. chest trauma with ongoing loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both;
    b. increased amounts of fluid in the lung cavities requiring chest tube drainage;
    c. lung cancer within the last 2 years;
    d. lung abscess(s);
    e. anatomical bronchial obstruction;
    f. suspected atypical pneumonia;
    g. chemical pneumonitis (e.g., inhalation injury);
    h. cystic fibrosis
    6. Immunocompromised patients, including those with neutropenia NOT due to the current infection (absolute neutrophil count < 500/mm3), leukemia, lymphoma, human immunodeficiency virus (HIV) infection with CD4 count < 200 cells/mm3, or splenectomy; those who are early post-transplantation (< 3 months post-transplant, or > 3 months post-transplant with evidence of organ rejection by clinical criteria, pathologic confirmation, or modification of immunosuppression within the past 4 weeks), are on cytotoxic chemotherapy, or are on high-dose steroids (e.g., > 40 mg of prednisone or its equivalent [> 160 mg hydrocortisone, > 32 mg methylprednisolone, > 6 mg dexamethasone, > 200 mg cortisone] daily for > 2 weeks)
    7. Evidence of significant renal impairment (serum creatinine > 4.0 mg/dL within 24 hours prior to screening). If serum creatinine is > 2.0 mg/dL, site must be capable of performing continuous renal replacement
    therapy, if clinically indicated. Patients with serum creatinine >4.0 mg/dL and being treated with continuous renal replacement therapy (continuous venous-venous hemofiltration or continuous venous-venous hemodialysis) or chronic hemodialysis are eligible
    8. Evidence of ototoxicity (history of hearing aid use prior to current hospitalization)
    9. Evidence of hepatotoxicity (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3X the upper limit of normal value within 24 hours prior to screening)
    10. Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive age)
    11. On mechanical ventilation for > 28 days
    12. Glasgow Coma Scale score = 3 at Screening
    13. Participating in or has participated in other investigational interventional studies (drug or device) within the last 30 days (or 5 times the half-life of the previously administered investigational compound, whichever is longer) prior to study treatment
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in Clinical Pulmonary Infection Score (CPIS) during the planned 10-day treatment period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Daily CPIS will be determined by one blinded, central reviewer in order to minimize inter-observer variability.
    E.5.2Secondary end point(s)
    Secondary Outcome Measures:
    - The hierarchical composite endpoint of mortality, and clinical cure (defined as both absence of Gram negative bacteria [negative culture or no sputum available to culture in an extubated patient] and CPIS at Day 14 < 6), using the win ratio method of Pocock et al.
    - The hierarchical composite endpoint of mortality, and ventilator-free days using the win ratio method of Pocock et al1
    - Number of days free of mechanical ventilation from Day 1 through Day 28
    - Number of ICU days from Day 1 through Day 28
    - Microbiological response rates at Day 14 in patients whose pre-study treatment bronchoalveolar lavage (BAL) was positive for MDR Gram-negative bacteria
    - Mortality from Day 1 through Day 28
    - Clinical relapse rates (defined as a new episode of pneumonia requiring reinstitution of IV antibiotics)
    from Day 11 through Day 28
    Pharmacokinetic Endpoints:
    - Analysis of amikacin and fosfomycin systemic concentrations prior to the AM doses on Days 3 and 10
    - Analysis of amikacin and fosfomycin tracheal aspirate concentrations 15 minutes after the AM doses on Days 3 and 10 (only if the patient continues to be intubated)
    Safety Endpoints:
    - Adverse events (AEs)
    - Serial hematology, biochemistry, and urinalysis
    - Changes in airway peak and plateau pressures before and after Investigational Product administration
    -Oximetry during Investigational Product administration

    Exploratory Endpoints:
    -Clinical response at Day 14
    Clinical response would require the following: improvement in CPIS from pre-study treatment score, and no rescue IV antibiotics needed from Day 1 through Day 14
    -Total number of days of Gram-negative IV antibiotics per patient from Day 1 through Day 14, and from Day 15 through Day 28
    - Number of hospital days from Day 1 through Day 28
    - % Failed, as measured by a PaO2/FiO2 ratio worsened by > 30% compared to baseline value, measured over the 10 days of study drug treatment
    - % Failed, as measured by change in CPIS from baseline, during the planned 10-day treatment period
    - % Successful, as measured by a PaO2/FiO2 ratio improved by >30% compared to baseline value, measured over the 10 days of study drug treatment
    - Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for MRSA
    - Microbiological response rates at Day 14 in all patients
    - Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for extremely drug resistant (XDR) Gram-negative bacteria
    - Change from baseline in Procalcitonin levels collected at Screening and on Days 3, 7, 10, and 14
    - Change from baseline in CPIS during the planned 10-day treatment period using a modified CPIS, in which no points are scored for culture of tracheal aspirate
    E.5.2.1Timepoint(s) of evaluation of this end point
    -The hierarchical composite endpoint of mortality, and ventilator-free days using the win ratio method of Pocock et all
    -No. of days free of mechanical ventilation from Day 1-28
    -No. of ICU days from Day 1-28
    -Microbiological response rates at Day 14 in patients whose pre-study treatment BAL was positive for MDR Gram-negative bacteria
    -Mortality from Day 1-28
    -Clinical relapse rates from Day 11-28
    -Analysis of amikacin and fosfomycin systemic concentrations prior to the AM doses on Days 3 and 10
    -Analysis of amikacin and fosfomycin tracheal aspirate concentrations 15 minutes after the AM doses on Days 3 and 10 (only if the patient continues to be intubated)
    -AEs- Day 1-28
    -Serial hematology, biochemistry, and urinalysis
    Please see the further info in the protocol-section 3.3.
    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 Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    France
    Greece
    Hungary
    Puerto Rico
    Spain
    Turkey
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days0
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 2013-11-29. 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
    Subjects intubated and mechanically-ventilated
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 150
    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)
    Not different from the expected normal treatment
    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 Decision2014-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-29
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