Fexinidazole in Human African Trypanosomiasis Due to T. b. Rhodesiense

Efficacy and Safety of Fexinidazole in Patients With Human African Trypanosomiasis (HAT) Due to Trypanosoma Brucei Rhodesiense: a Multicentre, Open-label Clinical Trial

The ultimate goal of this study is to show that fexinidazole offers an alternative over the existing treatments of Human African trypanosomiasis due to Trypanosoma brucei rhodesiense (r-HAT): melarsoprol in patients with stage 2 r-HAT and suramin in patients with stage 1 r-HAT. The main questions it aims to answer are:

• Is the short-term fatality rate and failure rate associated with fexinidazole lower than those of melarsoprol in patients with stage 2 r-HAT?
• Is the long-term failure rate associated with fexinidazole lower than that of melarsoprol in patients with stage 2 r-HAT?
• Can fexinidazole in patients with stage 1 r-HAT replace the treatment with suramin?
• Is fexinidazole treatment safe in patient with r-HAT, regardless of stage?

Participants will receive fexinidazole oral treatment for 10 days. Regular blood draws and lumbar punctures will be performed over 12 months to confirm the cure of the disease. Other assessments will include the recording of adverse events, signs and symptoms of the disease, laboratory tests, vital signs, electrocardiograms.

Study Overview

• Status: Completed
• Conditions: Trypanosomiasis, African; Sleeping Sickness; Trypanosoma Brucei Rhodesiense; Infection
• Intervention / Treatment: Drug: Fexinidazole

Detailed Description

Nowadays, the only treatment available for the stage 2 of HAT due to t.b rhodesiense is melarsoprol, a very toxic drug.

The primary objective of this trial is to evaluate fexinidazole as an alternative treatment over melarsoprol in patients with stage 2 of HAT disease due to t.b rhodesiense in a Phase II/III cohort trial with 34 stage 2 patients. All stages of the disease will be recruited but the recruitment will stop once 34 evaluable stage-2 patients have reached the end of treatment.

The trial will be a multicentre, non-randomized, clinical trial in patients with r-HAT.

Subjects will be recruited among the patients reporting to Lwala Hospital (Uganda) and Rumphi District Hospital (Malawi). If feasible, r-HAT patients from other hospitals and centres in Kaberamaido/Dokolo Districts (Uganda) and Rumphi/Mzimba North District (Malawi) and well as Zambia bordering areas, will be referred to Lwala and Rumphi Hospitals, respectively, for treatment.

Fexinidazole is an oral treatment which has to be taken every day for 10 days. In case of lack of efficacy (e.g. disease relapse) the patients will be switched to the standart treatment that is part of the National Control Program in each country (melarsoprol for stage-2 patients and suramin for stage-1 patients)

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Malawi
  • Rumphi, Malawi, PO Box 225
    • Rumphi District Hospital
• Uganda
  • Kadeberamaido
    • Lwala, Kadeberamaido, Uganda, PO Box 650
      • Lwala Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed Informed Consent Form (plus assent for children)
• ≥ 6 years old
• ≥ 20 kg body weight
• Ability to ingest at least one complete meal per day (or at least one Plumpy'Nut® sachet)
• Karnofsky index ≥ 40
• Parasitological confirmation of T. b. rhodesiense infection
• Having a permanent address or being traceable by others and willing and able to comply with follow-up visit schedule
• Agreement to be hospitalised for a minimum of 13 days and to receive the study treatment

Exclusion Criteria:

• Active clinically relevant medical conditions other than HAT that may jeopardize subject safety or at the investigator discretion may interfere with participation in the study.
• Compromised general health or severely deteriorated general condition, such as severe malnutrition, cardiovascular shock, respiratory distress, or terminal illness
• Patients with severe hepatic impairment (e.g.: clinical signs of cirrhosis or jaundice)
• Known hypersensitivity to fexinidazole, to any nitroimidazole drugs (e.g. metronidazole, tinidazole), or to any of the excipients
• Patients previously enrolled in the study or having already received fexinidazole

