<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/NCT01685827</url>
  </required_header>
  <id_info>
    <org_study_id>DNDiFEX004</org_study_id>
    <nct_id>NCT01685827</nct_id>
  </id_info>
  <brief_title>Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2</brief_title>
  <official_title>Efficacy and Safety of Fexinidazole Compared to Nifurtimox-Eflornithine Combination Therapy (NECT) in Patients With Late-stage Human African Trypanosomiasis (HAT) Due to T.b. Gambiense: Pivotal, Non-inferiority, Multicentre, Randomised, Open-label Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Drugs for Neglected Diseases</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Drugs for Neglected Diseases</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical trial is designed to prove the efficacy and safety of Fexinidazole as an oral&#xD;
      treatment for human african trypanosomiasis in advanced stage. The Fexinidazole is compared&#xD;
      to reference treatment NECT. The trial will try to demonstrate that Fexinidazole is not&#xD;
      inferior to NECT treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Human African Trypanosomiasis (HAT) is a life-threatening and neglected disease.&#xD;
&#xD;
      Few treatment options are currently available for stage 2 (meningo-encephalitic stage) HAT,&#xD;
      with NECT being the most commonly used one since 2010. Though NECT represents a significant&#xD;
      improvement over current therapies, it is still far from ideal given the environment in which&#xD;
      HAT patients live (remote, poor areas with little health infrastructure, if any, and&#xD;
      difficult logistics). There is an urgent need for less toxic and more easily manageable&#xD;
      compounds to treat this fatal disease.&#xD;
&#xD;
      Fexinidazole is a 2-5-nitroimidazole, formulated for oral administration, which has been&#xD;
      shown to possess in vitro and in vivo activity against both T. b. rhodesiense and T. b.&#xD;
      gambiense parasites.&#xD;
&#xD;
      Predicted CSF concentrations reached target levels after repeated dosing. Its efficacy and&#xD;
      safety must now be tested in patients with stage 2 HAT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">April 26, 2017</completion_date>
  <primary_completion_date type="Actual">November 11, 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>success or failure at 18 months FU visit</measure>
    <time_frame>18 months after treatment</time_frame>
    <description>The primary endpoint is the outcome (success or failure) at the test of cure (ToC) visit 18 months after the end of treatment (EOT) adapted from WHO criteria.&#xD;
Success at 18 months is:&#xD;
Either cure:&#xD;
patient alive,&#xD;
AND with no evidence of trypanosomes in any body fluid,&#xD;
AND 20 or less WBC/µl CSF&#xD;
Or Probable cure:&#xD;
Patient with no parasitological evidence of relapse in blood and lymph&#xD;
AND who refuses lumbar puncture OR whose CSF sample is haemorrhagic without trypanosomes&#xD;
AND whose clinical condition is satisfactory (without clinical symptom or signs) OR whose clinical status is unlikely to be due to HAT</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety endpoint</measure>
    <time_frame>18 days - observation period</time_frame>
    <description>Occurrence of any grade (all grades combined) adverse events during the observation period (D1-18) including:&#xD;
any worsening of clinical symptoms listed in the inclusion checklist of symptoms and signs,&#xD;
laboratory abnormalities of grade ≥ 2&#xD;
Occurrence of grade ≥ 3 adverse events during the observation period&#xD;
Occurrence of drug-related adverse events (grade ≥ 3 and any grade) during the observation period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety endpoint</measure>
    <time_frame>24 months</time_frame>
    <description>Occurrence of any serious adverse events from first drug intake to the end of follow-up period (18 months), and from M18 to M24.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics endpoint</measure>
    <time_frame>from D8 to D12 after first dosing</time_frame>
    <description>Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QT evaluation</measure>
    <time_frame>D0 - D4 - D10</time_frame>
    <description>recording of triplicates ECG</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">394</enrollment>
  <condition>Human African Trypanosomiasis (HAT)</condition>
  <condition>Sleeping Sickness</condition>
  <arm_group>
    <arm_group_label>NECT (Nifurtimox Eflornithine Combination Therapy)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Nifurtimox tablets will be given orally three times a day, at the daily dose of 15 mg/kg/day, for 10 days.&#xD;
Eflornithine (400 mg/kg/day) will be given twice daily for 7 days, as a 2-hour IV infusion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fexinidazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fexinidazole, 600 mg tablets given by oral route, after the main daily meal (within 30 minutes from the start of the meal), at the daily dose of:&#xD;
1 800 mg (3 tablets) once a day for 4 days,&#xD;
Followed by 1 200 mg (2 tablets) once a day for 6 days. Total duration of treatment will be 10 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fexinidazole</intervention_name>
    <arm_group_label>Fexinidazole</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nifurtimox</intervention_name>
    <arm_group_label>NECT (Nifurtimox Eflornithine Combination Therapy)</arm_group_label>
    <other_name>Lampit</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eflornithine</intervention_name>
    <arm_group_label>NECT (Nifurtimox Eflornithine Combination Therapy)</arm_group_label>
