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    Summary
    EudraCT Number:2016-003020-23
    Sponsor's Protocol Code Number:1615R2132
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-08-31
    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 number2016-003020-23
    A.3Full title of the trial
    A Multicenter, Randomized, Double-blind, Parallelgroup, Clinical Study of S-649266 Compared with Meropenem for the Treatment of Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international research study on humans of the antibiotic S 649266 to treat pneumonia acquired in hospital or health care structures or ventilator-associated, caused by Gram-negative bacteria and compared to an antibiotic already on market (Meropenem)
    A.4.1Sponsor's protocol code number1615R2132
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03032380
    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 SponsorShionogi 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 supportShionogi & Co., Ltd.
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShionogi & Co., Ltd
    B.5.2Functional name of contact pointCorporate Communications Department
    B.5.3 Address:
    B.5.3.1Street Address3-1-8, Doshomachi 3-chome
    B.5.3.2Town/ cityChuo-ku, Osaka
    B.5.3.3Post code541-0045
    B.5.3.4CountryJapan
    B.5.4Telephone number+8166209 7885
    B.5.6E-mailshionogiclintrials-admin@shionogi.co.jp
    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 nameCefiderocol
    D.3.2Product code S-649266
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCefiderocol
    D.3.9.3Other descriptive nameS-649266
    D.3.9.4EV Substance CodeSUB131099
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    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.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.2.1.1.1Trade name Meropenem
    D.2.1.1.2Name of the Marketing Authorisation holderFresenius Kabi
    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 nameMeropenem
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMeropenem
    D.3.9.1CAS number 96036-03-2
    D.3.9.3Other descriptive nameMeropenem trihydrate
    D.3.9.4EV Substance CodeSUB08778MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    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
    Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens.
    E.1.1.1Medical condition in easily understood language
    Bacterial Pneumonia Caused by Gram-negative Pathogens acquired during hospitalization or during a stay in a healthcare institution or after a patient is intubated and received mechanical ventilation.
    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10021881
    E.1.2Term Infections and infestations
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10076918
    E.1.2Term Hospital acquired pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    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 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare all-cause mortality at Day 14 of subjects who receive S-649266 with that of subjects who receive the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP),ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives:
    • To compare the clinical outcome of treatment with S-649266 with that of
    meropenem in subjects at test of cure (TOC)
    • To compare the microbiologic outcome of treatment with S-649266 with that of meropenem at TOC
    Other Secondary Objectives:
    Efficacy:
    • To compare the clinical outcome of treatment with S-649266 with that of meropenem in subjects at early assessment (EA)2, end of treatment (EOT), and follow-up (FU)
    • To compare the microbiologic outcome of treatment with S-649266 with that of meropenem at EA, EOT, and FU
    • To compare the all-cause mortality at Day 28 of subjects treated with S-649266 with that of subjects treated with meropenem
    • To compare the all-cause mortality during treatment and the FU period of subjects treated with S-649266 with that of meropenem
    • To compare the resource utilization required for the 2 study treatments for the study-qualifying infection
    Safety:
    • To assess the safety of S-649266
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects 18 years or older at the time of signing informed consent
    2. Subjects who have provided written informed consent or their informed consent has been provided by Legally Authorized Representative (LAR) (Note: Country-specific rules and local Ethics Committee approval for LAR informed consent will determine whether or not and how a subject unable to comprehend or sign the informed consent is allowed to be enrolled in the study)
    3. Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP
    4. All subjects must fulfill at least 1 of the following clinical criteria at screening:
    a. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation
    b. Hypoxemia (eg, a partial pressure of oxygen [PaO2] less than 60 mm Hg while the subject is breathing room air, as determined by arterial blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of inspired oxygen [PaO2/FiO2])
    c. Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure
    d. New onset of or increase in (quantity or characteristics) suctioned respiratory secretions, demonstrating evidence of inflammation and absence of contamination
    5. All subjects must have at least 1 of the following signs:
    a. Documented fever (ie, core body temperature [tympanic, rectal, esophageal] not less than [NLT] 38°C [100.4°F], oral temperature NLT 37.5°C, or axillary temperature NLT 37°C)
    b. Hypothermia (ie, core body temperature [tympanic, rectal, esophageal] not more than [NMT] 35°C [95.0°F], oral temperature NMT 35.5°C and axillary temperature NMT 36°C)
    c. Leukocytosis with a total peripheral white blood cell (WBC) count NLT 10,000 cells/mm3
    d. Leukopenia with total peripheral WBC count NMT 4500 cells/mm3
    e. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear
    6. All subjects must have a chest radiograph during screening or have a previous chest radiograph within 48 hours prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography (CT) scan in the same time window showing the same findings could also be acceptable.
