<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03248063</url>
  </required_header>
  <id_info>
    <org_study_id>P160943J</org_study_id>
    <nct_id>NCT03248063</nct_id>
  </id_info>
  <brief_title>Non-inferiority Trial Comparing Cloxacillin vs Cefazolin in Methicillin-susceptible Staphylococcus Aureus Bacteremia</brief_title>
  <acronym>CLOCEBA</acronym>
  <official_title>A Multicenter Non-inferiority Randomized Trial Comparing Cloxacillin Versus Cefazolin Efficacy for the Treatment of Bacteremia Caused by Methicillin-susceptible Staphylococcus Aureus (MSSA)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      &quot;Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of&#xD;
      community- or hospital-acquired bloodstream infections with an overall mortality estimated&#xD;
      around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are&#xD;
      recommended as first-line agents. With the exception of first-generation cephalosporin (1GC)&#xD;
      such as cefazolin, no alternative has yet proven a similar efficacy. Due to an unfavourable&#xD;
      safety profile for high doses used in severe infection, an uneasy dosing schedule in patients&#xD;
      with renal failure and possible recurrent stock-out events for APs, alternative to APs are&#xD;
      needed. This led to propose an open-label, randomized, controlled parallel groups, phase IV,&#xD;
      non-inferiority trial comparing the efficacy, the safety, and the ecological impact of&#xD;
      cefazolin versus cloxacillin for the treatment of MSSA bacteremia in adults.&#xD;
&#xD;
      The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at&#xD;
      day 90 after the inclusion. &quot;&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      &quot;Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of&#xD;
      community- or hospital-acquired bloodstream infections with an overall mortality estimated&#xD;
      around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are&#xD;
      recommended as first-line agents. With the exception of first-generation cephalosporin (1GC)&#xD;
      such as cefazolin, no alternative has yet proven a similar efficacy: studies evaluating other&#xD;
      β-lactams exhibited 2 fold-increased rates of mortality, while a 3 fold-increased mortality&#xD;
      rate was observed with vancomycin.&#xD;
&#xD;
      Recently, the safety of APs has been questioned, as both hypersensitivity reactions and renal&#xD;
      impairment have been reported to be higher than 10%. Premature discontinuation of APs&#xD;
      attributed to adverse events occurred in &gt;20% of patients treated with high dosing of&#xD;
      oxacillin (12g/day) for complicated MSSA bacteremia. This might be linked to the growing&#xD;
      number of cumulative comorbid conditions and to ageing. In particular, administration and&#xD;
      dosing schedule for APs are not well defined in patients with chronic kidney disease with&#xD;
      decreased rate of glomerular filtration. Today, data are missing for renal adjustment.&#xD;
&#xD;
      In addition, stock-outs of essential antimicrobials are more and more frequent. In 2011, the&#xD;
      production of the main generic for injectable oxacillin, distributed in France, was stopped.&#xD;
      More recently, cloxacillin was also stock-out because of manufacturing problems. A limited&#xD;
      production is currently available.&#xD;
&#xD;
      Due to an unfavourable safety profile for high doses used in severe infection, an uneasy&#xD;
      dosing schedule in patients with renal failure and possible recurrent stock-out events for&#xD;
      APs, alternative to APs are needed.&#xD;
&#xD;
      Cefazolin, intravenous 1GC, is more and more commonly used. Based on several large&#xD;
      observational studies, its efficacy is believed to be similar to that of APs both in terms of&#xD;
      relapse and mortality, even in complicated cases such as osteo-arthritis or infective&#xD;
      endocarditis. The potential hydrolysis of cefazolin by Staphylococcus aureus type A&#xD;
      ßlactamases had no clinical impact. These data led the American and European infectious&#xD;
      disease Societies to consider cefazolin as the first alternative line agent for treatment of&#xD;
      MSSA-associated infective endocarditis. Nevertheless, except for chronic dialysis question,&#xD;
      all existing studies assessing the efficacy profiles of cefazolin compared to the APs contain&#xD;
      a retrospective design and no randomized clinical trial (RCT) has been performed.&#xD;
&#xD;
      However, in the current context of growing bacterial resistance, especially for&#xD;
      third-generation cephalosporins (3GCs) resistance in Enterobacteriaceae, the use of&#xD;
      cefazolin, which has a large antibacterial spectrum, instead of APs, whose antibacterial&#xD;
      spectrum is very narrow, remains to be investigated. Few data are available to assess the&#xD;
      impact of cefazolin and APs on the bacterial floras.&#xD;
&#xD;
      This is an open-label, randomized, controlled parallel groups, phase IV, non-inferiority&#xD;
      trial comparing the efficacy of cefazolin versus cloxacillin for the treatment of MSSA&#xD;
      bacteremia in adults.&#xD;
&#xD;
      The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at&#xD;
      day 90 after the inclusion.&#xD;
&#xD;
      The primary endpoint is a composite efficacy criterion of (at least one of) the following:&#xD;
&#xD;
        -  Survival at day 90&#xD;
&#xD;
        -  Bacteriologic success at day 5&#xD;
&#xD;
        -  Absence of relapse at day 90&#xD;
&#xD;
        -  Clinical success at day 90.&#xD;
&#xD;
      Secondary objectives include, according to treatment group:&#xD;
&#xD;
      Efficacy objectives&#xD;
