<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/NCT02224040</url>
  </required_header>
  <id_info>
    <org_study_id>64/12</org_study_id>
    <nct_id>NCT02224040</nct_id>
  </id_info>
  <brief_title>Typhoid Fever: Combined vs. Single Antibiotic Therapy</brief_title>
  <official_title>Typhoid Fever: Combined vs. Single Antibiotic Therapy. A Prospective Randomized Controlled Study in Nepal.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sheba Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current study goal is to examine the effect of Cephalosporins, Azithromycin and the&#xD;
      combination of both on typhoid fever therapy in endemic population.&#xD;
&#xD;
      The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove&#xD;
      superior to each drug, ceftriaxone or azithromycin, alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Typhoid Fever is a highly prevalent infection in the Indian subcontinent. Due to multidrug&#xD;
      resistant strains in these areas, third generation cephalosporins, such as ceftriaxone, are&#xD;
      the treatment of choice. However, the latter regimen exhibits a slow response with mean time&#xD;
      of 5 to 7 days or even longer to defervescence, which could be attributed to poor penetration&#xD;
      capability of the drug into cells, and thus difficulty to eradicate the bacteria from the&#xD;
      intracellular niche.&#xD;
&#xD;
      Attempts have been made to overcome this setback by introducing alternative antibiotic&#xD;
      regimens, such as azithromycin. However studies comparing between azithromycin and a&#xD;
      third-generation cephalosporin for the treatment of typhoid fever in adult population in the&#xD;
      Indian subcontinent are lacking.&#xD;
&#xD;
      Over the last few years our approach towards non-immunized travelers, who acquired typhoid&#xD;
      fever in the Indian subcontinent, was to administer a combination therapy of intravenous&#xD;
      ceftriaxone with oral azithromycin. The rationale of this dual regimen was its&#xD;
      pharmacokinetic profile, which suggests a complimentary action of the two agents -&#xD;
      ceftriaxone on the extracellular compartment and azithromycin on the intracellular&#xD;
      compartment. Moreover, in our clinical experience, preliminary published data has proven&#xD;
      combination therapy significantly superior to ceftriaxone alone albeit in a small group of&#xD;
      travelers.&#xD;
&#xD;
      In the current study the investigators intend to compare the efficacy of ceftriaxone vs.&#xD;
      azithromycin and vs. combined therapy of both agents for the treatment of uncomplicated&#xD;
      typhoid fever in terms of time to defervescence.&#xD;
&#xD;
      4 different treatment strategies will be examined (as mentioned in the arm section). All&#xD;
      participants will be checked for vital signs, will undergo physical examination, ECG,&#xD;
      laboratory testing, blood, urine and stool culture and tests for susceptibility to&#xD;
      antibiotics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>August 2013</start_date>
  <completion_date type="Anticipated">August 2015</completion_date>
  <primary_completion_date type="Anticipated">December 2014</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>Fever clearance time</measure>
    <time_frame>One month</time_frame>
    <description>Time to fever clearance will be measured and will be defined as an oral temperature that is below 37.50 C</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment failure</measure>
    <time_frame>One month</time_frame>
    <description>Secondary endpoints will be treatment failure (defined as the need to switch antibiotic treatment according to physician's decision such as high grade fever after 5 days of treatment, appearance of typhoid complications under the treatment), clearance of bacteremia, development of typhoid-related complications, late relapse, fecal carriage and adverse drug reactions.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Typhoid Fever</condition>
  <arm_group>
    <arm_group_label>Ceftriaxone I.V</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The participants in this arm will receive the following drug and dosage: adult: Ceftriaxone intravenous 2 gr once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day (maximum dose 2.5 g/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ceftriaxone I.V+Azithromycin P.O</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The participants in this arm will receive the following drugs and dosages: adult: 2 g intravenous ceftriaxone and 500 mg oral azithromycin once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day and oral 20 mg/kg azithromycin suspension once a day. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Azithromycin P.O</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The participants in this arm will receive the following drug and dosage: adult: azithromycin oral 500 mg once a day. Pediatric: oral 20 mg/kg azithromycin suspension once a day (maximum dose 1000 mg/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Azithromycin P.O+Cefixime P.O</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The participants in this arm will receive the following drugs and dosages: adult: 500 mg azithromycin and 400 mg cefixime. Pediatric: oral 20 mg/kg azithromycin suspension once a day and oral 10 mg/kg cefixime. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ceftriaxone</intervention_name>
    <arm_group_label>Ceftriaxone I.V</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ceftriaxone and azithromycin</intervention_name>
    <arm_group_label>Ceftriaxone I.V+Azithromycin P.O</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>azithromycin</intervention_name>
    <arm_group_label>Azithromycin P.O</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>azithromycin and cefixime</intervention_name>
    <arm_group_label>Azithromycin P.O+Cefixime P.O</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Blood culture-proven typhoid fever (S. typhi or S. paratyphi)&#xD;
&#xD;
          -  Signed informed consent to participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to ceftriaxone or macrolides&#xD;
&#xD;
          -  Major typhoid fever-associated complications&#xD;
&#xD;
          -  Inability to swallow oral medication&#xD;
&#xD;
          -  Underlying illness&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Lactation&#xD;
&#xD;
          -  Treatment within the past 4 days with an antibiotic that may be effective against&#xD;
             typhoid fever&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eli Schwartz, MD, DTMH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheba Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Eli Schwartz, MD, DTMH</last_name>
    <phone>+97235308456</phone>
    <email>Eli.schwartz@sheba.health.gov.il</email>
  </overall_contact>
  <location>
    <facility>
      <name>Dhulikhel hospital</name>
      <address>
        <city>Dhulikhel</city>
        <zip>11008</zip>
        <country>Nepal</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sudeep Shrestha, M.D</last_name>
      <email>itsactionpotential@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Nepal</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 21, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2014</study_first_posted>
  <last_update_submitted>August 26, 2014</last_update_submitted>
  <last_update_submitted_qc>August 26, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 27, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Prof. Eli Schwartz MD, DTMH</investigator_full_name>
    <investigator_title>Principal Investigator of the geographic clinical</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Typhoid Fever</mesh_term>
    <mesh_term>Fever</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azithromycin</mesh_term>
    <mesh_term>Ceftriaxone</mesh_term>
    <mesh_term>Cefixime</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/NCT02224040
org study id: 64/12
nct id: NCT02224040
lead sponsor: 
has dmc: No
The current study goal is to examine the effect of Cephalosporins, Azithromycin and the
      combination of both on typhoid fever therapy in endemic population.

