<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/NCT01723150</url>
  </required_header>
  <id_info>
    <org_study_id>A-KLASS</org_study_id>
    <nct_id>NCT01723150</nct_id>
  </id_info>
  <brief_title>Antibiotics for Klebsiella Liver Abscess Study</brief_title>
  <official_title>A Multi-centre Randomised Open-label Active Comparator-controlled Non-inferiority Trial Comparing Oral to Intravenous Antibiotics in the Early Management of Klebsiella Pneumoniae Liver Abscess</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National University Hospital, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tan Tock Seng Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Singapore General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National University Hospital, Singapore</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Klebsiella pneumoniae liver abscess is the most common etiology of liver abscess&#xD;
      in Singapore and much of Asia, and its incidence is increasing. Current management includes&#xD;
      prolonged intravenous antibiotic therapy, but there is limited evidence to guide oral&#xD;
      conversion. The implicated K1/K2 capsule strain of Klebsiella pneumoniae is almost&#xD;
      universally susceptible to ciprofloxacin, an antibiotic with high oral bioavailability. Our&#xD;
      primary aim is to compare the efficacy of early (&lt;1 week) step-down to oral antibiotics, to&#xD;
      continuing 4 weeks of intravenous antibiotics, in patients with Klebsiella liver abscess.&#xD;
&#xD;
      Methods/Design: The study is designed as a multi-centre randomised open-label active&#xD;
      comparator-controlled non-inferiority trial, with a non-inferiority margin of 12%. Eligible&#xD;
      participants will be inpatients over the age of 21 with a CT or ultrasound scan suggestive of&#xD;
      a liver abscess, and Klebsiella pneumoniae isolated from abscess fluid or blood.&#xD;
      Randomisation into intervention or active control arms will be performed with a 1:1&#xD;
      allocation ratio. Participants randomised to the active control arm will receive IV&#xD;
      ceftriaxone 2 grams daily to complete a total of 4 weeks of IV antibiotics. Participants&#xD;
      randomised to the intervention arm will be immediately converted to oral ciprofloxacin 750mg&#xD;
      twice daily. At week 4, all participants will have abdominal imaging and be assessed for&#xD;
      clinical response (CRP &lt;20 mg/l, absence of fever, plus scan showing that the maximal&#xD;
      diameter of the abscess has reduced). If criteria are met, antibiotics are stopped; if not,&#xD;
      oral antibiotics are continued, with reassessment for clinical response fortnightly. If&#xD;
      criteria for clinical response are met by week 12, the primary endpoint of clinical cure is&#xD;
      met. A cost analysis will be performed to assess the cost saving of early conversion to oral&#xD;
      antibiotics, and a quality-of-life analysis will be performed to assess if treatment with&#xD;
      oral antibiotics is less burdensome than prolonged IV antibiotics.&#xD;
&#xD;
      Discussion: Our results would help inform local and international practice guidelines&#xD;
      regarding the optimal antibiotic management of Klebsiella liver abscess. A finding of&#xD;
      non-inferiority may translate to the wider adoption of a more cost-effective strategy that&#xD;
      reduces hospital length of stay and improves patient-centered outcomes and satisfaction.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 5, 2013</start_date>
  <completion_date type="Actual">January 16, 2018</completion_date>
  <primary_completion_date type="Actual">January 16, 2018</primary_completion_date>
  <phase>Phase 4</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>Clinical cure</measure>
    <time_frame>Week 12</time_frame>
    <description>The primary endpoint is &quot;clinical cure&quot;, determined at Week 12 post-randomisation, and defined as CRP&lt; 20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical response</measure>
    <time_frame>Week 4</time_frame>
    <description>The main secondary endpoint is &quot;clinical response&quot;, determined at Week 4 post-randomisation, and defined as CRP &lt;20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>all-cause mortality at any point between randomisation and week 12</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• unplanned readmission for any cause at any point between hospital discharge and week 12</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• unplanned need for drainage after enrolment at any point between randomisation and week 12 (the screening visit will document any plans for elective drainage)</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• metastatic complications occurring at any point between randomisation and week 12</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>new K. pneumoniae bacteraemia occurring at any point between the first negative blood culture, and week 12, with the