<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/NCT02260102</url>
  </required_header>
  <id_info>
    <org_study_id>temocillin-pediatrics</org_study_id>
    <nct_id>NCT02260102</nct_id>
  </id_info>
  <brief_title>Temocillin Pharmacokinetics in Paediatrics</brief_title>
  <acronym>TEMOPEDI</acronym>
  <official_title>Temocillin Pharmacokinetics in Paediatrics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Université Catholique de Louvain</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Temocillin (6-methoxy-ticarcillin) is a beta-lactam antibiotic with exceptional resistance to&#xD;
      most beta-lactamases. In this context, it is now increasingly used as carbapenem-sparing&#xD;
      antibiotic in patients with suspected infection by Enterobactreriaceae suspected to produce&#xD;
      extended-spectrum beta-lactamases. Little is known about dosing and elimination of temocillin&#xD;
      in children. While available literature of temocillin use in paediatrics refers mainly to its&#xD;
      clinical efficacy in the treatment of urinary tract infections, the drug is also used for the&#xD;
      treatment of suspicion of cholangitis in cirrhotic paediatric patients, and as antibiotic&#xD;
      prophylaxis following an hepatic transplant in children (both off-label indications). There&#xD;
      is, therefore, a pressing need to explore the pharmacokinetics and pharmacodynamics of&#xD;
      temocillin in the paediatric population, in order to provide clear guidance on an appropriate&#xD;
      dosing regimen. The study objectives are: (1) characterisation of the pharmacokinetics (PK)&#xD;
      of temocillin in 3 paediatric populations, (2) proposal and development of a dosing schedule&#xD;
      that can ensure therapeutic concentrations (40% ƒT &gt; MIC) and optimize treatment chances of&#xD;
      success, and (3) characterization of MICs of microbiological strains (when available) to&#xD;
      temocillin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Introduction Temocillin is a beta-lactam antibiotic active against Gram-negative bacteria.&#xD;
      Its spectrum covers family members of the Enterobacteriaceae (including many of those&#xD;
      producing beta-lactamases), Haemophilus influenzae and Neisseria spp 1,2, but not&#xD;
      Pseudomonas. It is currently licensed for use in septicemia, urinary tract infection (UTIs),&#xD;
      and lower respiratory tract infection.3 There is also evidence of its clinical efficacy in&#xD;
      the treatment of biliary tract infections in adults.4,5 Temocillin biliary levels can be&#xD;
      several times-fold superior to serum concentrations in patients with cholelithiasis, although&#xD;
      they can also be characterised by high interindividual variation.6,7 In addition, its&#xD;
      prolonged half-life (4.5-5 hours) and its Gram-negative spectrum make temocillin particularly&#xD;
      suited for the treatment of hepatobiliary infections.5 One study documents the efficacy of&#xD;
      temocillin in this indication (16 patients with biliary tract infections; daily dose of 2g of&#xD;
      temocillin).7&#xD;
&#xD;
      The interest of this molecule has been greatly enhanced in the recent years due to the&#xD;
      increased incidence of infections caused by organisms producing extended-spectrum&#xD;
      beta-lactamases (ESBL), making it to become a sparing-drug for carbapenems.8-10 Temocillin&#xD;
      presents MICs ranging from 2 to 32 mg/L against Enterobacteriaceae, including most ESBL&#xD;
      producers.1,2 Like all beta-lactam antibiotics, the time above MIC for free drug&#xD;
      concentrations (ƒT&gt;MIC) is the important PK-PD parameter correlating with its efficacy.11&#xD;
      When the beta-lactam antibiotic concentrations do not exceed the MIC for 40% to 50% of the&#xD;
      dosing interval, the efficacy of a beta-lactam antibiotic can be compromised. When a cut-off&#xD;
      of a ƒT&gt;MIC of 40% is used, a Monte-Carlo simulation of the available data defines a clinical&#xD;
      PK/PD breakpoint of 8 to 16 mg/L for temocillin.11-13 The available temocillin&#xD;
      pharmacokinetics data (distribution, metabolism, and elimination) comes from studies&#xD;
      performed in adults. It is mainly excreted unchanged (80%) in the urine by glomerular&#xD;
      filtration and tubular secretion.3&#xD;
&#xD;
      Little is known about dosing and elimination of temocillin in children. The summary of&#xD;
      product characteristics of temocillin proposes a daily dose of 25 - 50 mg/kg for paediatric&#xD;
      use,14 but there are no studies that back-up this recommendation. This dose probably arises&#xD;
      from scaling-down the typical adult daily dose of 2-4 g assuming an adult weight of 70kg. In&#xD;
      the literature, the use of temocillin in paediatrics refers mainly to its clinical efficacy&#xD;
      in the treatment of urinary tract infections.15,16 In the present hospital, temocillin is&#xD;
      also used for the treatment of suspicion of cholangitis in cirrhotic paediatric patients, and&#xD;
      as antibiotic prophylaxis following an hepatic transplant in children (both off-label&#xD;
      indications). There is, therefore, a pressing need to explore the pharmacokinetics and&#xD;
      pharmacodynamics of temocillin in the paediatric population, in order to provide clear&#xD;
      guidance on an appropriate dosing regimen.&#xD;
&#xD;
      2. Study Objectives&#xD;