&#xD;
        1. To compare the mortality at day 90&#xD;
&#xD;
        2. To compare the bacteriological efficacy at day 3, at day 5 and at day 90&#xD;
&#xD;
        3. To compare the rate of bacteriologic relapse at day 90&#xD;
&#xD;
        4. To compare the clinical efficacy at day 7 and at day 90&#xD;
&#xD;
        5. To compare the proportions of patients for whom consensual treatment duration is&#xD;
           respected Safety objectives&#xD;
&#xD;
        6. To compare the occurrence of any adverse event (AE) at day 7, at the end of studied&#xD;
           antibiotic therapy (EoST) and at the end of all antibiotic therapy (EoAT)&#xD;
&#xD;
        7. To compare the occurrence of grade 3 or grade 4 AE at day 7, at EoST and at EoAT&#xD;
&#xD;
        8. To compare the rate of premature discontinuation of studied antibiotic therapy due to&#xD;
           the occurrence of an adverse event&#xD;
&#xD;
        9. To compare the occurrence C. difficile infection&#xD;
&#xD;
      Ancillary studies will be performed for evaluating the impact of S. aureus beta lactamases on&#xD;
      the effectiveness, for determination of PKPD (pharmacokinetic and pharmacodynamic) parameters&#xD;
      of cloxacillin and cefazolin predictive of therapeutic effectiveness, and for comparing&#xD;
      cloxacillin and cefazolin impact on the emergence of 3rd generation resistant enterobacteria&#xD;
      and on the intestinal microbiota (evaluated by 16 rRNA (ribosomal ribonucleic acid) gene&#xD;
      profiling).&#xD;
&#xD;
      Patients with a positive blood culture for Gram-positive cocci and a time-to-positivity ≤20&#xD;
      hours will be assessed for eligibility. The cut-off of 20 hours for the time-to-positivity&#xD;
      was chosen according to data from the VIRSTA study, in which about 90% of SAB (staphylococcus&#xD;
      aureus bacteremia) were positive in less than 20 hours after blood sampling. Median and 75th&#xD;
      percentile were 13 hours and 18 hours after blood sampling. Concordant data have already been&#xD;
      reported .&#xD;
&#xD;
      A rapid molecular test for detection of protein A, mecA and mecSCC genes will be performed on&#xD;
      the blood culture by GeneXpert real-time PCR, according to the manufacturer's specifications&#xD;
      (Cepheid, Sunnyvale, CA).&#xD;
&#xD;
      Patients with methicillin-susceptible Staphylococcus aureus positive blood culture will be&#xD;
      randomized after full information and verification of inclusion criteria. Randomization will&#xD;
      be stratified on center and vascular access-associated bacteremia with a 1:1 ratio.&#xD;
&#xD;
      There is no limitation on the nature of antibiotics that patients might receive prior to the&#xD;
      randomization. However, antibiotic treatment active against MSSA should have begun in the&#xD;
      last 48 hours before the randomization.&#xD;
&#xD;
      All patients will undergo transthoracic echocardiography within 7 days following&#xD;
      randomization for diagnosing infective endocarditis. Other radiological exams will be&#xD;
      performed depending on the clinical suspicion for the origin of bacteremia or for the&#xD;
      presence of deep abscess.&#xD;
&#xD;
      According to the guidelines, patients with MSSA bacteremia will be treated with intravenous&#xD;
      antimicrobial therapy for 2 weeks. The total treatment duration will be left to the choice of&#xD;
      the clinician in charge of the patient but will be not below 14 days. Nevertheless, after 7&#xD;
      days, the nature of the antimicrobial treatment will be let to the choice of the clinician in&#xD;
      charge of the patient. Treatment duration according to the final diagnosis will be defined by&#xD;
      consensual guidelines. These guidelines are being developed using a methodology inspired by&#xD;
      the Delphi method as part of the Tep-Star clinical trial. The coordinating investigator of&#xD;
      the Tep-Star trial is Vincent Le Moing and its scientific director is Xavier Duval. Both are&#xD;
      members of the scientific committee of this trial. Antimicrobials for switch of the first&#xD;
      treatment line will be let to the choice of the investigator in charge of the patient.&#xD;
&#xD;
      Clinical evaluations for efficacy and safety will be performed at day -1, at day 7, at EoAT,&#xD;
      and 90 days after the beginning of therapy. Blood cultures for efficacy evaluation will be&#xD;
      performed at days 1, 3, 5 and 90. Biological evaluation for safety will be performed at days&#xD;
      -1, 1, 3, 7, at EoST, at EoAT and at day 90.&#xD;
&#xD;
      The epidemiology of blaZ β-lactamases will be studied in all strains of S. aureus isolated&#xD;
      from the blood culture vials.&#xD;
&#xD;
      The ancillary study of the antibiotic impact on the bacterial flora will be performed on a&#xD;
      subgroup of 150 patients (75 in each treatment group). Rectal swabs will be collected just&#xD;
      before and at day 7, at EoAT and at day 90.&#xD;
&#xD;
      The pharmacokinetic ancillary study will be performed on a subgroup of 50 patients (25 in&#xD;
      each treatment group). For pharmacokinetic calculations, plasma cefazolin and cloxacillin&#xD;
      levels will be determined at day 3, just before the 7th administration of cefazolin and the&#xD;
      9th administration of cloxacillin, and 1, 1.5, 2, and 4 hours after the beginning of&#xD;
      infusion.&quot;&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 5, 2018</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">June 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Therapeutic efficacy</measure>
    <time_frame>90 days after beginning of antibiotic treatment</time_frame>
