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    Summary
    EudraCT Number:2017-001699-43
    Sponsor's Protocol Code Number:BPR-CS-009
    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:2018-08-16
    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 number2017-001699-43
    A.3Full title of the trial
    A randomized, double-blind, multi-center study to establish the efficacy and safety of ceftobiprole medocaril compared to daptomycin in the treatment of Staphylococcus aureus bacteremia, including infective endocarditis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of ceftobiprole medocaril compared to daptomycin in the treatment of Staphylococcus aureus bacteremia, including infective endocarditis
    A.4.1Sponsor's protocol code numberBPR-CS-009
    A.5.4Other Identifiers
    Name:IND number Number:64,407
    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 SponsorBasilea Pharmaceutica International Ltd
    B.1.3.4CountrySwitzerland
    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 supportBasilea Pharmaceutica International Ltd
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportBiomedical Advanced Research and Development Authority (BARDA)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBasilea Pharmaceutica International Ltd
    B.5.2Functional name of contact pointDoerthe Hansen
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 487
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4005
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+4179 6109097
    B.5.6E-mailDoerthe.Hansen@basilea.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 Yes
    D.2.1.1.1Trade name Zevtera
    D.2.1.1.2Name of the Marketing Authorisation holderCorrevio
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameCeftobiprole medocaril
    D.3.4Pharmaceutical form Powder for concentrate 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 INNCeftobiprole medocaril sodium
    D.3.9.1CAS number 252188-71-9
    D.3.9.2Current sponsor codeBAL5788
    D.3.9.3Other descriptive nameCEFTOBIPROLE MEDOCARIL SODIUM
    D.3.9.4EV Substance CodeSUB130376
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number666.6
    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 Daptomycin
    D.2.1.1.2Name of the Marketing Authorisation holderratiopharm 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 nameDaptomycin
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNDAPTOMYCIN
    D.3.9.1CAS number 103060-53-3
    D.3.9.4EV Substance CodeSUB06910MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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: 3
    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 Aztreonam for Injection
    D.2.1.1.2Name of the Marketing Authorisation holderFresenius Kabi USA, LLC
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAztreonam
    D.3.2Product code J01DF01
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNAZTREONAM
    D.3.9.1CAS number 78110-38-0
    D.3.9.4EV Substance CodeSUB05664MIG
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complicated staphylococcus aureus bacteremia (cSAB)
    E.1.1.1Medical condition in easily understood language
    Complicated staphylococcus aureus bacteremia (cSAB)
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10058887
    E.1.2Term Staphylococcus aureus bacteremia
    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
    To demonstrate the non-inferiority of ceftobiprole to daptomycin for overall success as assessed by an independent Data Review Committee (DRC) in the treatment of S. aureus bacteremia (SAB), including infective endocarditis (IE), at the post-treatment evaluation (PTE) visit in the modified intent-to-treat (mITT) population.
    E.2.2Secondary objectives of the trial
    To compare ceftobiprole with daptomycin with respect to:
    1. All-cause mortality through Day 70 (PTE visit) and Day 28 in the intent-to-treat (ITT) and mITT populations.
    2. Microbiological eradication rates (negative blood culture for S. aureus) at Day 4, Day 8, and the end-of-treatment (EOT) and PTE visits.
    3. Overall success rates in the mITT, ITT, and clinically evaluable (CE) populations:
    a) at the EOT and PTE visits (ITT and CE populations only)
    b) at the EOT and PTE visits, for IE vs non-IE SAB
    c) at the EOT and PTE visits, by renal-function status
    4. Development of new metastatic foci, or other complications of SAB, after Day 7.
    5. Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-negative for S. aureus, obtained at least 24 h after the first negative blood-culture.
    6. Safety and tolerability (Safety population).
    To assess the pharmacokinetics (PK) of ceftobiprole.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years of age.
    2. Informed consent signed by the patient (or by their legally acceptable representative, if appropriate) indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study.
    3. SAB, based on at least one S. aureus-positive blood culture obtained within the 72 h prior to randomization:
    (a) identified by culture laboratory report, or
    (b) positive diagnostic test for S. aureus (e.g., polymerase chain reaction [PCR], tube coagulase test and fluorescent in situ hybridization[FISH]) obtained from a blood culture.
    Note: The microbiological work-up of the blood culture may:
    • Occur prior to informed consent to participation in the study
    • Be undertaken either on-site or in an external microbiology laboratory specifically appointed for the purposes of this study.
    • Use a diagnostic test:
    – routinely performed locally for the detection of S. aureus from blood cultures
    or
    – provided to the laboratory for the purpose of this study, if the test has regulatory approval in the country where the test is being performed.
