<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/NCT04437836</url>
  </required_header>
  <id_info>
    <org_study_id>TMA2017CDF-1876-HighRif-C</org_study_id>
    <nct_id>NCT04437836</nct_id>
  </id_info>
  <brief_title>Evaluation of Pharmacokinetics and Safety Tolerability of Higher Doses of Rifampic</brief_title>
  <acronym>HighRif - C</acronym>
  <official_title>Evaluation of Pharmacokinetics and Safety Tolerability of Higher Doses of Rifampicin in Children With Newly Diagnosed Uncomplicated Tuberculosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kilimanjaro Clinical Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European and Developing Countries Clinical Trials Partnership (EDCTP)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kilimanjaro Clinical Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Tuberculosis in children is a major public health problem and it contributes 10% of the total&#xD;
      TB cases worldwide. TB treatment outcomes in children are challenged by insufficient&#xD;
      consideration of the relationships between doses administered, concentrations achieved and&#xD;
      eventual desirable and undesirable effects (pharmacodynamics) of TB drugs. Rifampicin is a&#xD;
      pivotal TB drug and data from adults suggest that a much higher dose of rifampicin (35 mg/kg&#xD;
      instead of 10 mg/kg), resulting in much higher rifampicin exposures in plasma, is safe and&#xD;
      tolerable and may provide a higher efficacy. The dose needed in children to achieve the same&#xD;
      exposure in plasma is unknown.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tuberculosis (TB) in children is a major public health problem . It has a global estimate of&#xD;
      &gt;100,000 deaths per year and is included in the top ten causes of mortality in children&#xD;
      worldwide. Children contribute 10% of the total TB cases worldwide. More than 75% of the&#xD;
      worldwide estimated cases of TB in children occur in the 30 high burden countries, Tanzania&#xD;
      being one of them. The enormous burden of pediatric TB in these countries is due to the TB&#xD;
      epidemic amongst adults and the simultaneous HIV pandemic and a child less than 14 years of&#xD;
      age whether HIV infected or not is at a high risk of developing the disease. Subsequent&#xD;
      dissemination of the mycobacterium and progression of the disease is also fast in children.&#xD;
&#xD;
      Knowledge on the efficacy and safety of medicines for children is still very limited and&#xD;
      sometimes children are still being treated as small adults. However, adult dosing cannot be&#xD;
      logically extrapolated to children according to weight or age because of different&#xD;
      pharmacokinetics, i.e. the relationship between doses administered and exposures (drug&#xD;
      concentrations) achieved, in children as compared with adults . More specifically, these&#xD;
      pharmacokinetic differences occur in the subsequent processes of absorption, distribution,&#xD;
      metabolism and elimination of drugs, which are subject to physiological changes due to growth&#xD;
      and development in children. Especially in young children, maturation of liver metabolism&#xD;
      pathways and renal function are not completed.&#xD;
&#xD;
      In contrast, the pharmacodynamics of a drug, i.e. the relationship between concentrations&#xD;
      achieved and eventual response is generally considered similar between adults and children,&#xD;
      although differences in drug metabolism between children and adults may lead to differences&#xD;
      in susceptibility to some adverse drug reactions. Thus, because of the differences in&#xD;
      pharmacokinetics in children with different ages, they should not receive the same drug doses&#xD;
      on mg/kg base as adults, and drug dosage selection in children should rather be based upon&#xD;
      stages of growth and development. These drug doses should target the exposures that are&#xD;
      efficacious in adults.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 1, 2019</start_date>
  <completion_date type="Anticipated">July 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Safety and tolerability study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>Enroll children participant and giving them treatment care as well as safety monitoring</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluation of high dose rifampicin</measure>
    <time_frame>36 months</time_frame>
    <description>To know the maximum tolerable dose of rifampicin in children aged 1-14 years</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration</measure>
    <time_frame>36 months</time_frame>
    <description>Maximum observed concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time</measure>
    <time_frame>36 months</time_frame>
    <description>Time needed to get maximum concentration</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Clinical Trial</condition>
  <arm_group>
    <arm_group_label>Control arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive standard treatment of rifampicin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>First High dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive 30mg per kg body weight of rifampicin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Second high dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Particpants will receive 40mg per kg body weight of rifampicin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Evaluation of high dose rifampicin in children</intervention_name>
    <description>Evaluation of severity of adverse event from grade 1 to 5</description>
    <arm_group_label>Control arm</arm_group_label>
    <arm_group_label>First High dose</arm_group_label>
    <arm_group_label>Second high dose</arm_group_label>
    <other_name>Safety monitoring</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children aged 1 to 14 years with newly diagnosed Tuberculosis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Children with elevated liver function&#xD;
&#xD;
