Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

Phase 2

Completed

• Conditions: Human African Trypanosomiasis (HAT); Sleeping Sickness
• Interventions: Drug: Nifurtimox; Drug: Fexinidazole; Drug: Eflornithine

• Registration Number: NCT01685827
• Lead Sponsor: Drugs for Neglected Diseases

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.

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 Timeline

• Study First Submitted: 2012-09-12
• Study First Submitted QC: 2012-09-13
• Study First Posted: 2012-09-14
• Study Start: 2012-10
• Primary Completion: 2016-11-11
• Study Completion: 2017-04-26
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-17
• Last Update Posted: 2018-02-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 394

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NECT (Nifurtimox Eflornithine Combination Therapy)	Nifurtimox	* 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.
NECT (Nifurtimox Eflornithine Combination Therapy)	Eflornithine	* 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.
Fexinidazole	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.

Primary Outcome Measures

Name	Time	Method
success or failure at 18 months FU visit	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

Name	Time	Method
Safety endpoint	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.
Pharmacokinetics endpoint	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.
QT evaluation	D0 - D4 - D10	recording of triplicates ECG

Trial Locations

Locations (10)

CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital; 🇨🇬 Mbuji Mayi, East Kasai, Congo

HGR ISANGI hospital; 🇨🇬 Isangi, Province Orientale, Congo

Masi Manimba Hospital; 🇨🇬 Masi Manimba, Bandundu - DRC, Congo

Batangafo; 🇨🇫 Batangafo, Central African Republic

Bagata Hospital; 🇨🇩 Bagata, Bandundu, Congo, The Democratic Republic of the

Vanga Hospital; 🇨🇬 Vanga, Bandundu - DRC, Congo

HGR Mushie hospital; 🇨🇬 Mushie, Bandundu, Congo

HS Katanda hospital; 🇨🇬 Katanda, Kasaï Oriental, Congo

HGR (General Reference Hospital) Bandundu; 🇨🇬 Bandundu, Congo

Dingila; 🇨🇬 Dingila, Congo