    Nevertheless, patients without a Central Microbiology Laboratory assessment may be included in the mITT population if there is unequivocal documented evidence of a baseline blood culture positive for S. aureus at the local laboratory
    4. At least one of the following signs or symptoms of bacteremia within the 72 h prior to randomization (may be based on measurements obtained before or after informed consent but within the 72 h prior to randomisation):
    (a) fever > 38°C/100.4°F measured orally, > 38.5 °C / 101.3 °F measured tympanically, > 37.5° C / 99.5 °F measured by axillary method, or > 39 °C / 102.2 °F measured rectally
    (b) white blood cell (WBC) count > 10.0 × 109/L, or < 4.0 × 109/L, or > 10% immature neutrophils (bands)
    (c) tachycardia (heart rate > 90 bpm)
    (d) hypotension (systolic blood pressure < 90 mmHg)
    5. Required duration of study antibacterial treatment ≤ 42 days.
    6. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis.
    7. Persistent SAB: documented failure of bloodstream clearance, defined as a positive blood culture for S. aureus within the 72 h prior to randomization, after prior appropriate anti-staphylococcal treatment (except failure under daptomycin therapy) of at least 3 complete days.
    8. Other forms of complicated SAB, including the following:
    (a) Acute bacterial skin or skin-structure infections (ABSSSIs)
    (b) Metastatic infection of native tissue
    Examples include but are not limited to:
    • Septic arthritis or bacterial joint infection/empyema
    • Septic or suppurative thrombophlebitis
    • Visceral soft-tissue abscesses requiring ≤ 42 days of study antibacterial treatment
    • Septic pulmonary emboli/infarction
    Note: The diagnosis of a septic pulmonary embolism will be made by the investigator based on clinical symptoms of fever, cough, putum/hemoptysis in the presence of an extrapulmonary infection, sepsis, or risk factors for septic emboli (e.g., intravenous drug use) and will be based on the following radiological signs:
    Contrast-enhanced CT (preferred):
    Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedgeshaped infiltrates
    – with/without a feeding vessel sign (vessel leading to the nodule)
    – with/without pleural effusion or features suggestive of pleural empyema
    Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast administration):
    Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedgeshaped infiltrates
    – with/without pleural effusion or features suggestive of pleural empyema
    Plain X-ray (e.g., in patients unable to undergo a CT):
    Multifocal nodular densities or wedge-shaped infiltrates in varying stages of cavitation with or without pleural effusion or features suggestive of pleural empyema
    9. Definite native-valve right-sided IE (RIE) by Modified Duke’s Criteria
    Note: Patients with left-sided infective endocarditis (LIE) are excluded from the study. If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In the event that the investigator decides to discontinue the study therapy, the patient will be included in the mITT population and considered a failure.
    The minimum requirements for a diagnosis of RIE and LIE (Modified Duke’s Criteria), and the minimum diagnostic requirements for other forms of complicated SAB, are provided in Appendix 1 and 2 of the protocol
    10. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis)
    11. Epidural or cerebral abscess
    E.4Principal exclusion criteria
    1. Treatment with potentially effective (anti-staphylococcal) systemic antibacterial treatment for more than 48 h within the 7 days prior to randomization.
    2. Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria that are known (at Screening) to be non-susceptible to either ceftobiprole or aztreonam.
    3. Confirmed uncomplicated SAB (e.g., catheter-related non-persistent SAB without signs of SAB complications, unless the patient has end-stage renal disease and is on intermittent hemodialysis or peritoneal dialysis).
    4. Left sided infective endocarditis (known or suspected to be present at the time of randomization).
    Note: If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In the event that the investigator decides to discontinue the study therapy, the patient will be included in the mITT population and considered failure.
    5. Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic implantable cardioverter-defibrillator, or left-ventricular assist devices.
    6. Complicated SAB in patients with other foreign body material that cannot be removed within the 7 days after randomization.
    Exceptions:
    • Patients with non-infected coronary stents may be included regardless of the time of stent implantation.
    • Patients with non-infected (no signs or symptoms of clinical involvement at the time of randomization) prosthetic joints, plates, spinal hardware, or other extravascular material may be included if implantation of the foreign material was performed at least 60 days before randomization.