&#xD;
        1. Characterisation of the pharmacokinetics (PK) of temocillin (total and free&#xD;
           concentrations) in 3 paediatric populations:&#xD;
&#xD;
             1. children requiring antibiotic treatment for urinary tract infections&#xD;
&#xD;
             2. cirrhotic children requiring antibiotic treatment due to suspicion of cholangitis&#xD;
&#xD;
             3. children requiring antibiotic prophylaxis following an hepatic transplant&#xD;
&#xD;
        2. Proposal and development of a dosing schedule that can ensure therapeutic concentrations&#xD;
           (40% ƒT &gt; MIC) and optimize treatment chances of success.&#xD;
&#xD;
        3. Characterization of MICs of microbiological strains (when available) to temocillin.&#xD;
&#xD;
      3. Criteria for patients' selection 3.1 Inclusion Criteria&#xD;
&#xD;
      1. Male or female patient requiring temocillin&#xD;
&#xD;
        1. for the treatment of urinary tract infections, or&#xD;
&#xD;
        2. for the treatment of suspicion of cholangitis associated with cirrhosis, or&#xD;
&#xD;
        3. as antibiotic prophylaxis following an hepatic transplant. 2. Requirement of&#xD;
           hospitalization (not for social or other non-medical reasons) for at least up to 5 days&#xD;
           3. Patients aged 6 months - 3 years at the beginning of the treatment with temocillin 4.&#xD;
           Parents or legal representatives able to give written informed consent in accordance&#xD;
           with GCP and local regulatory requirements, prior to any study procedure&#xD;
&#xD;
           3.2 Exclusion Criteria&#xD;
&#xD;
             1. Ig-E mediated allergy to penicillins&#xD;
&#xD;
             2. Previous treatment with temocillin for the current cholangitis episode&#xD;
&#xD;
             3. Diagnosis of Alagille syndrome&#xD;
&#xD;
             4. Estimated life-expectance of &lt; 5 days due to major co-morbid conditions&#xD;
&#xD;
             5. Other serious illnesses, e.g. HIV, serious infections requiring other antibiotics,&#xD;
                malignancy&#xD;
&#xD;
             6. Patients with acute or chronic renal failure (eGFR &lt; 30ml/min)&#xD;
&#xD;
             7. Patients having participated in another study &lt; 30 days before inclusion in the&#xD;
                present study&#xD;
&#xD;
           4. Investigational Plan 4.1 Study design and plan This is a prospective, open,&#xD;
           non-interventional and monocentric study that will take place at the &quot;Service de&#xD;
           Gastro-entérologie pédiatrique&quot; of the &quot;Cliniques Universitaires St-Luc&quot; in Brussels,&#xD;
           Belgium. All patients eligible for treatment with temocillin will be evaluated and&#xD;
           considered for inclusion in the study.&#xD;
&#xD;
           For each of the 3 paediatric populations, a total of 30-35 patients eligible for&#xD;
           participation will be included in the study. According to the manufacturer's&#xD;
           information14 a dose of 25mg/kg (in cases of prophylaxis) or 50mg/kg (in cases of&#xD;
           treatment) per day divided in 2 administrations will be used and administered by IV&#xD;
           route. Blood samples will be drawn on day 1 and day 4 of treatment at 0.5, 2, 4, 8, 12&#xD;
           hours after dose administration. The patient's physician will decide on the duration of&#xD;
           temocillin use.&#xD;
&#xD;
           The expected total duration of the trial is 1 year (or more if patient enrollment is&#xD;
           slow; number of patients to be included: 10-15 for each of the 3 paediatric populations;&#xD;
           see next sentence for a justification of the addition of 15-20 patients per group after&#xD;
           acceptance of an amendment to the initial protocol).&#xD;
&#xD;
           An interim analysis on the first 14 patients from populations b and c suggested that the&#xD;
           dose was too low to reach the pharmacodynamic target. An amendment has been submitted to&#xD;
           the ethical committee of the cliniques universitaires Saint Luc and accepted (on&#xD;
           26/08/2019), to administer 25 mg/kg every 8 hours. This scheme will be used for the new&#xD;
           patients to be recruted. 15-20 patients will be included with this new dosing regimen.&#xD;
&#xD;
           4.2 Study procedures All blood samples (3mL each) will be taken from an arterial or&#xD;
           venous catheter and collected in additive-free blood tubes. After blood clotting, they&#xD;
           will be centrifuged and the serum will be frozen (-80°C) until analysis. Total&#xD;
           concentration and free concentration will be determined by a validated High Pressure&#xD;
           Liquid chromatography-Ultra Violet detection (HPLC-UV) method.12,17&#xD;
&#xD;
           In addition, the following parameters will be recorded during study period: time of&#xD;
           temocillin administration, patient's weight, renal and liver function markers (including&#xD;
           total serum protein), infection markers, concomitant medications.&#xD;
&#xD;
           5. Statistics&#xD;
&#xD;
           The temocillin concentrations versus time data in serum will be analysed using a&#xD;
           non-linear mixed effects modeling approach using a Nonlinear Mixed-Effects Modelling&#xD;
           software (NONMEM version 7.3; ICON Development Solutions, Ellicott City, MD). The&#xD;