same strain of K. pneumoniae as the original blood culture or abscess fluid culture</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• length of hospital stay (from the date of randomisation to the end of inpatient stay, censored at week 12)</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• length of time the subject requires medical leave following hospital discharge (censored at week 12)</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• subject quality of life as defined by the WHOQOL-BREF assessed at week 4 and week 12 post-randomisation</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• overall cost of each treatment strategy from the payer and total societal perspective for the course of the study until the final twelve week follow-up</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• level of adherence during the entire study period, assessed at twelve weeks. Subject deemed to be compliant if 80% or more of prescribed antibiotics have been taken</measure>
    <time_frame>Week 12</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">152</enrollment>
  <condition>Liver Abscess, Pyogenic</condition>
  <arm_group>
    <arm_group_label>Oral antibiotics</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The intervention arm switched to oral antibiotics to complete 4 weeks of therapy. Oral antibiotics will be ciprofloxacin (or trimethoprim/sulfamethoxazole if the isolate is resistant).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous antibiotics</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The active comparator arm continues intravenous antibiotics to complete 4 weeks of therapy. Intravenous antibiotics will be ceftriaxone (or ertapenem if the isolate is resistant).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ciprofloxacin</intervention_name>
    <arm_group_label>Oral antibiotics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ceftriaxone</intervention_name>
    <arm_group_label>Intravenous antibiotics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trimethoprim/sulfamethoxazole</intervention_name>
    <arm_group_label>Oral antibiotics</arm_group_label>
    <other_name>Bactrim</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ertapenem</intervention_name>
    <arm_group_label>Intravenous antibiotics</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Inpatient at time of enrollment&#xD;
&#xD;
          2. Age &gt;= 21 years&#xD;
&#xD;
          3. Computed tomography (CT) or ultrasound (US) within the preceding 7 days suggestive of&#xD;
             a liver abscess, as defined by presence of one or more focal areas of hypo- or&#xD;
             hyper-attenuation within the liver&#xD;
&#xD;
          4. Klebsiella pneumoniae isolated from abscess fluid or blood collected within the&#xD;
             preceding 7 days&#xD;
&#xD;
          5. Able and willing to give informed consent&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        All subjects meeting any of the following exclusion criteria at baseline will be excluded&#xD;
        from participation:&#xD;
&#xD;
        1) Polymicrobial abscess - additional organisms isolated from blood or abscess fluid within&#xD;
        the preceding 7 days 2a) Klebsiella pneumoniae resistant to Ceftriaxone AND Ertapenem 2b)&#xD;
        Klebsiella pneumoniae resistant to Ciprofloxacin AND Cotrimoxazole 3) On effective* IV&#xD;
        antibiotics &gt; 7 days 4a) Hypersensitivity to cephalosporins AND carbapenems; as defined by&#xD;
        history of rash, urticaria, angiodema, bronchospasm or circulatory collapse following prior&#xD;
        administration.&#xD;
&#xD;
        4b) Hypersensitivity to fluoroquinolones AND sulpha drugs; as defined by history of rash,&#xD;
        urticaria, angioedema, bronchospasm or circulatory collapse following prior administration.&#xD;
&#xD;
        4c) History of penicillin anaphylaxis (angioedema, bronchospasm or circulatory collapse).&#xD;
        Subjects with a history of only rash or urticaria or unknown reaction to penicillin can be&#xD;
        included.&#xD;
&#xD;
        5) Inability to take oral medications for any reason 6) Severe sepsis or septic shock&#xD;
        defined as unresolved hypotension (MAP&lt;70) or tachycardia (HR&gt;110), or requirement of&#xD;
        inotropic support or ventilation at time of eligibility. Should the subject's hypotension&#xD;
        or tachycardia subsequently resolve, and they cease to require inotropes and ventilation&#xD;
        within 7 days, they may be reconsidered for eligibility.&#xD;
&#xD;
        7) Established endophthalmitis at time of screening (patients with visual symptoms should&#xD;
        have ophthalmology review prior to enrollment) 8) Established central nervous system&#xD;
        abscess at time of screening (patients with focal neurology should have CT head prior to&#xD;
        enrollment) 9) Women who are pregnant or breastfeeding 10) Inability to obtain consent from&#xD;
        subject 11) Patients on tizanidine or theophylline 12) Patients on concomitant drugs that&#xD;
