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Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

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ClinicalTrials.gov Identifier: NCT01685827
Recruitment Status : Completed
First Posted : September 14, 2012
Last Update Posted : February 20, 2018
Sponsor:
Information provided by (Responsible Party):
Drugs for Neglected Diseases

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Human African Trypanosomiasis (HAT) Sleeping Sickness Drug: Fexinidazole Drug: Nifurtimox Drug: Eflornithine Phase 2 Phase 3

Detailed Description:

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 394 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
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
Study Start Date : October 2012
Actual Primary Completion Date : November 11, 2016
Actual Study Completion Date : April 26, 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: NECT (Nifurtimox Eflornithine Combination Therapy)
  • 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.
 Drug: Nifurtimox
Other Name: Lampit

Drug: Eflornithine
Other Name: Ornidyl
Experimental: Fexinidazole

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.
 Drug: Fexinidazole


Outcome Measures
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Primary Outcome Measures :
  1. success or failure at 18 months FU visit [ Time Frame: 18 months after treatment ]

    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


Secondary Outcome Measures :
  1. Safety endpoint [ Time Frame: 18 days - observation period ]

    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

  2. Safety endpoint [ Time Frame: 24 months ]
    Occurrence of any serious adverse events from first drug intake to the end of follow-up period (18 months), and from M18 to M24.

  3. Pharmacokinetics endpoint [ Time Frame: from D8 to D12 after first dosing ]
    Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.

  4. QT evaluation [ Time Frame: D0 - D4 - D10 ]
    recording of triplicates ECG


Eligibility Criteria
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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 15 years old or more
  • Male or female
  • Able to ingest at least one complete meal per day (or at least one Plumpy'Nut® sachet)
  • Karnofsky index>50 (see Appendix 2 - Karnofsky Scale; p81)
  • Parasitologically confirmed late-stage African trypanosomiasis infection with T. b. gambiense in the blood and/or lymph and/or CSF, attested by mobile team report (with detail of exams performed and values of WBC measured in CSF) or done at the study centre. If parasitologically negative in CSF, WBC >20/µl detected in the CSF to document stage 2 infection.
  • Having a permanent address and able to comply with follow-up visit schedule
  • Signed Informed Consent Form

Exclusion Criteria:

  • Severely malnourished patients, defined as having a BMI < 16.
  • Patients unable to take oral medication.*
  • Pregnancy or lactation
  • Active clinically relevant medical conditions that, in the Investigator's opinion, may jeopardize subject safety or interfere with participation in the study, including but not limited to significant liver or cardiovascular disease, active documented or suspected infection, CNS trauma or seizure disorders, coma or altered consciousness.
  • Severely deteriorated general condition, such as cardiovascular shock, respiratory distress, or terminal illness.
  • Any condition which compromises ability to communicate with the Investigator as required for the completion of this study.
  • Any contraindication to imidazole products (known hypersensitivity to imidazoles) and NECT (known hypersensitivity to eflornithine).
  • Patients previously treated for HAT.
  • Patients previously enrolled in the study.
  • Follow-up expectable difficulties (migrants, refugees, traders, etc.).
  • History of alcohol abuse or any drug addiction.
  • Clinically significant abnormal laboratory value
  • Pregnancy
  • Unstable ECG abnormalities
  • QTcF≥ 450 msec in resting position (confirmed by 2 measurement).
  • Patients not tested for malaria and/or treated adequately for this infection
  • Patients not treated adequately for soil transmitted helminthic diseases
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01685827


Locations
Central African Republic
Batangafo
Batangafo, Central African Republic
Congo, The Democratic Republic of the
Bagata Hospital
Bagata, Bandundu, Congo, The Democratic Republic of the
Congo
Masi Manimba Hospital
Masi Manimba, Bandundu - DRC, Congo
Vanga Hospital
Vanga, Bandundu - DRC, Congo
HGR Mushie hospital
Mushie, Bandundu, Congo
CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital
Mbuji Mayi, East Kasai, Congo
HS Katanda hospital
Katanda, Kasaï Oriental, Congo
HGR ISANGI hospital
Isangi, Province Orientale, Congo
HGR (General Reference Hospital) Bandundu
Bandundu, Congo
Dingila
Dingila, Congo
Sponsors and Collaborators
Drugs for Neglected Diseases
Investigators
Principal Investigator: Victor KANDE, MD HAT National Control Program in DRC
More Information
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Additional Information:
Sponsor Website  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT01685827     History of Changes
Other Study ID Numbers: DNDiFEX004
First Posted: September 14, 2012    Key Record Dates
Last Update Posted: February 20, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Trypanosomiasis
Trypanosomiasis, African
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Eflornithine
Nifurtimox
Antineoplastic Agents
 Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Ornithine Decarboxylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action