           population pharmacokinetic model will then be defined, and used to simulated different&#xD;
           dosing regimens with Monte Carlo simulations, that will be used for calculating the&#xD;
           probability of target attainment (40% ƒT&gt;MIC) for free concentration by MIC. Statistical&#xD;
           significance is defined as P value of &lt; 0.05. JMP version 11 software (SAS Institute,&#xD;
           Cary, NC, USA) will be used for statistical analysis. If the clinical isolates for each&#xD;
           patient are not available, the MIC distributions of the hospital will be considered for&#xD;
           data analysis.&#xD;
&#xD;
           6. Administrative Matters The trial will be carried out in compliance with the protocol,&#xD;
           the principles laid down in the Declaration of Helsinki, in accordance with the&#xD;
           International Committee on Harmonisation (ICH) Harmonised Tripartite Guideline for Good&#xD;
           Clinical Practice (GCP) and in accordance with applicable regulatory requirements.&#xD;
&#xD;
           6.1 Institutional Review Board / Independent Ethics Committee The trial will not be&#xD;
           initiated before the protocol and informed consent and subject information form have&#xD;
           been reviewed and received approval / favourable opinion from the local Institutional&#xD;
           Review Board (IRB) or an Independent Ethics Committee (IEC).&#xD;
&#xD;
           6.2 Informed Consent and Subject Information Prior to subject participation in the&#xD;
           trial, written informed consent will be obtained from each subject's legally accepted&#xD;
           representative according to the regulatory and legal requirements. Each signature must&#xD;
           be dated by each signatory and the informed consent and any additional subject&#xD;
           information form retained by the investigator as part of the study records. A signed&#xD;
           copy of the informed consent and any additional subject information must be given to the&#xD;
           subject's legally authorised representative.&#xD;
&#xD;
           7. Timeframe: Outcome measure will be assessed within a maximum of 18 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 17, 2016</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum levels of temocillin</measure>
    <time_frame>18 months</time_frame>
    <description>Characterisation of the pharmacokinetics (PK) of temocillin (total and free concentrations) in the 3 paediatric populations included</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">45</enrollment>
  <condition>Infection</condition>
  <condition>Liver Dysfunction</condition>
  <condition>Urinary Tract Infection</condition>
  <arm_group>
    <arm_group_label>urinary tract infections</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Children requiring antibiotic treatment for urinary tract infections. Intervention: blood sampling for assay of temocillin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>cholangitis</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cirrhotic children requiring antibiotic treatment due to suspicion of cholangitis.&#xD;
Intervention: blood sampling for assay of temocillin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>hepatic transplant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Children requiring antibiotic prophylaxis following a hepatic transplant. Intervention: blood sampling for assay of temocillin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temocillin</intervention_name>
    <description>Venous blood will be drawn (as per the protocol) for assay of temocillin on day 1 and day 4 of treatment. This is not part of our standard of care and is, therefore, an intervention. Patients are enrolled only if receiving temocillin as part of their normal standard of care (and the drug will be administered based on current recommendations [no change due to enrollment in the study]).</description>
    <arm_group_label>cholangitis</arm_group_label>
    <arm_group_label>hepatic transplant</arm_group_label>
    <arm_group_label>urinary tract infections</arm_group_label>
    <other_name>NEGABAN</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patient requiring temocillin&#xD;
&#xD;
               1. for the treatment of urinary tract infections, or&#xD;
&#xD;
               2. for the treatment of suspicion of cholangitis associated with cirrhosis, or&#xD;
&#xD;
               3. as antibiotic prophylaxis following an hepatic transplant.&#xD;
&#xD;
          -  patient requiring hospitalization (not for social or other non-medical reasons) for at&#xD;
             least up to 5 days&#xD;
&#xD;
          -  Parents or legal representatives able to give written informed consent in accordance&#xD;
             with GCP and local regulatory requirements, prior to any study procedure&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Ig-E mediated allergy to penicillins&#xD;
&#xD;
          2. Previous treatment with temocillin for the current cholangitis episode&#xD;
&#xD;
          3. Diagnosis of Alagille syndrome&#xD;
&#xD;
          4. Estimated life-expectance of &lt; 5 days due to major co-morbid conditions&#xD;
&#xD;
          5. Other serious illnesses, e.g. HIV, serious infections requiring other antibiotics,&#xD;
             malignancy&#xD;
&#xD;
          6. Patients with acute or chronic renal failure (eGFR &lt; 30ml/min)&#xD;
&#xD;