    <description>&quot;Composite efficacy criterion of the following:&#xD;
Survival at day 90&#xD;
Bacteriologic success at day 5&#xD;
Absence of relapse at day 90&#xD;
Clinical success at day 90&quot;</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>day 90</time_frame>
    <description>Mortality rate at day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacteriological efficacy</measure>
    <time_frame>day 3, day 5 and day 90</time_frame>
    <description>Proportions of patients with a negative set of blood culture at day 3, at day 5 and at day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacteriologic relapse</measure>
    <time_frame>day 5</time_frame>
    <description>Proportion of patients with bacteriologic success at day 5 in whom a strain of S. aureus with identical in vitro antibiotic susceptibility pattern than the one isolated at inclusion is isolated from at least 1 blood culture during the follow up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical efficacy</measure>
    <time_frame>day 7 and day 90</time_frame>
    <description>Proportions of patients improving all signs and symptoms related to the infection at day 7 and at day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of patients for whom consensual treatment duration is respected</measure>
    <time_frame>day 90</time_frame>
    <description>Proportion of patients for whom the antibiotic duration from randomization is in accordance with consensual guidelines obtained by the Delphi method</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of any adverse event</measure>
    <time_frame>at day 7 and up to 6 weeks</time_frame>
    <description>Proportions of patients with any adverse event at day 7, at the end of studied antibiotic therapy (EoST) and at the end of all antibiotic therapy (EoAT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of grade 3 or grade 4 adverse event</measure>
    <time_frame>at day 7 and up to 6 weeks</time_frame>
    <description>7. Proportions of patients with any grade 3 or grade 4 adverse event at day 7, at EoST and at EoAT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event</measure>
    <time_frame>day 90</time_frame>
    <description>Proportion of patients with premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence C. difficile infection</measure>
    <time_frame>day 90</time_frame>
    <description>Proportion of patients with C. difficile infection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of BlaZ genes in S. aureus strains isolated from patients with MSSA bacteremia</measure>
    <time_frame>at inclusion</time_frame>
    <description>Proportion of type A, type B, type C and type D BlaZ genes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Link between BlaZ typing and bacteriologic efficacy</measure>
    <time_frame>day 5</time_frame>
    <description>Type of BlaZ gene. Proportion of patients with a negative blood culture at day 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MICs distribution of cefazolin and cloxacillin in S. aureus strains isolated from patients with MSSA bacteremia</measure>
    <time_frame>at inclusion</time_frame>
    <description>MICs of cefazolin and cloxacillin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Emergence of antimicrobial resistance in the faecal microbiota</measure>
    <time_frame>at day 7, up to 6 weeks and at day 90</time_frame>
    <description>Proportion of patients with emergence of 3rd generation cephalosporin-resistant Enterobacteriaceae in fecal swabs at day 7, at EoAT and at day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in relative abundance of each bacterial phylum</measure>
    <time_frame>at day 7, up to 6 weeks and at day 90</time_frame>
    <description>comparison of the variation from baseline of the logarithm of proportions of each bacterial phylum at inclusion, EoAT and day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in bacterial diversity within the intestinal microbiota</measure>
    <time_frame>at day 7, up to 6 weeks and at day 90</time_frame>
    <description>comparison of the change from baseline of shannon index within the intestinal microbiota between inclusion and day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total body clearance of cloxacillin and cefazolin in patients with MSSA bacteremia</measure>
    <time_frame>at day 3</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total body volume of distribution of cloxacillin and cefazolin in patients with MSSA bacteremia</measure>
    <time_frame>at day 3</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration versus time curve (AUC) of cloxacillin and cefazolin</measure>
    <time_frame>at day 5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Plasma Concentration (Cmax) of cloxacillin and cefazolin</measure>
    <time_frame>at day 5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal inhibitory concentration (MIC) of cloxacillin and cefazolin</measure>
    <time_frame>at day 5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual concentration (Cres) of cloxacillin and cefazolin</measure>
    <time_frame>at day 5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of time between 2 administration during which the plasma concentration of the antimicrobial is above the MIC (%T&gt;MIC).</measure>
    <time_frame>at day 5</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Bacteremia Due to Methicillin Susceptible Staphylococcus Aureus</condition>
  <arm_group>
    <arm_group_label>Cloxacillin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cefazolin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cloxacillin</intervention_name>
    <description>Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion. This treatment will be administered for at least 7 days by intravenous route.&#xD;