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with stage 1 r-HAT; Patients with stage 1 r-HAT were patients without trypanosomes in the cerebrospinal fluid (CSF) but with trypanosomes in the blood and/or lymph and CSF white blood cells (WBC) ≤5 cells/µL. Patients were to receive fexinidazole orally for 10 days.	Drug: Fexinidazole; Tablets of 600 mg; Participants with a weight between 20 and 34 kg received 1200 mg (2 tablets) for 4 days, then 600 mg (1 tablet) for 6 days (with food); Participants with a weight of 35 kg and above received 1800 mg (3 tablets) for 4 days, then 1200 mg (2 tablets) for 6 days (with food)
Experimental: Patients with stage 2 r-HAT; Patients with stage 2 r-HAT were patients with trypanosomes in the CSF (and/or in blood/lymph) and/or CSF WBC >5 cells/µL. Patients were to receive fexinidazole orally for 10 days.	Drug: Fexinidazole; Tablets of 600 mg; Participants with a weight between 20 and 34 kg received 1200 mg (2 tablets) for 4 days, then 600 mg (1 tablet) for 6 days (with food); Participants with a weight of 35 kg and above received 1800 mg (3 tablets) for 4 days, then 1200 mg (2 tablets) for 6 days (with food)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Evaluable Patients With Stage 2 r-HAT Who Died by the End of Hospitalization, Considering Only Deaths Possibly Related to r-HAT or Fexinidazole	The percentage of patients who died between the first intake of fexinidazole until the End-of-Hospitalization Visit (Day 12-18), considering only deaths possibly related to r-HAT or study treatment as assessed by the Data Safety Monitoring Board (DSMB), was calculated. The World Health Organization(WHO) verbal autopsy questionnaire was used since anatomopathological techniques were not available at the study sites (unless the death occurred at the hospital, in which case the investigator was present). In case of death that was not related to r-HAT nor to the study treatment during the hospitalization, the patient is considered as non-evaluable for efficacy purposes. Any patient who left the hospital without being medically discharged by the site Investigator before the planned End-of-Hospitalization Visit, and for whom no outcome could be retrieved, is also to be considered as non-evaluable.	12 to 18 days after start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Evaluable Patients With Stage 2 r-HAT, Whose Treatment Outcome is a Failure at the End of Hospitalization	Treatment outcome at end of hospitalization (Day 12-18) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid at end of treatment (Day 11), death related to r-HAT or fexinidazole at end of hospitalization according to the DSMB, or absence of clinical improvement leading to the use of rescue medication. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 to 18 days after start of treatment
Percentage of Evaluable Patients With Stage 2 r-HAT, Whose Treatment Outcome is a Failure at 12 Months	Treatment outcome at test of cure (Month 12) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid, death related to r-HAT or fexinidazole according to the DSMB, absence of clinical improvement leading to the use of rescue medication, or WBC count in the CSF >20 cells/μL which was unlikely due to causes other than HAT. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 months after start of treatment
Percentage of Evaluable Patients With Stage 1 r-HAT, Whose Treatment Outcome is a Failure at the End of Hospitalization	Treatment outcome at end of hospitalization (Day 12-18) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid at end of treatment (Day 11), death related to r-HAT or fexinidazole at end of hospitalization according to the DSMB, or absence of clinical improvement leading to the use of rescue medication. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 to 18 days after start of treatment
Percentage of Evaluable Patients With Stage 1 r-HAT, Whose Treatment Outcome is a Failure at 12 Months	Treatment outcome at test of cure (Month 12) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid, death related to r-HAT or fexinidazole according to the DSMB, absence of clinical improvement leading to the use of rescue medication, or WBC count in the CSF >20 cells/μL which was unlikely due to causes other than HAT. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 months after start of treatment
Percentage of Evaluable Patients With Any r-HAT Stage Who Died by the End of Hospitalization, Considering Only Deaths Possibly Related to r-HAT or Fexinidazole	The percentage of patients who died between the first intake of fexinidazole until the End-of-Hospitalization Visit (Day 12-18), considering only deaths possibly related to r-HAT or study treatment as assessed by the DSMB, was calculated. The WHO verbal autopsy questionnaire was used since anatomopathological techniques were not available at the study sites (unless the death occurred at the hospital, in which case the investigator was present). In case of death that was not related to r-HAT nor to the study treatment during the hospitalization, the patient is considered as non-evaluable for efficacy purposes. Any patient who left the hospital without being medically discharged by the site Investigator before the planned End-of-Hospitalization Visit, and for whom no outcome could be retrieved, is also to be considered as non-evaluable.	12 to 18 days after start of treatment
Percentage of Evaluable Patients With Any r-HAT Stage, Whose Treatment Outcome is a Failure at the End of Hospitalization	Treatment outcome at end of hospitalization (Day 12-18) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid at end of treatment (Day 11), death related to r-HAT or fexinidazole at end of hospitalization according to the DSMB, or absence of clinical improvement leading to the use of rescue medication. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 to 18 days after start of treatment
Percentage of Evaluable Patients With Any r-HAT Stage, Whose Treatment Outcome is a Failure at 12 Months	Treatment outcome at test of cure (Month 12) is categorized as success or failure. Failure is defined as any of the following: presence of trypanosomes in any body fluid, death related to r-HAT or fexinidazole according to the DSMB, absence of clinical improvement leading to the use of rescue medication, or WBC count in the CSF >20 cells/μL which was unlikely due to causes other than HAT. Unrelated deaths are neither success nor failure (the patient is considered non-evaluable for efficacy purposes).	12 months after start of treatment
Number of Participants With Any AE (Including Abnormal Laboratory or ECG Finding if Considered Clinically Significant) Until the End of Hospitalization	Treatment-emergent AEs during the observation period were recorded from the first intake of fexinidazole (Day 1) until the End-of-Hospitalization Visit (between Day 12 and Day 18).	12 to 18 days (between Day 1 and Day 12-18)
Number of Participants With Any AE Considered as Serious Until the End of the Follow-up Period	Treatment-emergent AEs considered as serious were collected from the first intake of fexinidazole (Day 1) until the End-of-Study Visit (Month 12). An AE was considered as serious if resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was an important medical event.	12 months (between Day 1 and Month 12)
Number of Participants With Any AE Considered as Possibly Related to Fexinidazole Until the End of the Follow-up Period	Treatment-emergent AEs considered as possibly related to fexinidazole were collected from the first intake of fexinidazole (Day 1) until the End-of-Study Visit (Month 12).	12 months (between Day 1 and Month 12)

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Principal Investigator: Enock Matovu, Prof, Makerere University

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2019
• Primary Completion (Actual): November 30, 2021
• Study Completion (Actual): October 12, 2022

Study Registration Dates

• First Submitted: May 23, 2019
• First Submitted That Met QC Criteria: June 3, 2019
• First Posted (Actual): June 4, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: HAT; Neglected Tropical Disease; Trypanosoma Brucei (T. b.) rhodesiense
• Additional Relevant MeSH Terms: Vector Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Euglenozoa Infections; Trypanosomiasis; Trypanosomiasis, African
• Other Study ID Numbers: DNDi-FEX-07-HAT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No