          7. Patients having participated in another study &lt; 30 days before inclusion in the&#xD;
             present study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>3 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Françoise Van Bambeke, PharmD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Université Catholique de Louvain</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paul M Tulkens, MD, PhD</last_name>
    <phone>+32-2-762*-2136</phone>
    <email>tulkens@facm.ucl.ac.be</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Françoise Van Bambeke, PharmD, PhD</last_name>
    <phone>+32-2-764-7378</phone>
    <email>francoise.vanbambeke@uclouvain.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cliniques universitaires St-Luc</name>
      <address>
        <city>Bruxelles</city>
        <zip>B1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Etienne Sokal, MD</last_name>
      <phone>0113227641386</phone>
      <email>etienne.sokal@uclouvain.be</email>
    </contact>
    <contact_backup>
      <last_name>Xavier Stephenne, MD</last_name>
      <phone>0113227641387</phone>
      <email>xavier.stephenne@uclouvain.be</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <link>
    <url>http://bijsluiters.fagg-afmps.be/?localeValue=en</url>
    <description>Official Belgian &quot;Summary of Product Characteristics&quot; of temocillin (enter NEGABAN [trade name of temocillin] in the search window)</description>
  </link>
  <reference>
    <citation>De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008 Feb;61(2):382-8. doi: 10.1093/jac/dkm467. Epub 2007 Dec 10.</citation>
    <PMID>18070831</PMID>
  </reference>
  <reference>
    <citation>Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother. 2009 Feb;63(2):243-5. doi: 10.1093/jac/dkn511. Epub 2008 Dec 18.</citation>
    <PMID>19095679</PMID>
  </reference>
  <reference>
    <citation>Miranda Bastos AC, Vandecasteele SJ, Tulkens PM, Spinewine A, Van Bambeke F. Development and validation of a high performance liquid chromatography assay for the determination of temocillin in serum of haemodialysis patients. J Pharm Biomed Anal. 2014 Mar;90:192-7. doi: 10.1016/j.jpba.2013.12.002. Epub 2013 Dec 12.</citation>
    <PMID>24389461</PMID>
  </reference>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>October 1, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 9, 2014</study_first_posted>
  <last_update_submitted>May 24, 2022</last_update_submitted>
  <last_update_submitted_qc>May 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Université Catholique de Louvain</investigator_affiliation>
    <investigator_full_name>Paul M. Tulkens</investigator_full_name>
    <investigator_title>Invited Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Urinary Tract Infections</mesh_term>
    <mesh_term>Liver Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temocillin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02260102
org study id: temocillin-pediatrics
nct id: NCT02260102
lead sponsor: 
has dmc: No
Temocillin (6-methoxy-ticarcillin) is a beta-lactam antibiotic with exceptional resistance to
      most beta-lactamases. In this context, it is now increasingly used as carbapenem-sparing
      antibiotic in patients with suspected infection by Enterobactreriaceae suspected to produce
      extended-spectrum beta-lactamases. Little is known about dosing and elimination of temocillin
      in children. While available literature of temocillin use in paediatrics refers mainly to its
      clinical efficacy in the treatment of urinary tract infections, the drug is also used for the
      treatment of suspicion of cholangitis in cirrhotic paediatric patients, and as antibiotic
      prophylaxis following an hepatic transplant in children (both off-label indications). There
      is, therefore, a pressing need to explore the pharmacokinetics and pharmacodynamics of
      temocillin in the paediatric population, in order to provide clear guidance on an appropriate
      dosing regimen. The study objectives are: (1) characterisation of the pharmacokinetics (PK)
      of temocillin in 3 paediatric populations, (2) proposal and development of a dosing schedule
      that can ensure therapeutic concentrations (40% ƒT > MIC) and optimize treatment chances of
      success, and (3) characterization of MICs of microbiological strains (when available) to
      temocillin.
1. Introduction Temocillin is a beta-lactam antibiotic active against Gram-negative bacteria.
      Its spectrum covers family members of the Enterobacteriaceae (including many of those
      producing beta-lactamases), Haemophilus influenzae and Neisseria spp 1,2, but not
      Pseudomonas. It is currently licensed for use in septicemia, urinary tract infection (UTIs),
      and lower respiratory tract infection.3 There is also evidence of its clinical efficacy in
      the treatment of biliary tract infections in adults.4,5 Temocillin biliary levels can be
      several times-fold superior to serum concentrations in patients with cholelithiasis, although
      they can also be characterised by high interindividual variation.6,7 In addition, its
      prolonged half-life (4.5-5 hours) and its Gram-negative spectrum make temocillin particularly
      suited for the treatment of hepatobiliary infections.5 One study documents the efficacy of
      temocillin in this indication (16 patients with biliary tract infections; daily dose of 2g of
      temocillin).7