Dosing regimen will be adapted in patients with chronic renal failure (glomerular filtration rate below 30ml/min/1.73m²) and in patient with impaired hepatic function associated with renal impairment whatever the level of the estimation of the glomerular filtration rate, according to SPC.</description>
    <arm_group_label>Cloxacillin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cefazolin</intervention_name>
    <description>Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion. This treatment will be administered for 14 days by intravenous route. Dosing regimen will be adapted in case of glomerular filtration rate between 30-50ml/min according to SPC. As currently recommended, investigators will be encouraged to use the intravenous route for the entire duration of treatment. However, in order to interfere as little as possible with usual practice in each center, the antimicrobial therapy will be let to the choice of the physician in charge of the patient after a minimum of 7 days of intravenous treatment.</description>
    <arm_group_label>Cefazolin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age above 18 years&#xD;
&#xD;
          2. Blood culture positive to MSSA identified by standard bacteriologic techniques or by&#xD;
             GeneXpert PCR&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous type 1 or grade 3 - 4 according to CTCAE hypersensitivity reaction to&#xD;
             beta-lactams&#xD;
&#xD;
          2. Known pregnancy or breastfeeding women&#xD;
&#xD;
          3. Parenteral antimicrobial therapy active against MSSA for more than 72 hours after the&#xD;
             positive SA blood culture ponction&#xD;
&#xD;
          4. Chronic renal failure defined by a glomerular filtration rate estimated &lt; 30&#xD;
             mL/min/1,73m².&#xD;
&#xD;
          5. Presence of an intra-vascular implant (vascular or valvular prosthesis or&#xD;
             cardiovascular implantable electronic device)&#xD;
&#xD;
          6. Patient with implanted material considered to be infected by SAMS and whose antibiotic&#xD;
             treatment is longer than 70 days&#xD;
&#xD;
          7. New cerebro-spinal signs in the preceding month&#xD;
&#xD;
          8. Clinical examination compatible with recent stroke (&lt;1 month), brain abscess or&#xD;
             meningitis&#xD;
&#xD;
          9. Current other antibiotic therapy which cannot be ceased or substituted by study&#xD;
             treatment&#xD;
&#xD;
         10. Mixed blood culture with more than one pathogen (excluding contaminants:&#xD;
             Corynebacterium sp., Propionibacterium sp., Coagulase-Negative Staphylococci)&#xD;
&#xD;
         11. coagulapthy with TP&lt; 50% (excepted for patients under avk anticoagulant treatment)&#xD;
&#xD;
         12. Absence of written informed consent from the patient&#xD;
&#xD;
         13. Limitation of care with expected life duration below 90 days&#xD;
&#xD;
         14. Patient under guardianship or trusteeship&#xD;
&#xD;
         15. No affiliation to social security (beneficiary or assignee)&#xD;
&#xD;
         16. Subject already involved in another interventional clinical research evaluating a&#xD;
             medicinal product&#xD;
&#xD;
        Secondary exclusion criteria:&#xD;
&#xD;
          1. Diagnosis of meningitis made after randomisation&#xD;
&#xD;
          2. Diagnosis of brain abscess made after randomisation&#xD;
&#xD;
          3. Diagnosis of multiple infection made after randomisation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xavier Lescure, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Xavier Lescure, MD, PhD</last_name>
    <phone>01 40 25 69 94</phone>
    <phone_ext>33</phone_ext>
    <email>xavier.lescure@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Charles Burdet, MD, PhD</last_name>
    <email>charles.burdet@inserm.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>François-Xavier Lescure</name>
      <address>
        <city>Paris</city>
        <zip>75018</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>François-Xavier Lescure, MD-PhD</last_name>
      <email>xavier.lescure@aphp.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 14, 2017</study_first_posted>
  <last_update_submitted>December 7, 2022</last_update_submitted>
  <last_update_submitted_qc>December 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Staphylococcus aureus</keyword>
  <keyword>bacteremia</keyword>
  <keyword>cloxacillin</keyword>
  <keyword>cefazolin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Staphylococcal Infections</mesh_term>
    <mesh_term>Bacteremia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cefazolin</mesh_term>
    <mesh_term>Cloxacillin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03248063
org study id: P160943J
nct id: NCT03248063
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
"Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of
      community- or hospital-acquired bloodstream infections with an overall mortality estimated
      around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are
      recommended as first-line agents. With the exception of first-generation cephalosporin (1GC)
      such as cefazolin, no alternative has yet proven a similar efficacy. Due to an unfavourable
      safety profile for high doses used in severe infection, an uneasy dosing schedule in patients
      with renal failure and possible recurrent stock-out events for APs, alternative to APs are
      needed. This led to propose an open-label, randomized, controlled parallel groups, phase IV,
      non-inferiority trial comparing the efficacy, the safety, and the ecological impact of
      cefazolin versus cloxacillin for the treatment of MSSA bacteremia in adults.