    • Patients with non-infected (no signs or symptoms of clinical involvement at the time of randomization) intravascular prosthetic material or vena cava filters may be included if implantation of the foreign material was performed at least 90 days before randomization
    7. Cardiac native-valve surgery planned within 3 days after randomization.
    8. Community- or hospital-acquired pneumonia.
    Note: The diagnosis of pneumonia will be made by the investigator based on respiratory complaints (e.g., cough, dyspnea, purulent secretions, and chest pain) and new or worsening infiltrates suggestive of bacterial pneumonia on a chest radiograph or a high-resolution CT. Equivocal findings on a chest radiograph should be further assessed by the conduct of a high-resolution chest CT (if feasible) and/or the
    conduct of lung ultrasound to support the presence or absence of a diagnosis of pneumonia.
    9. High probability of death within 7 days due to the underlying SAB or SAB-associated disease, or high probability of death within 28 days from an unrelated underlying disease.
    10. Clinically-relevant hypersensitivity to beta-lactam antibacterials or daptomycin.
    11. Known infection due to Staphylococcus aureus that exhibits reduced susceptibility to daptomycin (minimum inhibitory concentration[MIC] > 1 mg/L), or ceftobiprole (MIC > 2 mg/L).
    12. Absolute neutrophil count < 0.5 × 109/L.
    13. Either: a) a history of opportunistic infections (e.g., invasive fungal infections or cytomegalovirus [CMV]) within 30 days prior to randomization, where the underlying cause of these infections is still active (e.g., leukemia, transplant, acquired immunodeficiency Syndrome [AIDS]); or b) CD4 count < 100 cells/mm3 in patients with AIDS; or c) patients treated with cotrimoxazole as prophylaxis for pneumocystis pneumonia.
    14. Requirement or expected requirement between randomization and the PTE visit for potentially effective (anti-staphylococcal) systemic antibacterial treatment that is unrelated to the Treatment of SAB, e.g., in the context of planned surgery, gynecological or other procedures requiring antibacterial prophylaxis or other anticipated uses of antibacterials such as treatment for acne vulgaris.
    15. Requirement for continuous renal-replacement therapy at the time of randomization, or high likelihood of requirement for continuous renal-replacement therapy during the study period.
    Note: Patients undergoing chronic intermittent hemodialysis or peritoneal dialysis are permitted to participate in the study.
    16. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8 × the upper limit of normal, or severe hepatic disease with Child-Pugh class C.
    17. Women who are pregnant or nursing.
    18. Women who are of childbearing potential and unwilling to use an acceptable method of birth control during the study:
    19. Use of an investigational drug in a Phase I study within the 30 days prior to the study start of study treatment.
    Note: Use of investigational drugs in Phase 2 or Phase 3 studies within the 30 days prior to the start of study drug treatment is allowed.
    E.5 End points
    E.5.1Primary end point(s)
    Overall success at the PTE visit (Day 70±5 days post-randomization) in the mITT analysis set, as assessed by the DRC.
    The primary endpoint will be tested for the non-inferiority of ceftobiprole versus daptomycin using a non-inferiority margin of 15%.
    Overall success is defined as all of the following criteria being met:
    1. Patient alive at Day 70 (±5 days) post-randomization.
    2. No new metastatic foci or complications of the SAB infection.
    3. Resolution or improvement of SAB-related clinical signs and symptoms.
    4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus):
    • at least one while the patient is on active study treatment; AND
    confirmed by at least one subsequent negative blood culture for S. aureus,
    - either in the period between 7 days after the EOT visit and the PTE visit
    -or at the PTE visit
    Treatment failure is defined as any of the following:
    1. Premature discontinuation of study treatment due to DRC-assessed lack of efficacy (as assessed by the DRC) or for adverse events (AEs) that represent manifestation of disease progression or relapse, at any time between first dose of study drug and the PTE visit.
    2. Development of new metastatic or other complications related to SAB between Day 8 and the PTE visit. Development of new metastatic or other complications of SAB prior to Day 8 will be assessed by the DRC on a case-by-case basis to assess whether These constitute a delayed manifestation of the baseline disease or new complications.
    3. SAB relapse or reinfection based on evidence from a blood culture positive for S. aureus (after documented clearance of S. aureus from the bloodstream and clinical improvement) between the EOT and PTE visits.
    4. Receipt of systemic non-study antibacterial treatment, other than those permitted under the protocol, for the treatment of SAB. This includes patients who are prematurely discontinued from study therapy due to an AE, but who require continuation of antibacterial treatment for SAB.