      The interest of this molecule has been greatly enhanced in the recent years due to the
      increased incidence of infections caused by organisms producing extended-spectrum
      beta-lactamases (ESBL), making it to become a sparing-drug for carbapenems.8-10 Temocillin
      presents MICs ranging from 2 to 32 mg/L against Enterobacteriaceae, including most ESBL
      producers.1,2 Like all beta-lactam antibiotics, the time above MIC for free drug
      concentrations (ƒT>MIC) is the important PK-PD parameter correlating with its efficacy.11
      When the beta-lactam antibiotic concentrations do not exceed the MIC for 40% to 50% of the
      dosing interval, the efficacy of a beta-lactam antibiotic can be compromised. When a cut-off
      of a ƒT>MIC of 40% is used, a Monte-Carlo simulation of the available data defines a clinical
      PK/PD breakpoint of 8 to 16 mg/L for temocillin.11-13 The available temocillin
      pharmacokinetics data (distribution, metabolism, and elimination) comes from studies
      performed in adults. It is mainly excreted unchanged (80%) in the urine by glomerular
      filtration and tubular secretion.3

      Little is known about dosing and elimination of temocillin in children. The summary of
      product characteristics of temocillin proposes a daily dose of 25 - 50 mg/kg for paediatric
      use,14 but there are no studies that back-up this recommendation. This dose probably arises
      from scaling-down the typical adult daily dose of 2-4 g assuming an adult weight of 70kg. In
      the literature, the use of temocillin in paediatrics refers mainly to its clinical efficacy
      in the treatment of urinary tract infections.15,16 In the present hospital, temocillin is
      also used for the treatment of suspicion of cholangitis in cirrhotic paediatric patients, and
      as antibiotic prophylaxis following an hepatic transplant in children (both off-label
      indications). There is, therefore, a pressing need to explore the pharmacokinetics and
      pharmacodynamics of temocillin in the paediatric population, in order to provide clear
      guidance on an appropriate dosing regimen.