      The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at
      day 90 after the inclusion. "
"Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of
      community- or hospital-acquired bloodstream infections with an overall mortality estimated
      around 25%. Anti-staphylococcal penicillins (APs) such as oxacillin or cloxacillin are
      recommended as first-line agents. With the exception of first-generation cephalosporin (1GC)
      such as cefazolin, no alternative has yet proven a similar efficacy: studies evaluating other
      β-lactams exhibited 2 fold-increased rates of mortality, while a 3 fold-increased mortality
      rate was observed with vancomycin.

      Recently, the safety of APs has been questioned, as both hypersensitivity reactions and renal
      impairment have been reported to be higher than 10%. Premature discontinuation of APs
      attributed to adverse events occurred in >20% of patients treated with high dosing of
      oxacillin (12g/day) for complicated MSSA bacteremia. This might be linked to the growing
      number of cumulative comorbid conditions and to ageing. In particular, administration and
      dosing schedule for APs are not well defined in patients with chronic kidney disease with
      decreased rate of glomerular filtration. Today, data are missing for renal adjustment.

      In addition, stock-outs of essential antimicrobials are more and more frequent. In 2011, the
      production of the main generic for injectable oxacillin, distributed in France, was stopped.
      More recently, cloxacillin was also stock-out because of manufacturing problems. A limited
      production is currently available.

