<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/NCT03227653</url>
  </required_header>
  <id_info>
    <org_study_id>EFV Kids</org_study_id>
    <nct_id>NCT03227653</nct_id>
  </id_info>
  <brief_title>Neuropsychiatric Side Effects of Efavirenz in Children Living With HIV</brief_title>
  <official_title>Neuropsychiatric Adverse Effects of Efavirenz in Children Living With HIV in Kilimanjaro, Tanzania</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kilimanjaro Christian Medical Centre, Tanzania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kilimanjaro Clinical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Efavirenz is among the preferred antiretroviral drugs for HIV-infected children. Increasing&#xD;
      evidence shows that central nervous system side-effects in adults are more common than&#xD;
      previously thought. Still, reliable data in children are lacking. As HIV-infected children&#xD;
      nowadays have a prospect of reaching adulthood, there is an urgent need to identify potential&#xD;
      long-term central nervous system side-effects, interfering with neurodevelopment and&#xD;
      psychosocial maturation. Using validated tools, we assessed (1) competence&#xD;
      (social/activities/school) and psychopathology (internalizing/externalizing problems), (2)&#xD;
      cognitive performance (intelligence and working memory), and (3) adherence in Tanzanian&#xD;
      children on an efavirenz or non-efavirenz based regimen&#xD;
&#xD;
      In this cross-sectional observational study the investigators will examine neuropsychiatric&#xD;
      and neurocognitive functioning in 126 children (aged 6-11 years) on long-term combination&#xD;
      antiretroviral therapy (cART) with or without efavirenz.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this cross-sectional observational study, we include HIV-infected children (6-12 years) on&#xD;
      cART for ≥ 6 months, with viral loads ≤ 1000 copies/ml in Kilimanjaro Region, Tanzania.&#xD;
      Psychopathology and competence will be assessed using the Child Behaviour Checklist.&#xD;
      Cognitive performance will be assessed using the Raven's Coloured Progressive Matrices and&#xD;
      the digit span test. Non-adherence is defined as any reported missed doses over the previous&#xD;
      3 days or &lt;100% adherence since the last clinical visit. Analysis of covariance and logistic&#xD;
      regression models will be used to assess differences between groups. .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 19, 2017</start_date>
  <completion_date type="Actual">December 31, 2017</completion_date>
  <primary_completion_date type="Actual">December 31, 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Neuropsychological symptoms: competence and psychopathology (internalizing/externalizing symptoms)</measure>
    <time_frame>At day of inclusion</time_frame>
    <description>Neuropsychological symptoms will be assessed using the Swahili version of the Child Behavior Checklist for 6-18 years (CBCL6-18)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cognitive functioning - non-verbal cognitive ability (general intelligence)</measure>
    <time_frame>At day of inclusion</time_frame>
    <description>Non-verbal cognitive ability will be assessed using the Raven's Progressive Matrices</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive functioning - working memory</measure>
    <time_frame>At day of inclusion</time_frame>
    <description>Working memory will be assessed using the Wechsler Intelligence Scale for Children (WISC-III) Digit Span Test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment adherence</measure>
    <time_frame>At day of inclusion</time_frame>
    <description>Treatment adherence will be measured using an adherence questionnaire, adapted from the PENTA 16 trial (permission obtained from the author prof. Giaquinto)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Central nervous system symptoms</measure>
    <time_frame>At day of inclusion</time_frame>
    <description>The presence of central nervous system symptoms (yes/no) in the week prior to study visit will be assessed using a checklist composed of symptoms that have been linked to efavirenz in literature.</description>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">144</enrollment>
  <condition>Efavirenz</condition>
  <condition>Child Behavior</condition>
  <condition>Cognitive Symptom</condition>
  <condition>Medication Adherence</condition>
  <condition>Drug-Related Side Effects and Adverse Reactions</condition>
  <arm_group>
    <arm_group_label>Efavirenz</arm_group_label>
    <description>Children using efavirenz-based cART for at least 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-efavirenz</arm_group_label>
    <description>Children using non-efavirenz-based cART (nevirapine or Lopinavir-Ritonavir Drug Combination) for at least 6 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Efavirenz</intervention_name>
    <description>Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS</description>
    <arm_group_label>Efavirenz</arm_group_label>
    <other_name>Efavirenz-group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nevirapine</intervention_name>
    <description>Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS</description>
    <arm_group_label>Non-efavirenz</arm_group_label>
    <other_name>Non-efavirenz group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lopinavir-Ritonavir Drug Combination</intervention_name>