    <other_name>Ornidyl</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  15 years old or more&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Able to ingest at least one complete meal per day (or at least one Plumpy'Nut® sachet)&#xD;
&#xD;
          -  Karnofsky index&gt;50 (see Appendix 2 - Karnofsky Scale; p81)&#xD;
&#xD;
          -  Parasitologically confirmed late-stage African trypanosomiasis infection with T. b.&#xD;
             gambiense in the blood and/or lymph and/or CSF, attested by mobile team report (with&#xD;
             detail of exams performed and values of WBC measured in CSF) or done at the study&#xD;
             centre. If parasitologically negative in CSF, WBC &gt;20/µl detected in the CSF to&#xD;
             document stage 2 infection.&#xD;
&#xD;
          -  Having a permanent address and able to comply with follow-up visit schedule&#xD;
&#xD;
          -  Signed Informed Consent Form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severely malnourished patients, defined as having a BMI &lt; 16.&#xD;
&#xD;
          -  Patients unable to take oral medication.*&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Active clinically relevant medical conditions that, in the Investigator's opinion, may&#xD;
             jeopardize subject safety or interfere with participation in the study, including but&#xD;
             not limited to significant liver or cardiovascular disease, active documented or&#xD;
             suspected infection, CNS trauma or seizure disorders, coma or altered consciousness.&#xD;
&#xD;
          -  Severely deteriorated general condition, such as cardiovascular shock, respiratory&#xD;
             distress, or terminal illness.&#xD;
&#xD;
          -  Any condition which compromises ability to communicate with the Investigator as&#xD;
             required for the completion of this study.&#xD;
&#xD;
          -  Any contraindication to imidazole products (known hypersensitivity to imidazoles) and&#xD;
             NECT (known hypersensitivity to eflornithine).&#xD;
&#xD;
          -  Patients previously treated for HAT.&#xD;
&#xD;
          -  Patients previously enrolled in the study.&#xD;
&#xD;
          -  Follow-up expectable difficulties (migrants, refugees, traders, etc.).&#xD;
&#xD;
          -  History of alcohol abuse or any drug addiction.&#xD;
&#xD;
          -  Clinically significant abnormal laboratory value&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Unstable ECG abnormalities&#xD;
&#xD;
          -  QTcF≥ 450 msec in resting position (confirmed by 2 measurement).&#xD;
&#xD;
          -  Patients not tested for malaria and/or treated adequately for this infection&#xD;
&#xD;
          -  Patients not treated adequately for soil transmitted helminthic diseases&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Victor KANDE, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>HAT National Control Program in DRC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Batangafo</name>
      <address>
        <city>Batangafo</city>
        <country>Central African Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bagata Hospital</name>
      <address>
        <city>Bagata</city>
        <state>Bandundu</state>
        <country>Congo, The Democratic Republic of the</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Masi Manimba Hospital</name>
      <address>
        <city>Masi Manimba</city>
        <state>Bandundu - DRC</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanga Hospital</name>
      <address>
        <city>Vanga</city>
        <state>Bandundu - DRC</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HGR Mushie hospital</name>
      <address>
        <city>Mushie</city>
        <state>Bandundu</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital</name>
      <address>
        <city>Mbuji Mayi</city>
        <state>East Kasai</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HS Katanda hospital</name>
      <address>
        <city>Katanda</city>
        <state>Kasaï Oriental</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HGR ISANGI hospital</name>
      <address>
        <city>Isangi</city>
        <state>Province Orientale</state>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HGR (General Reference Hospital) Bandundu</name>
      <address>
        <city>Bandundu</city>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dingila</name>
      <address>
        <city>Dingila</city>
        <country>Congo</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Central African Republic</country>
    <country>Congo</country>
    <country>Congo, The Democratic Republic of the</country>
  </location_countries>
  <link>
    <url>http://www.dndi.org</url>
    <description>Sponsor Website</description>
  </link>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 14, 2012</study_first_posted>
  <last_update_submitted>February 17, 2018</last_update_submitted>
  <last_update_submitted_qc>February 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 20, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trypanosomiasis</mesh_term>
    <mesh_term>Trypanosomiasis, African</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Eflornithine</mesh_term>
    <mesh_term>Nifurtimox</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>February 4, 2019</submitted>
    <returned>May 3, 2019</returned>
  </pending_results>
  <!-- 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/NCT01685827
org study id: DNDiFEX004
nct id: NCT01685827
lead sponsor: 
has dmc: Yes
This clinical trial is designed to prove the efficacy and safety of Fexinidazole as an oral
      treatment for human african trypanosomiasis in advanced stage. The Fexinidazole is compared
      to reference treatment NECT. The trial will try to demonstrate that Fexinidazole is not
      inferior to NECT treatment.