      Due to an unfavourable safety profile for high doses used in severe infection, an uneasy
      dosing schedule in patients with renal failure and possible recurrent stock-out events for
      APs, alternative to APs are needed.

      Cefazolin, intravenous 1GC, is more and more commonly used. Based on several large
      observational studies, its efficacy is believed to be similar to that of APs both in terms of
      relapse and mortality, even in complicated cases such as osteo-arthritis or infective
      endocarditis. The potential hydrolysis of cefazolin by Staphylococcus aureus type A
      ßlactamases had no clinical impact. These data led the American and European infectious
      disease Societies to consider cefazolin as the first alternative line agent for treatment of
      MSSA-associated infective endocarditis. Nevertheless, except for chronic dialysis question,
      all existing studies assessing the efficacy profiles of cefazolin compared to the APs contain
      a retrospective design and no randomized clinical trial (RCT) has been performed.

      However, in the current context of growing bacterial resistance, especially for
      third-generation cephalosporins (3GCs) resistance in Enterobacteriaceae, the use of
      cefazolin, which has a large antibacterial spectrum, instead of APs, whose antibacterial
      spectrum is very narrow, remains to be investigated. Few data are available to assess the
      impact of cefazolin and APs on the bacterial floras.

      This is an open-label, randomized, controlled parallel groups, phase IV, non-inferiority
      trial comparing the efficacy of cefazolin versus cloxacillin for the treatment of MSSA
      bacteremia in adults.

      The primary objective is to compare the therapeutic efficacy of cefazolin vs cloxacillin at
      day 90 after the inclusion.

      The primary endpoint is a composite efficacy criterion of (at least one of) the following:

        -  Survival at day 90

        -  Bacteriologic success at day 5

        -  Absence of relapse at day 90

        -  Clinical success at day 90.

      Secondary objectives include, according to treatment group:

      Efficacy objectives

        1. To compare the mortality at day 90

        2. To compare the bacteriological efficacy at day 3, at day 5 and at day 90

        3. To compare the rate of bacteriologic relapse at day 90

        4. To compare the clinical efficacy at day 7 and at day 90

        5. To compare the proportions of patients for whom consensual treatment duration is
           respected Safety objectives

        6. To compare the occurrence of any adverse event (AE) at day 7, at the end of studied
           antibiotic therapy (EoST) and at the end of all antibiotic therapy (EoAT)

        7. To compare the occurrence of grade 3 or grade 4 AE at day 7, at EoST and at EoAT

        8. To compare the rate of premature discontinuation of studied antibiotic therapy due to
           the occurrence of an adverse event

        9. To compare the occurrence C. difficile infection

      Ancillary studies will be performed for evaluating the impact of S. aureus beta lactamases on
      the effectiveness, for determination of PKPD (pharmacokinetic and pharmacodynamic) parameters
      of cloxacillin and cefazolin predictive of therapeutic effectiveness, and for comparing
      cloxacillin and cefazolin impact on the emergence of 3rd generation resistant enterobacteria
      and on the intestinal microbiota (evaluated by 16 rRNA (ribosomal ribonucleic acid) gene
      profiling).

      Patients with a positive blood culture for Gram-positive cocci and a time-to-positivity ≤20
      hours will be assessed for eligibility. The cut-off of 20 hours for the time-to-positivity
      was chosen according to data from the VIRSTA study, in which about 90% of SAB (staphylococcus
      aureus bacteremia) were positive in less than 20 hours after blood sampling. Median and 75th
      percentile were 13 hours and 18 hours after blood sampling. Concordant data have already been
      reported .