        can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics)&#xD;
        or with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected&#xD;
        hypokalemia) 13) Patients whose K. pneumoniae tests resistant to ciprofloxacin, and those&#xD;
        with contraindications to ciprofloxacin will be tested for G6PD deficiency, and excluded if&#xD;
        deficient 14) Severe immunocompromise (e.g., active leukemia or lymphoma, generalized&#xD;
        malignancy, aplastic anemia, solid organ transplant, bone marrow transplant within 2 years&#xD;
        of transplantation, or transplants of longer duration still on immunosuppressive drugs or&#xD;
        with graft-versus-host disease, congenital immunodeficiency, current radiation therapy,&#xD;
        HIV/AIDS with CD4 lymphocyte count &lt;200 and patients or on immunosuppressant medications)&#xD;
        15) Creatinine clearance &lt;15 ml/min&#xD;
&#xD;
        *defined as antibiotics to which the Klebsiella pneumoniae isolate in blood or abscess&#xD;
        fluid is susceptible&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sophia Archuleta, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Singapore General Hospital</name>
      <address>
        <city>Singapore</city>
        <zip>169856</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National University Hospital</name>
      <address>
        <city>Singapore</city>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tan Tock Seng Hospital</name>
      <address>
        <city>Singapore</city>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <reference>
    <citation>Molton J, Phillips R, Gandhi M, Yoong J, Lye D, Tan TT, Fisher D, Archuleta S. Oral versus intravenous antibiotics for patients with Klebsiella pneumoniae liver abscess: study protocol for a randomized controlled trial. Trials. 2013 Oct 31;14:364. doi: 10.1186/1745-6215-14-364.</citation>
    <PMID>24176222</PMID>
  </reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>November 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 7, 2012</study_first_posted>
  <last_update_submitted>August 23, 2018</last_update_submitted>
  <last_update_submitted_qc>August 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Klebsiella pneumoniae</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Abscess</mesh_term>
    <mesh_term>Klebsiella Infections</mesh_term>
    <mesh_term>Liver Abscess</mesh_term>
    <mesh_term>Liver Abscess, Pyogenic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ciprofloxacin</mesh_term>
    <mesh_term>Ceftriaxone</mesh_term>
    <mesh_term>Ertapenem</mesh_term>
    <mesh_term>Trimethoprim</mesh_term>
    <mesh_term>Sulfamethoxazole</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/NCT01723150
org study id: A-KLASS
nct id: NCT01723150
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Background: Klebsiella pneumoniae liver abscess is the most common etiology of liver abscess
      in Singapore and much of Asia, and its incidence is increasing. Current management includes
      prolonged intravenous antibiotic therapy, but there is limited evidence to guide oral
      conversion. The implicated K1/K2 capsule strain of Klebsiella pneumoniae is almost
      universally susceptible to ciprofloxacin, an antibiotic with high oral bioavailability. Our
      primary aim is to compare the efficacy of early (<1 week) step-down to oral antibiotics, to
      continuing 4 weeks of intravenous antibiotics, in patients with Klebsiella liver abscess.

      Methods/Design: The study is designed as a multi-centre randomised open-label active
      comparator-controlled non-inferiority trial, with a non-inferiority margin of 12%. Eligible
      participants will be inpatients over the age of 21 with a CT or ultrasound scan suggestive of
      a liver abscess, and Klebsiella pneumoniae isolated from abscess fluid or blood.
      Randomisation into intervention or active control arms will be performed with a 1:1
      allocation ratio. Participants randomised to the active control arm will receive IV
      ceftriaxone 2 grams daily to complete a total of 4 weeks of IV antibiotics. Participants
      randomised to the intervention arm will be immediately converted to oral ciprofloxacin 750mg
      twice daily. At week 4, all participants will have abdominal imaging and be assessed for
      clinical response (CRP <20 mg/l, absence of fever, plus scan showing that the maximal
      diameter of the abscess has reduced). If criteria are met, antibiotics are stopped; if not,
      oral antibiotics are continued, with reassessment for clinical response fortnightly. If
      criteria for clinical response are met by week 12, the primary endpoint of clinical cure is
      met. A cost analysis will be performed to assess the cost saving of early conversion to oral
      antibiotics, and a quality-of-life analysis will be performed to assess if treatment with
      oral antibiotics is less burdensome than prolonged IV antibiotics.