      The investigator's hypothesize that the combination of azithromycin and ceftriaxone may prove
      superior to each drug, ceftriaxone or azithromycin, alone.
Typhoid Fever is a highly prevalent infection in the Indian subcontinent. Due to multidrug
      resistant strains in these areas, third generation cephalosporins, such as ceftriaxone, are
      the treatment of choice. However, the latter regimen exhibits a slow response with mean time
      of 5 to 7 days or even longer to defervescence, which could be attributed to poor penetration
      capability of the drug into cells, and thus difficulty to eradicate the bacteria from the
      intracellular niche.

      Attempts have been made to overcome this setback by introducing alternative antibiotic
      regimens, such as azithromycin. However studies comparing between azithromycin and a
      third-generation cephalosporin for the treatment of typhoid fever in adult population in the
      Indian subcontinent are lacking.

      Over the last few years our approach towards non-immunized travelers, who acquired typhoid
      fever in the Indian subcontinent, was to administer a combination therapy of intravenous
      ceftriaxone with oral azithromycin. The rationale of this dual regimen was its
      pharmacokinetic profile, which suggests a complimentary action of the two agents -
      ceftriaxone on the extracellular compartment and azithromycin on the intracellular
      compartment. Moreover, in our clinical experience, preliminary published data has proven
      combination therapy significantly superior to ceftriaxone alone albeit in a small group of
      travelers.

      In the current study the investigators intend to compare the efficacy of ceftriaxone vs.
      azithromycin and vs. combined therapy of both agents for the treatment of uncomplicated
      typhoid fever in terms of time to defervescence.

      4 different treatment strategies will be examined (as mentioned in the arm section). All
      participants will be checked for vital signs, will undergo physical examination, ECG,
      laboratory testing, blood, urine and stool culture and tests for susceptibility to
      antibiotics.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Fever clearance time
time frame: One month
description: Time to fever clearance will be measured and will be defined as an oral temperature that is below 37.50 C
measure: Treatment failure
time frame: One month
description: Secondary endpoints will be treatment failure (defined as the need to switch antibiotic treatment according to physician's decision such as high grade fever after 5 days of treatment, appearance of typhoid complications under the treatment), clearance of bacteremia, development of typhoid-related complications, late relapse, fecal carriage and adverse drug reactions.
arm group label: Ceftriaxone I.V
arm group type: Experimental
description: The participants in this arm will receive the following drug and dosage: adult: Ceftriaxone intravenous 2 gr once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day (maximum dose 2.5 g/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).
arm group label: Ceftriaxone I.V+Azithromycin P.O
arm group type: Experimental
description: The participants in this arm will receive the following drugs and dosages: adult: 2 g intravenous ceftriaxone and 500 mg oral azithromycin once a day. Pediatric: intravenous 75 mg/kg ceftriaxone once a day and oral 20 mg/kg azithromycin suspension once a day. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards. Patients will be hospitalized during the entire treatment course (including the afebrile period).
arm group label: Azithromycin P.O
arm group type: Experimental
description: The participants in this arm will receive the following drug and dosage: adult: azithromycin oral 500 mg once a day. Pediatric: oral 20 mg/kg azithromycin suspension once a day (maximum dose 1000 mg/day). Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.
arm group label: Azithromycin P.O+Cefixime P.O
arm group type: Experimental
description: The participants in this arm will receive the following drugs and dosages: adult: 500 mg azithromycin and 400 mg cefixime. Pediatric: oral 20 mg/kg azithromycin suspension once a day and oral 10 mg/kg cefixime. Patients will receive antibiotic treatment until defervescence and for 3 days afterwards.
intervention type: Drug
intervention name: ceftriaxone
arm group label: Ceftriaxone I.V
intervention type: Drug
intervention name: ceftriaxone and azithromycin
arm group label: Ceftriaxone I.V+Azithromycin P.O
intervention type: Drug
intervention name: azithromycin
arm group label: Azithromycin P.O
intervention type: Drug
intervention name: azithromycin and cefixime
arm group label: Azithromycin P.O+Cefixime P.O
criteria: 
gender: All
minimum age: 2 Years
maximum age: 80 Years
healthy volunteers: No
last name: Eli Schwartz, MD, DTMH
role: Principal Investigator
affiliation: Sheba Medical Center
last name: Eli Schwartz, MD, DTMH
phone: +97235308456
email: Eli.schwartz@sheba.health.gov.il
facility: 
status: Recruiting
contact: 
country: Nepal
responsible party type: Principal Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Prof. Eli Schwartz MD, DTMH
investigator title: Principal Investigator of the geographic clinical
mesh term: Typhoid Fever
mesh term: Fever
mesh term: Azithromycin
mesh term: Ceftriaxone
mesh term: Cefixime