    <description>Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS</description>
    <arm_group_label>Non-efavirenz</arm_group_label>
    <other_name>Non-efavirenz group</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Tanzanian children (6-12 years) living with HIV and receiving cART&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 6 until 12 years&#xD;
&#xD;
          -  HIV seropositive&#xD;
&#xD;
          -  Using cART, with or without efavirenz, for at least 6 months&#xD;
&#xD;
          -  Registered patient at one of the participating centres&#xD;
&#xD;
          -  In the presence of at least one parent or caregiver who is part if the child's&#xD;
             life/upbringing&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Switch of cART regimen in the last 6 months&#xD;
&#xD;
          -  History of brain injury, mental health and cognitive impairment before starting cART&#xD;
&#xD;
          -  HIV RNA &gt;1000 copies/mL within the past year&#xD;
&#xD;
          -  Any AIDS-defining illness or acute illness (e.g. fever, lowered consciousness,&#xD;
             dehydration) at time of inclusion&#xD;
&#xD;
          -  Children with parent(s) or caregiver(s) not wanting or not able to give informed&#xD;
             consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Grace Kinabo, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kilimanjaro Christian Medical Centre</affiliation>
  </overall_official>
  <overall_official>
    <last_name>André van der Ven, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kilimanjaro Christian Medical Centre</name>
      <address>
        <city>Moshi</city>
        <state>Kilimanjaro Region</state>
        <zip>3010</zip>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mawenzi Regional Hospital</name>
      <address>
        <city>Moshi</city>
        <state>Kilimanjaro Region</state>
        <zip>3054</zip>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kibosho Hospital</name>
      <address>
        <city>Kibosho</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kiboroloni Dispensary</name>
      <address>
        <city>Moshi</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Majengo Health Centre</name>
      <address>
        <city>Moshi</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pasua Health Centre</name>
      <address>
        <city>Moshi</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <reference>
    <citation>Van de Wijer L, Schellekens AFA, Burger DM, Homberg JR, de Mast Q, van der Ven AJAM. Rethinking the risk-benefit ratio of efavirenz in HIV-infected children. Lancet Infect Dis. 2016 May;16(5):e76-e81. doi: 10.1016/S1473-3099(16)00117-1. Epub 2016 Apr 18.</citation>
    <PMID>27599655</PMID>
  </reference>
  <reference>
    <citation>Mothapo KM, Schellekens A, van Crevel R, Keuter M, Grintjes-Huisman K, Koopmans P, van der Ven A. Improvement of Depression and Anxiety After Discontinuation of Long- Term Efavirenz Treatment. CNS Neurol Disord Drug Targets. 2015;14(6):811-8. doi: 10.2174/1871527314666150325235847.</citation>
    <PMID>25808896</PMID>
  </reference>
  <reference>
    <citation>Van de Wijer L, Kinabo GD, Mchaile DN, de Mast Q, Schellekens AFA, van der Ven AJAM. Safety Evaluation of Efavirenz in Children: Don't Forget the Central Nervous System. Clin Infect Dis. 2018 Mar 19;66(7):1150. doi: 10.1093/cid/cix926. No abstract available.</citation>
    <PMID>29088326</PMID>
  </reference>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>July 18, 2017</study_first_submitted>
  <study_first_submitted_qc>July 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>July 9, 2018</last_update_submitted>
  <last_update_submitted_qc>July 9, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Efavirenz</keyword>
  <keyword>Child Behavior</keyword>
  <keyword>Cognition</keyword>
  <keyword>Medication Adherence</keyword>
  <keyword>Drug-Related Side Effects</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurobehavioral Manifestations</mesh_term>
    <mesh_term>Drug-Related Side Effects and Adverse Reactions</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Lopinavir</mesh_term>
    <mesh_term>Nevirapine</mesh_term>
    <mesh_term>Efavirenz</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03227653
org study id: EFV Kids
nct id: NCT03227653
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Efavirenz is among the preferred antiretroviral drugs for HIV-infected children. Increasing
      evidence shows that central nervous system side-effects in adults are more common than
      previously thought. Still, reliable data in children are lacking. As HIV-infected children
      nowadays have a prospect of reaching adulthood, there is an urgent need to identify potential
      long-term central nervous system side-effects, interfering with neurodevelopment and
      psychosocial maturation. Using validated tools, we assessed (1) competence
      (social/activities/school) and psychopathology (internalizing/externalizing problems), (2)
      cognitive performance (intelligence and working memory), and (3) adherence in Tanzanian
      children on an efavirenz or non-efavirenz based regimen

      In this cross-sectional observational study the investigators will examine neuropsychiatric
      and neurocognitive functioning in 126 children (aged 6-11 years) on long-term combination
      antiretroviral therapy (cART) with or without efavirenz.