    5. Treatment of infections other than SAB with systemic non-study antibacterial treatment which is potentially effective against S. aureus , and which is considered by the DRC to have a relevant impact on the primary endpoint
    6. Death for any reason between first administration of study drug and the PTE visit.
    7. Indeterminate outcome, defined as any data needed to determine whether the outcome is success or failure missing at the PTE visit, including but not limited to:
    a) missing PTE visit, or missing key data to evaluate the primary endpoint
    b) lost-to-follow-up, or patients who withdrew consent prior to the PTE visit
    c) patients not meeting the criteria for Success or Failure, or patients not meeting all criteria for overall success
    8. Requirement for systemic antibacterial treatment for SAB beyond EOT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 70 (±5 days) post-randomization, day 8, beyond EOT
    E.5.2Secondary end point(s)
    1. All-cause mortality (mITT population) at Day 70 (PTE visit)
    All-cause mortality will also be assessed at Day 28, and in the ITT population, and will be assessed descriptively.
    2. Microbiological eradication (mITT population) at Day 70 (PTE visit)
    Microbiological eradication will also be assessed in the CE population, and at Day 4, Day 8, and the EOT visit, and will be assessed descriptively.
    Eradication: No growth of the baseline pathogen(s), secondary to an adequate clinical response based on a negative blood culture while the patient is on active study treatment which is confirmed by at least one subsequent negative blood culture for S. aureus, either in the period between 7 days after EOT and the PTE visit, or at the PTE visit.
    Failure: Persistence relapse, or reinfection of S. aureus infection, defined as one or more of:
    • Ongoing positive blood cultures leading to discontinuation for the study drug ,
    Subsequent isolation of S. aureus from a blood culture after clearance of bacteremia and clinical improvement,
    Relapse bloodstream infection with same pathogen isolated at baseline based on genotyping
    Reinfection: blood stream infection with a different S. aureus strain to that isolated at baseline based on genotyping.
    • Absence of at least two negative blood cultures (at least one negative blood culture on active study treatment, and at least one post-treatment) to confirm eradication.
    Relapse or reinfection between EOT and PTE that is reported to the investigator from a healthcare provider not involved in the study (e.g., from another hospital), needs to be thoroughly documented and will be reviewed by the investigator and the DRC for determination.
    3. Overall success rate at PTE (CE population)
    The overall success rate will also be assessed at the EOT visit in the mITT, ITT and CE populations, and in the ITT population at the PTE visit, and will be assessed descriptively.
    4. Development of new metastatic foci or other complications of SAB after Day 7 (mITT population)
    Development of new metastatic foci or other complications of SAB after Day 7 will also be assessed in the CE population, and will be assessed descriptively.
    Timepoints: Day 8–EOT, and PTE
    Newly diagnosed IE or complicated SAB with metastatic foci or other complications of S. aureus infection, including metastatic foci in the vertebral column (vertebral abscess, osteomyelitis, discitis or epidural abscess), cerebral abscess/infarction, splenic abscess/infarction, renal abscess/infarction, psoas abscess or other deep-tissue abscess, other metastatic infection of native tissue, septic Arthritis (or bacterial joint infection/empyema), septic or suppurative thrombophlebitis and septic pulmonary emboli/infarction.
    5. Time to S. aureus bloodstream clearance (mITT and CE populations)
    Timepoints: Day 3–EOT
    Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-negative for S. aureus obtained at least 24 h after the first negative blood-culture.
    6. Safety/Tolerability (Safety population)
    Timepoints: First dose of study drug–PTE
    Incidence, type, severity, and relationship to study medication of AEs; and changes in laboratory tests (hematology, biochemistry including haptoglobin, urinalysis, and Coombs-test).
    7. Pharmacokinetics of ceftobiprole (PK population)
    Plasma levels of ceftobiprole and the beta-lactam ring-open product BAL1029
    Sparse PK sampling (all patients)
    • Day 3: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
    • Day 12: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
    Rich PK sampling (selected sites, N=40 ceftobiprole-treated patients [i.e., approximately 80 patients overall])
    • Day 3: predose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h
    • Day 12: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
    Plasma-concentration data will be analyzed at each time point and will be presented as individual concentrations with descriptive statistics (mean, SD, CV%, min, median, max).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 3, Day 4, Day 7, Day 8, Day 12, Day 28, Day 35, Day 42, Day 70, Day 3-EOT, EOT
    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 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) 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Daptomycin
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Argentina
    Brazil
    Bulgaria
    Georgia
    Germany
    Hungary
    Israel
    Italy
    Mexico
    Russian Federation
    South Africa
    Spain
    Ukraine
    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
    The End of Study is defined as the completion of the last study-related contact with any patient, referred to as the date of ‘Last Patient, Last Visit’ (LPLV).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    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: 240
    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 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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 390
    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)
    The patients will be treated according to standard of care.
    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 Decision2018-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-11
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