Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

Sponsor

Drugs for Neglected Diseases (Other)

Overall Status

Completed

CT.gov ID

NCT01685827

Collaborator

(none)

394

Enrollment

Locations

Arms

54.8

Duration (Months)

39.4

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Oct 1, 2012

Actual Primary Completion Date :

Nov 11, 2016

Actual Study Completion Date :

Apr 26, 2017

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Safety endpoint [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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country
1	Batangafo	Batangafo		Central African Republic
2	Bagata Hospital	Bagata	Bandundu	Congo, The Democratic Republic of the
3	Masi Manimba Hospital	Masi Manimba	Bandundu - DRC	Congo
4	Vanga Hospital	Vanga	Bandundu - DRC	Congo
5	HGR Mushie hospital	Mushie	Bandundu	Congo
6	CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital	Mbuji Mayi	East Kasai	Congo
7	HS Katanda hospital	Katanda	Kasaï Oriental	Congo
8	HGR ISANGI hospital	Isangi	Province Orientale	Congo
9	HGR (General Reference Hospital) Bandundu	Bandundu		Congo
10	Dingila	Dingila		Congo