Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

February 17, 2018 updated by: Drugs for Neglected Diseases

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

394

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Central African Republic
      • Batangafo, Central African Republic
        • Batangafo
  • Congo
      • Bandundu, Congo
        • HGR (General Reference Hospital) Bandundu
      • Dingila, Congo
        • Dingila
    • Bandundu
      • Mushie, Bandundu, Congo
        • HGR Mushie hospital
    • Bandundu - DRC
      • Masi Manimba, Bandundu - DRC, Congo
        • Masi Manimba Hospital
      • Vanga, Bandundu - DRC, Congo
        • Vanga Hospital
    • East Kasai
      • Mbuji Mayi, East Kasai, Congo
        • CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital
    • Kasaï Oriental
      • Katanda, Kasaï Oriental, Congo
        • HS Katanda hospital
    • Province Orientale
      • Isangi, Province Orientale, Congo
        • HGR ISANGI hospital
  • Congo, The Democratic Republic of the
    • Bandundu
      • Bagata, Bandundu, Congo, The Democratic Republic of the
        • Bagata Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / 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 Names:
  • Lampit
Drug: Eflornithine
Other Names:
  • 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
18 months after treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
18 days - observation period
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.
24 months
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.
from D8 to D12 after first dosing
QT evaluation
Time Frame: D0 - D4 - D10
recording of triplicates ECG
D0 - D4 - D10

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Drugs for Neglected Diseases

Investigators

  • Principal Investigator: Victor KANDE, MD, HAT National Control Program in DRC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Actual)

November 11, 2016

Study Completion (Actual)

April 26, 2017

Study Registration Dates

First Submitted

September 12, 2012

First Submitted That Met QC Criteria

September 13, 2012

First Posted (Estimate)

September 14, 2012

Study Record Updates

Last Update Posted (Actual)

February 20, 2018

Last Update Submitted That Met QC Criteria

February 17, 2018

Last Verified

February 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DNDiFEX004

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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