    7. All subjects must have evidence of a Gram-negative infection involving the lower respiratory tract as documented by 1 or more of the following:
    a. Gram stain of lower respiratory secretions showing Gram-negative bacteria either alone or mixed with Gram-positive bacteria at or within 72 hours prior to randomization
    b. Microbiologic culture of respiratory tract secretions within 72 hours prior to randomization identifying Gram-negative aerobic bacteria
    c. Other diagnostic tests, including molecular tests, which provide evidence of Gram-negative bacterial infection of the lower respiratory tract
    d. Pneumonia highly suspected to be due to a Gram-negative bacteria based on prior antibiotic use or local epidemiologic evidence of Gram-negative infection outbreak.
    8. Subject is male (no contraception required) or female (if woman of child-bearing potential, must use highly effective birth control method, see protocol for details in line with CTFG recommendations)
    9. Subjects who failed empiric therapy will be allowed in this study. However, confirmation of both clinical and microbiological failure is necessary: see protocol for details
    E.4Principal exclusion criteria
    1. Subjects who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia, or chemical pneumonia (including aspiration of gastric contents, inhalation injury)
    2. Subjects who have a history of any hypersensitivity to cephalosporins or to carbapenems, or severe hypersensitivity to any other type of β-lactams other than cephalosporins and carbapenems (eg, penicillins, monobactams), or hypersensitivity to linezolid (Note: For β lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
    3. Subjects with a Gram-negative infection caused by a carbapenem-resistant pathogen, if known at the time of randomization (Note: Subjects who have a carbapenem-resistant pathogen identified after randomization should be evaluated clinically before discontinuation of study treatment.)
    4. Subjects with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
    5. Subjects who have central nervous system infection (eg, meningitis, brain abscess, shunt infection)
    6. Subjects with cystic fibrosis
    7. Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of randomization
    8. Subjects with neutropenia (ie, polymorphonuclear neutrophils < 500 cells/µL)
    9. Female subjects who have a positive pregnancy test at screening, who are lactating, or who refuse to use 1 of the previously specified methods of contraception
    10. Subjects with an Acute Physiology and Chronic Health Evaluation II (APACHE) II score of > 35
    11. Subjects who have received potentially effective antibiotic therapy for a continuous duration of more than 24 hours during the previous 72 hours prior to randomization (Note: Subjects failing empiric therapy as defined in inclusion criterion 9 may be eligible for inclusion.)
    12. Subjects with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of the study data
    13. Subjects receiving peritoneal dialysis (hemofiltration and hemodialysis are permitted)
    14. Subjects requiring continued treatment with methotrexate, procainamide, probenecid, monoamine oxidase inhibitors, or valproic acid (see Section 5.2)
    15. Subjects who have received another investigational drug or device within 30 days prior to study entry
    16. Subjects who have previously been randomized in this study or have previously received S-649266
    17. Subjects with 1 or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin level > 3 times the upper limit of normal (ULN), absolute neutrophil count < 100/μL, platelet count < 40,000/μL
    18. Subjects with bronchiectasis with symptoms of persistent or recurrent bronchial infection related to irreversibly damaged and dilated bronchi; namely, subjects with clinical bronchiectasis
    19. Subjects with lung abscesses
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint:
    All-cause mortality at Day 14 for S-649266 or the active-comparator, meropenem.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 14
    E.5.2Secondary end point(s)
    Key secondary endpoints:
    - The clinical outcome of treatment with S-649266 or meropenem per subject at TOC
    - The microbiologic outcome of treatment with S-649266 or meropenem per subject at TOC
    Other secondary efficacy:
    - The clinical outcome of treatment with S-649266 or meropenem per subject at EA, EOT, and FU
    - The microbiologic outcome of treatment with S-649266 or meropenem per subject at EA, EOT, and FU
    - The all-cause mortality at Day 28
    - The all-cause mortality during the full duration of the study
    - The resource utilization required for the treatment of the study qualifying infection
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical and Microbiological outcome will be evaluated at TOC, EA, EOT, and FU.
    The all-cause mortality will be also evaluated at Day 28 and until end of study.
    Facility utilization will be assessed by determination of the time in 24-hour days associated with the treatment of the infection.
    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 Yes
    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 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) Yes
    E.8.2.2Placebo No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    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
    Belgium
    Brazil
    Canada
    Colombia
    Czech Republic
    Estonia
    France
    Georgia
    Germany
    Hungary
    Israel
    Japan
    Latvia
    Philippines
    Russian Federation
    Serbia
    Spain
    Taiwan
    Ukraine
    United Kingdom
    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
    End of study treatment + 28 days.
    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 months10
    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 months10
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects may not be able to understand or personally sign the ICF at the time of screening due to their medical conditions. In this case the consent process will follow local Country requirement.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 94
    F.4.2.2In the whole clinical trial 300
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation National Institute Health Research, Clinical Research Network
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-09-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-04-01
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