      2. Study Objectives

        1. Characterisation of the pharmacokinetics (PK) of temocillin (total and free
           concentrations) in 3 paediatric populations:

             1. children requiring antibiotic treatment for urinary tract infections

             2. cirrhotic children requiring antibiotic treatment due to suspicion of cholangitis

             3. children requiring antibiotic prophylaxis following an hepatic transplant

        2. Proposal and development of a dosing schedule that can ensure therapeutic concentrations
           (40% ƒT > MIC) and optimize treatment chances of success.

        3. Characterization of MICs of microbiological strains (when available) to temocillin.

      3. Criteria for patients' selection 3.1 Inclusion Criteria

      1. Male or female patient requiring temocillin

        1. for the treatment of urinary tract infections, or

        2. for the treatment of suspicion of cholangitis associated with cirrhosis, or

        3. as antibiotic prophylaxis following an hepatic transplant. 2. Requirement of
           hospitalization (not for social or other non-medical reasons) for at least up to 5 days
           3. Patients aged 6 months - 3 years at the beginning of the treatment with temocillin 4.
           Parents or legal representatives able to give written informed consent in accordance
           with GCP and local regulatory requirements, prior to any study procedure

           3.2 Exclusion Criteria

             1. Ig-E mediated allergy to penicillins

             2. Previous treatment with temocillin for the current cholangitis episode

             3. Diagnosis of Alagille syndrome

             4. Estimated life-expectance of < 5 days due to major co-morbid conditions

             5. Other serious illnesses, e.g. HIV, serious infections requiring other antibiotics,
                malignancy

             6. Patients with acute or chronic renal failure (eGFR < 30ml/min)

             7. Patients having participated in another study < 30 days before inclusion in the
                present study

           4. Investigational Plan 4.1 Study design and plan This is a prospective, open,
           non-interventional and monocentric study that will take place at the "Service de
           Gastro-entérologie pédiatrique" of the "Cliniques Universitaires St-Luc" in Brussels,
           Belgium. All patients eligible for treatment with temocillin will be evaluated and
           considered for inclusion in the study.

           For each of the 3 paediatric populations, a total of 30-35 patients eligible for
           participation will be included in the study. According to the manufacturer's
           information14 a dose of 25mg/kg (in cases of prophylaxis) or 50mg/kg (in cases of
           treatment) per day divided in 2 administrations will be used and administered by IV
           route. Blood samples will be drawn on day 1 and day 4 of treatment at 0.5, 2, 4, 8, 12
           hours after dose administration. The patient's physician will decide on the duration of
           temocillin use.

           The expected total duration of the trial is 1 year (or more if patient enrollment is
           slow; number of patients to be included: 10-15 for each of the 3 paediatric populations;
           see next sentence for a justification of the addition of 15-20 patients per group after
           acceptance of an amendment to the initial protocol).

           An interim analysis on the first 14 patients from populations b and c suggested that the
           dose was too low to reach the pharmacodynamic target. An amendment has been submitted to
           the ethical committee of the cliniques universitaires Saint Luc and accepted (on
           26/08/2019), to administer 25 mg/kg every 8 hours. This scheme will be used for the new
           patients to be recruted. 15-20 patients will be included with this new dosing regimen.

           4.2 Study procedures All blood samples (3mL each) will be taken from an arterial or
           venous catheter and collected in additive-free blood tubes. After blood clotting, they
           will be centrifuged and the serum will be frozen (-80°C) until analysis. Total
           concentration and free concentration will be determined by a validated High Pressure
           Liquid chromatography-Ultra Violet detection (HPLC-UV) method.12,17

           In addition, the following parameters will be recorded during study period: time of
           temocillin administration, patient's weight, renal and liver function markers (including
           total serum protein), infection markers, concomitant medications.

           5. Statistics

           The temocillin concentrations versus time data in serum will be analysed using a
           non-linear mixed effects modeling approach using a Nonlinear Mixed-Effects Modelling
           software (NONMEM version 7.3; ICON Development Solutions, Ellicott City, MD). The
           population pharmacokinetic model will then be defined, and used to simulated different
           dosing regimens with Monte Carlo simulations, that will be used for calculating the
           probability of target attainment (40% ƒT>MIC) for free concentration by MIC. Statistical
           significance is defined as P value of < 0.05. JMP version 11 software (SAS Institute,
           Cary, NC, USA) will be used for statistical analysis. If the clinical isolates for each
           patient are not available, the MIC distributions of the hospital will be considered for
           data analysis.