      Discussion: Our results would help inform local and international practice guidelines
      regarding the optimal antibiotic management of Klebsiella liver abscess. A finding of
      non-inferiority may translate to the wider adoption of a more cost-effective strategy that
      reduces hospital length of stay and improves patient-centered outcomes and satisfaction.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Clinical cure
time frame: Week 12
description: The primary endpoint is "clinical cure", determined at Week 12 post-randomisation, and defined as CRP< 20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.
measure: Clinical response
time frame: Week 4
description: The main secondary endpoint is "clinical response", determined at Week 4 post-randomisation, and defined as CRP <20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.
measure: all-cause mortality at any point between randomisation and week 12
time frame: Week 12
measure: • unplanned readmission for any cause at any point between hospital discharge and week 12
time frame: Week 12
measure: • unplanned need for drainage after enrolment at any point between randomisation and week 12 (the screening visit will document any plans for elective drainage)
time frame: Week 12
measure: • metastatic complications occurring at any point between randomisation and week 12
time frame: Week 12
measure: new K. pneumoniae bacteraemia occurring at any point between the first negative blood culture, and week 12, with the same strain of K. pneumoniae as the original blood culture or abscess fluid culture
time frame: Week 12
measure: • length of hospital stay (from the date of randomisation to the end of inpatient stay, censored at week 12)
time frame: Week 12
measure: • length of time the subject requires medical leave following hospital discharge (censored at week 12)
time frame: Week 12
measure: • subject quality of life as defined by the WHOQOL-BREF assessed at week 4 and week 12 post-randomisation
time frame: Week 12
measure: • overall cost of each treatment strategy from the payer and total societal perspective for the course of the study until the final twelve week follow-up
time frame: Week 12
measure: • level of adherence during the entire study period, assessed at twelve weeks. Subject deemed to be compliant if 80% or more of prescribed antibiotics have been taken
time frame: Week 12
arm group label: Oral antibiotics
arm group type: Experimental
description: The intervention arm switched to oral antibiotics to complete 4 weeks of therapy. Oral antibiotics will be ciprofloxacin (or trimethoprim/sulfamethoxazole if the isolate is resistant).
arm group label: Intravenous antibiotics
arm group type: Active Comparator
description: The active comparator arm continues intravenous antibiotics to complete 4 weeks of therapy. Intravenous antibiotics will be ceftriaxone (or ertapenem if the isolate is resistant).
intervention type: Drug
intervention name: Ciprofloxacin
arm group label: Oral antibiotics
intervention type: Drug
intervention name: Ceftriaxone
arm group label: Intravenous antibiotics
intervention type: Drug
intervention name: Trimethoprim/sulfamethoxazole
arm group label: Oral antibiotics
other name: Bactrim
intervention type: Drug
intervention name: Ertapenem
arm group label: Intravenous antibiotics
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
last name: Sophia Archuleta, MD
role: Principal Investigator
affiliation: National University Hospital, Singapore
facility: 
facility: 
facility: 
country: Singapore
citation: Molton J, Phillips R, Gandhi M, Yoong J, Lye D, Tan TT, Fisher D, Archuleta S. Oral versus intravenous antibiotics for patients with Klebsiella pneumoniae liver abscess: study protocol for a randomized controlled trial. Trials. 2013 Oct 31;14:364. doi: 10.1186/1745-6215-14-364.
PMID: 24176222
responsible party type: Sponsor
mesh term: Abscess
mesh term: Klebsiella Infections
mesh term: Liver Abscess
mesh term: Liver Abscess, Pyogenic
mesh term: Ciprofloxacin
mesh term: Ceftriaxone
mesh term: Ertapenem
mesh term: Trimethoprim
mesh term: Sulfamethoxazole