Human African Trypanosomiasis (HAT) is a life-threatening and neglected disease.

      Few treatment options are currently available for stage 2 (meningo-encephalitic stage) HAT,
      with NECT being the most commonly used one since 2010. Though NECT represents a significant
      improvement over current therapies, it is still far from ideal given the environment in which
      HAT patients live (remote, poor areas with little health infrastructure, if any, and
      difficult logistics). There is an urgent need for less toxic and more easily manageable
      compounds to treat this fatal disease.

      Fexinidazole is a 2-5-nitroimidazole, formulated for oral administration, which has been
      shown to possess in vitro and in vivo activity against both T. b. rhodesiense and T. b.
      gambiense parasites.

      Predicted CSF concentrations reached target levels after repeated dosing. Its efficacy and
      safety must now be tested in patients with stage 2 HAT.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: success or failure at 18 months FU visit
time frame: 18 months after treatment
description: The primary endpoint is the outcome (success or failure) at the test of cure (ToC) visit 18 months after the end of treatment (EOT) adapted from WHO criteria.
Success at 18 months is:
Either cure:
patient alive,
AND with no evidence of trypanosomes in any body fluid,
AND 20 or less WBC/µl CSF
Or Probable cure:
Patient with no parasitological evidence of relapse in blood and lymph
AND who refuses lumbar puncture OR whose CSF sample is haemorrhagic without trypanosomes
AND whose clinical condition is satisfactory (without clinical symptom or signs) OR whose clinical status is unlikely to be due to HAT
measure: Safety endpoint
time frame: 18 days - observation period
description: Occurrence of any grade (all grades combined) adverse events during the observation period (D1-18) including:
any worsening of clinical symptoms listed in the inclusion checklist of symptoms and signs,
laboratory abnormalities of grade ≥ 2
Occurrence of grade ≥ 3 adverse events during the observation period
Occurrence of drug-related adverse events (grade ≥ 3 and any grade) during the observation period
measure: Safety endpoint
time frame: 24 months
description: Occurrence of any serious adverse events from first drug intake to the end of follow-up period (18 months), and from M18 to M24.
measure: Pharmacokinetics endpoint
time frame: from D8 to D12 after first dosing
description: Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.
measure: QT evaluation
time frame: D0 - D4 - D10
description: recording of triplicates ECG
arm group label: NECT (Nifurtimox Eflornithine Combination Therapy)
arm group type: Active Comparator
description: Nifurtimox tablets will be given orally three times a day, at the daily dose of 15 mg/kg/day, for 10 days.
Eflornithine (400 mg/kg/day) will be given twice daily for 7 days, as a 2-hour IV infusion.
arm group label: Fexinidazole
arm group type: Experimental
description: Fexinidazole, 600 mg tablets given by oral route, after the main daily meal (within 30 minutes from the start of the meal), at the daily dose of:
1 800 mg (3 tablets) once a day for 4 days,
Followed by 1 200 mg (2 tablets) once a day for 6 days. Total duration of treatment will be 10 days.
intervention type: Drug
intervention name: Fexinidazole
arm group label: Fexinidazole
intervention type: Drug
intervention name: Nifurtimox
arm group label: NECT (Nifurtimox Eflornithine Combination Therapy)
other name: Lampit
intervention type: Drug
intervention name: Eflornithine
arm group label: NECT (Nifurtimox Eflornithine Combination Therapy)
other name: Ornidyl
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: Victor KANDE, MD
role: Principal Investigator
affiliation: HAT National Control Program in DRC
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Central African Republic
country: Congo
country: Congo, The Democratic Republic of the
url: http://www.dndi.org
description: Sponsor Website
responsible party type: Sponsor
mesh term: Trypanosomiasis
mesh term: Trypanosomiasis, African
mesh term: Eflornithine
mesh term: Nifurtimox
submitted: February 4, 2019
returned: May 3, 2019