      A rapid molecular test for detection of protein A, mecA and mecSCC genes will be performed on
      the blood culture by GeneXpert real-time PCR, according to the manufacturer's specifications
      (Cepheid, Sunnyvale, CA).

      Patients with methicillin-susceptible Staphylococcus aureus positive blood culture will be
      randomized after full information and verification of inclusion criteria. Randomization will
      be stratified on center and vascular access-associated bacteremia with a 1:1 ratio.

      There is no limitation on the nature of antibiotics that patients might receive prior to the
      randomization. However, antibiotic treatment active against MSSA should have begun in the
      last 48 hours before the randomization.

      All patients will undergo transthoracic echocardiography within 7 days following
      randomization for diagnosing infective endocarditis. Other radiological exams will be
      performed depending on the clinical suspicion for the origin of bacteremia or for the
      presence of deep abscess.

      According to the guidelines, patients with MSSA bacteremia will be treated with intravenous
      antimicrobial therapy for 2 weeks. The total treatment duration will be left to the choice of
      the clinician in charge of the patient but will be not below 14 days. Nevertheless, after 7
      days, the nature of the antimicrobial treatment will be let to the choice of the clinician in
      charge of the patient. Treatment duration according to the final diagnosis will be defined by
      consensual guidelines. These guidelines are being developed using a methodology inspired by
      the Delphi method as part of the Tep-Star clinical trial. The coordinating investigator of
      the Tep-Star trial is Vincent Le Moing and its scientific director is Xavier Duval. Both are
      members of the scientific committee of this trial. Antimicrobials for switch of the first
      treatment line will be let to the choice of the investigator in charge of the patient.

      Clinical evaluations for efficacy and safety will be performed at day -1, at day 7, at EoAT,
      and 90 days after the beginning of therapy. Blood cultures for efficacy evaluation will be
      performed at days 1, 3, 5 and 90. Biological evaluation for safety will be performed at days
      -1, 1, 3, 7, at EoST, at EoAT and at day 90.

      The epidemiology of blaZ β-lactamases will be studied in all strains of S. aureus isolated
      from the blood culture vials.

      The ancillary study of the antibiotic impact on the bacterial flora will be performed on a
      subgroup of 150 patients (75 in each treatment group). Rectal swabs will be collected just
      before and at day 7, at EoAT and at day 90.