           6. Administrative Matters The trial will be carried out in compliance with the protocol,
           the principles laid down in the Declaration of Helsinki, in accordance with the
           International Committee on Harmonisation (ICH) Harmonised Tripartite Guideline for Good
           Clinical Practice (GCP) and in accordance with applicable regulatory requirements.

           6.1 Institutional Review Board / Independent Ethics Committee The trial will not be
           initiated before the protocol and informed consent and subject information form have
           been reviewed and received approval / favourable opinion from the local Institutional
           Review Board (IRB) or an Independent Ethics Committee (IEC).

           6.2 Informed Consent and Subject Information Prior to subject participation in the
           trial, written informed consent will be obtained from each subject's legally accepted
           representative according to the regulatory and legal requirements. Each signature must
           be dated by each signatory and the informed consent and any additional subject
           information form retained by the investigator as part of the study records. A signed
           copy of the informed consent and any additional subject information must be given to the
           subject's legally authorised representative.

           7. Timeframe: Outcome measure will be assessed within a maximum of 18 months.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Serum levels of temocillin
time frame: 18 months
description: Characterisation of the pharmacokinetics (PK) of temocillin (total and free concentrations) in the 3 paediatric populations included
arm group label: urinary tract infections
arm group type: Active Comparator
description: Children requiring antibiotic treatment for urinary tract infections. Intervention: blood sampling for assay of temocillin
arm group label: cholangitis
arm group type: Active Comparator
description: Cirrhotic children requiring antibiotic treatment due to suspicion of cholangitis.
Intervention: blood sampling for assay of temocillin
arm group label: hepatic transplant
arm group type: Active Comparator
description: Children requiring antibiotic prophylaxis following a hepatic transplant. Intervention: blood sampling for assay of temocillin
intervention type: Drug
intervention name: Temocillin
description: Venous blood will be drawn (as per the protocol) for assay of temocillin on day 1 and day 4 of treatment. This is not part of our standard of care and is, therefore, an intervention. Patients are enrolled only if receiving temocillin as part of their normal standard of care (and the drug will be administered based on current recommendations [no change due to enrollment in the study]).
arm group label: cholangitis
arm group label: hepatic transplant
arm group label: urinary tract infections
other name: NEGABAN
criteria: 
gender: All
minimum age: 6 Months
maximum age: 3 Years
healthy volunteers: No
last name: Françoise Van Bambeke, PharmD, PhD
role: Study Director
affiliation: Université Catholique de Louvain
last name: Paul M Tulkens, MD, PhD
phone: +32-2-762*-2136
email: tulkens@facm.ucl.ac.be
last name: Françoise Van Bambeke, PharmD, PhD
phone: +32-2-764-7378
email: francoise.vanbambeke@uclouvain.be
facility: 
status: Recruiting
contact: 
contact backup: 
country: Belgium
url: http://bijsluiters.fagg-afmps.be/?localeValue=en
description: Official Belgian "Summary of Product Characteristics" of temocillin (enter NEGABAN [trade name of temocillin] in the search window)
citation: De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008 Feb;61(2):382-8. doi: 10.1093/jac/dkm467. Epub 2007 Dec 10.
PMID: 18070831
citation: Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother. 2009 Feb;63(2):243-5. doi: 10.1093/jac/dkn511. Epub 2008 Dec 18.
PMID: 19095679
citation: Miranda Bastos AC, Vandecasteele SJ, Tulkens PM, Spinewine A, Van Bambeke F. Development and validation of a high performance liquid chromatography assay for the determination of temocillin in serum of haemodialysis patients. J Pharm Biomed Anal. 2014 Mar;90:192-7. doi: 10.1016/j.jpba.2013.12.002. Epub 2013 Dec 12.
PMID: 24389461
responsible party type: Principal Investigator
investigator affiliation: Université Catholique de Louvain
investigator full name: Paul M. Tulkens
investigator title: Invited Professor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Urinary Tract Infections
mesh term: Liver Diseases
mesh term: Temocillin