In this cross-sectional observational study, we include HIV-infected children (6-12 years) on
      cART for ≥ 6 months, with viral loads ≤ 1000 copies/ml in Kilimanjaro Region, Tanzania.
      Psychopathology and competence will be assessed using the Child Behaviour Checklist.
      Cognitive performance will be assessed using the Raven's Coloured Progressive Matrices and
      the digit span test. Non-adherence is defined as any reported missed doses over the previous
      3 days or <100% adherence since the last clinical visit. Analysis of covariance and logistic
      regression models will be used to assess differences between groups. .
observational model: Cohort
time perspective: Cross-Sectional
measure: Neuropsychological symptoms: competence and psychopathology (internalizing/externalizing symptoms)
time frame: At day of inclusion
description: Neuropsychological symptoms will be assessed using the Swahili version of the Child Behavior Checklist for 6-18 years (CBCL6-18)
measure: Cognitive functioning - non-verbal cognitive ability (general intelligence)
time frame: At day of inclusion
description: Non-verbal cognitive ability will be assessed using the Raven's Progressive Matrices
measure: Cognitive functioning - working memory
time frame: At day of inclusion
description: Working memory will be assessed using the Wechsler Intelligence Scale for Children (WISC-III) Digit Span Test
measure: Treatment adherence
time frame: At day of inclusion
description: Treatment adherence will be measured using an adherence questionnaire, adapted from the PENTA 16 trial (permission obtained from the author prof. Giaquinto)
measure: Central nervous system symptoms
time frame: At day of inclusion
description: The presence of central nervous system symptoms (yes/no) in the week prior to study visit will be assessed using a checklist composed of symptoms that have been linked to efavirenz in literature.
arm group label: Efavirenz
description: Children using efavirenz-based cART for at least 6 months
arm group label: Non-efavirenz
description: Children using non-efavirenz-based cART (nevirapine or Lopinavir-Ritonavir Drug Combination) for at least 6 months.
intervention type: Drug
intervention name: Efavirenz
description: Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS
arm group label: Efavirenz
other name: Efavirenz-group
intervention type: Drug
intervention name: Nevirapine
description: Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS
arm group label: Non-efavirenz
other name: Non-efavirenz group
intervention type: Drug
intervention name: Lopinavir-Ritonavir Drug Combination
description: Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS
arm group label: Non-efavirenz
other name: Non-efavirenz group
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 6 Years
maximum age: 12 Years
healthy volunteers: No
last name: Grace Kinabo, MD, PhD
role: Principal Investigator
affiliation: Kilimanjaro Christian Medical Centre
last name: André van der Ven, MD, PhD
role: Principal Investigator
affiliation: Radboud University Medical Center
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Tanzania
citation: Van de Wijer L, Schellekens AFA, Burger DM, Homberg JR, de Mast Q, van der Ven AJAM. Rethinking the risk-benefit ratio of efavirenz in HIV-infected children. Lancet Infect Dis. 2016 May;16(5):e76-e81. doi: 10.1016/S1473-3099(16)00117-1. Epub 2016 Apr 18.
PMID: 27599655
citation: Mothapo KM, Schellekens A, van Crevel R, Keuter M, Grintjes-Huisman K, Koopmans P, van der Ven A. Improvement of Depression and Anxiety After Discontinuation of Long- Term Efavirenz Treatment. CNS Neurol Disord Drug Targets. 2015;14(6):811-8. doi: 10.2174/1871527314666150325235847.
PMID: 25808896
citation: Van de Wijer L, Kinabo GD, Mchaile DN, de Mast Q, Schellekens AFA, van der Ven AJAM. Safety Evaluation of Efavirenz in Children: Don't Forget the Central Nervous System. Clin Infect Dis. 2018 Mar 19;66(7):1150. doi: 10.1093/cid/cix926. No abstract available.
PMID: 29088326
responsible party type: Sponsor
mesh term: Neurobehavioral Manifestations
mesh term: Drug-Related Side Effects and Adverse Reactions
mesh term: Ritonavir
mesh term: Lopinavir
mesh term: Nevirapine
mesh term: Efavirenz
sharing ipd: No