      The pharmacokinetic ancillary study will be performed on a subgroup of 50 patients (25 in
      each treatment group). For pharmacokinetic calculations, plasma cefazolin and cloxacillin
      levels will be determined at day 3, just before the 7th administration of cefazolin and the
      9th administration of cloxacillin, and 1, 1.5, 2, and 4 hours after the beginning of
      infusion."
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Therapeutic efficacy
time frame: 90 days after beginning of antibiotic treatment
description: "Composite efficacy criterion of the following:
Survival at day 90
Bacteriologic success at day 5
Absence of relapse at day 90
Clinical success at day 90"
measure: Mortality
time frame: day 90
description: Mortality rate at day 90
measure: Bacteriological efficacy
time frame: day 3, day 5 and day 90
description: Proportions of patients with a negative set of blood culture at day 3, at day 5 and at day 90
measure: Bacteriologic relapse
time frame: day 5
description: Proportion of patients with bacteriologic success at day 5 in whom a strain of S. aureus with identical in vitro antibiotic susceptibility pattern than the one isolated at inclusion is isolated from at least 1 blood culture during the follow up
measure: Clinical efficacy
time frame: day 7 and day 90
description: Proportions of patients improving all signs and symptoms related to the infection at day 7 and at day 90
measure: Proportions of patients for whom consensual treatment duration is respected
time frame: day 90
description: Proportion of patients for whom the antibiotic duration from randomization is in accordance with consensual guidelines obtained by the Delphi method
measure: Occurrence of any adverse event
time frame: at day 7 and up to 6 weeks
description: Proportions of patients with any adverse event at day 7, at the end of studied antibiotic therapy (EoST) and at the end of all antibiotic therapy (EoAT)
measure: Occurrence of grade 3 or grade 4 adverse event
time frame: at day 7 and up to 6 weeks
description: 7. Proportions of patients with any grade 3 or grade 4 adverse event at day 7, at EoST and at EoAT
measure: Premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event
time frame: day 90
description: Proportion of patients with premature discontinuation of studied antibiotic therapy due to the occurrence of an adverse event
measure: Occurrence C. difficile infection
time frame: day 90
description: Proportion of patients with C. difficile infection
measure: Prevalence of BlaZ genes in S. aureus strains isolated from patients with MSSA bacteremia
time frame: at inclusion
description: Proportion of type A, type B, type C and type D BlaZ genes
measure: Link between BlaZ typing and bacteriologic efficacy
time frame: day 5
description: Type of BlaZ gene. Proportion of patients with a negative blood culture at day 5.
measure: MICs distribution of cefazolin and cloxacillin in S. aureus strains isolated from patients with MSSA bacteremia
time frame: at inclusion
description: MICs of cefazolin and cloxacillin
measure: Emergence of antimicrobial resistance in the faecal microbiota
time frame: at day 7, up to 6 weeks and at day 90
description: Proportion of patients with emergence of 3rd generation cephalosporin-resistant Enterobacteriaceae in fecal swabs at day 7, at EoAT and at day 90
measure: Changes in relative abundance of each bacterial phylum
time frame: at day 7, up to 6 weeks and at day 90
description: comparison of the variation from baseline of the logarithm of proportions of each bacterial phylum at inclusion, EoAT and day 90
measure: Changes in bacterial diversity within the intestinal microbiota
time frame: at day 7, up to 6 weeks and at day 90
description: comparison of the change from baseline of shannon index within the intestinal microbiota between inclusion and day 90
measure: Total body clearance of cloxacillin and cefazolin in patients with MSSA bacteremia
time frame: at day 3
measure: Total body volume of distribution of cloxacillin and cefazolin in patients with MSSA bacteremia
time frame: at day 3
measure: Area under the plasma concentration versus time curve (AUC) of cloxacillin and cefazolin
time frame: at day 5
measure: Peak Plasma Concentration (Cmax) of cloxacillin and cefazolin
time frame: at day 5
measure: Minimal inhibitory concentration (MIC) of cloxacillin and cefazolin
time frame: at day 5
measure: Residual concentration (Cres) of cloxacillin and cefazolin
time frame: at day 5
measure: The proportion of time between 2 administration during which the plasma concentration of the antimicrobial is above the MIC (%T>MIC).
time frame: at day 5
arm group label: Cloxacillin
arm group type: Active Comparator
description: Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion.
arm group label: Cefazolin
arm group type: Experimental
description: Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion.
intervention type: Drug
intervention name: Cloxacillin
description: Intravenous treatment by cloxacillin, 25 to 50 mg/kg every 4 or 6 hours, without doing less than the minimum daily dose of 8 g/day and without exceeding the maximum daily dose of 12 g/day, administered as a 60-minutes infusion. This treatment will be administered for at least 7 days by intravenous route.
Dosing regimen will be adapted in patients with chronic renal failure (glomerular filtration rate below 30ml/min/1.73m²) and in patient with impaired hepatic function associated with renal impairment whatever the level of the estimation of the glomerular filtration rate, according to SPC.
arm group label: Cloxacillin
intervention type: Drug
intervention name: Cefazolin
description: Intravenous treatment by cefazolin, 25 to 50 mg/kg every 8 hours (without exceeding the maximum daily dose of 6 g/day), administered as a 30-minutes infusion. This treatment will be administered for 14 days by intravenous route. Dosing regimen will be adapted in case of glomerular filtration rate between 30-50ml/min according to SPC. As currently recommended, investigators will be encouraged to use the intravenous route for the entire duration of treatment. However, in order to interfere as little as possible with usual practice in each center, the antimicrobial therapy will be let to the choice of the physician in charge of the patient after a minimum of 7 days of intravenous treatment.
arm group label: Cefazolin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xavier Lescure, MD, PhD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Xavier Lescure, MD, PhD
phone: 01 40 25 69 94
phone ext: 33
email: xavier.lescure@aphp.fr
last name: Charles Burdet, MD, PhD
email: charles.burdet@inserm.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Staphylococcal Infections
mesh term: Bacteremia
mesh term: Cefazolin
mesh term: Cloxacillin
sharing ipd: Undecided