          -  Children allergic to first line anti-TB drugs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>14 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Hadija H Semvua, PhD</last_name>
    <phone>+255754377777</phone>
    <email>h.semvua@kcri.ac.tz</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tupokigwe S Jana, Diploma</last_name>
    <phone>+255784734602</phone>
    <email>t.jana@kcri.ac.tz</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Kilimanjaro Clinical Research Institute</name>
      <address>
        <city>Moshi</city>
        <state>Kilimanjaro</state>
        <zip>+255</zip>
        <country>Tanzania</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Kilimanjaro Clinical Research Institute</name>
      <address>
        <city>Moshi</city>
        <state>Kilimanjaro</state>
        <zip>+255</zip>
        <country>Tanzania</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hadija H Semvua, PhD</last_name>
      <phone>0754377777</phone>
      <email>h.semvua@kcri.ac.tz</email>
    </contact>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 18, 2020</study_first_posted>
  <last_update_submitted>September 13, 2021</last_update_submitted>
  <last_update_submitted_qc>September 13, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</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/NCT04437836
org study id: TMA2017CDF-1876-HighRif-C
nct id: NCT04437836
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Tuberculosis in children is a major public health problem and it contributes 10% of the total
      TB cases worldwide. TB treatment outcomes in children are challenged by insufficient
      consideration of the relationships between doses administered, concentrations achieved and
      eventual desirable and undesirable effects (pharmacodynamics) of TB drugs. Rifampicin is a
      pivotal TB drug and data from adults suggest that a much higher dose of rifampicin (35 mg/kg
      instead of 10 mg/kg), resulting in much higher rifampicin exposures in plasma, is safe and
      tolerable and may provide a higher efficacy. The dose needed in children to achieve the same
      exposure in plasma is unknown.
Tuberculosis (TB) in children is a major public health problem . It has a global estimate of
      >100,000 deaths per year and is included in the top ten causes of mortality in children
      worldwide. Children contribute 10% of the total TB cases worldwide. More than 75% of the
      worldwide estimated cases of TB in children occur in the 30 high burden countries, Tanzania
      being one of them. The enormous burden of pediatric TB in these countries is due to the TB
      epidemic amongst adults and the simultaneous HIV pandemic and a child less than 14 years of
      age whether HIV infected or not is at a high risk of developing the disease. Subsequent
      dissemination of the mycobacterium and progression of the disease is also fast in children.

      Knowledge on the efficacy and safety of medicines for children is still very limited and
      sometimes children are still being treated as small adults. However, adult dosing cannot be
      logically extrapolated to children according to weight or age because of different
      pharmacokinetics, i.e. the relationship between doses administered and exposures (drug
      concentrations) achieved, in children as compared with adults . More specifically, these
      pharmacokinetic differences occur in the subsequent processes of absorption, distribution,
      metabolism and elimination of drugs, which are subject to physiological changes due to growth
      and development in children. Especially in young children, maturation of liver metabolism
      pathways and renal function are not completed.

      In contrast, the pharmacodynamics of a drug, i.e. the relationship between concentrations
      achieved and eventual response is generally considered similar between adults and children,
      although differences in drug metabolism between children and adults may lead to differences
      in susceptibility to some adverse drug reactions. Thus, because of the differences in
      pharmacokinetics in children with different ages, they should not receive the same drug doses
      on mg/kg base as adults, and drug dosage selection in children should rather be based upon
      stages of growth and development. These drug doses should target the exposures that are
      efficacious in adults.
allocation: Non-Randomized
intervention model: Crossover Assignment
intervention model description: Safety and tolerability study
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: Enroll children participant and giving them treatment care as well as safety monitoring
measure: Evaluation of high dose rifampicin
time frame: 36 months
description: To know the maximum tolerable dose of rifampicin in children aged 1-14 years
measure: Plasma concentration
time frame: 36 months
description: Maximum observed concentration
measure: Time
time frame: 36 months
description: Time needed to get maximum concentration
arm group label: Control arm
arm group type: Experimental
description: Participants will receive standard treatment of rifampicin
arm group label: First High dose
arm group type: Experimental
description: Participants will receive 30mg per kg body weight of rifampicin
arm group label: Second high dose
arm group type: Experimental
description: Particpants will receive 40mg per kg body weight of rifampicin
intervention type: Drug
intervention name: Evaluation of high dose rifampicin in children
description: Evaluation of severity of adverse event from grade 1 to 5
arm group label: Control arm
arm group label: First High dose
arm group label: Second high dose
other name: Safety monitoring
criteria: 
gender: All
minimum age: 1 Year
maximum age: 14 Years
healthy volunteers: No
last name: Hadija H Semvua, PhD
phone: +255754377777
email: h.semvua@kcri.ac.tz
last name: Tupokigwe S Jana, Diploma
phone: +255784734602
email: t.jana@kcri.ac.tz
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
country: Tanzania
responsible party type: Sponsor
mesh term: Rifampin