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Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

Primary Purpose

Human African Trypanosomiasis (HAT), Sleeping Sickness

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Fexinidazole
Nifurtimox
Eflornithine
Sponsored by
Drugs for Neglected Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human African Trypanosomiasis (HAT)

Eligibility Criteria

15 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Batangafo
  • Bagata Hospital
  • Masi Manimba Hospital
  • Vanga Hospital
  • HGR Mushie hospital
  • CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital
  • HS Katanda hospital
  • HGR ISANGI hospital
  • HGR (General Reference Hospital) Bandundu
  • Dingila

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

NECT (Nifurtimox Eflornithine Combination Therapy)

Fexinidazole

Arm Description

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, 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.

Outcomes

Primary Outcome Measures

success or failure at 18 months FU visit
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
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
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
Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.
QT evaluation
recording of triplicates ECG

Full Information

First Posted
September 12, 2012
Last Updated
February 17, 2018
Sponsor
Drugs for Neglected Diseases
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1. Study Identification

Unique Protocol Identification Number
NCT01685827
Brief Title
Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2
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 Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
October 2012 (undefined)
Primary Completion Date
November 11, 2016 (Actual)
Study Completion Date
April 26, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Drugs for Neglected Diseases

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human African Trypanosomiasis (HAT), Sleeping Sickness

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
394 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NECT (Nifurtimox Eflornithine Combination Therapy)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Fexinidazole
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Fexinidazole
Intervention Type
Drug
Intervention Name(s)
Nifurtimox
Other Intervention Name(s)
Lampit
Intervention Type
Drug
Intervention Name(s)
Eflornithine
Other Intervention Name(s)
Ornidyl
Primary Outcome Measure Information:
Title
success or failure at 18 months FU visit
Description
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
Time Frame
18 months after treatment
Secondary Outcome Measure Information:
Title
Safety endpoint
Description
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
Time Frame
18 days - observation period
Title
Safety endpoint
Description
Occurrence of any serious adverse events from first drug intake to the end of follow-up period (18 months), and from M18 to M24.
Time Frame
24 months
Title
Pharmacokinetics endpoint
Description
Whole blood and CSF concentrations of fexinidazole, M1, M2 and PK parameters derived from a model of population PK data.
Time Frame
from D8 to D12 after first dosing
Title
QT evaluation
Description
recording of triplicates ECG
Time Frame
D0 - D4 - D10

10. Eligibility

Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Victor KANDE, MD
Organizational Affiliation
HAT National Control Program in DRC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Batangafo
City
Batangafo
Country
Central African Republic
Facility Name
Bagata Hospital
City
Bagata
State/Province
Bandundu
Country
Congo, The Democratic Republic of the
Facility Name
Masi Manimba Hospital
City
Masi Manimba
State/Province
Bandundu - DRC
Country
Congo
Facility Name
Vanga Hospital
City
Vanga
State/Province
Bandundu - DRC
Country
Congo
Facility Name
HGR Mushie hospital
City
Mushie
State/Province
Bandundu
Country
Congo
Facility Name
CRT (Centre de Réference et de Traitement) Dipumba, Dipumba general hospital
City
Mbuji Mayi
State/Province
East Kasai
Country
Congo
Facility Name
HS Katanda hospital
City
Katanda
State/Province
Kasaï Oriental
Country
Congo
Facility Name
HGR ISANGI hospital
City
Isangi
State/Province
Province Orientale
Country
Congo
Facility Name
HGR (General Reference Hospital) Bandundu
City
Bandundu
Country
Congo
Facility Name
Dingila
City
Dingila
Country
Congo

12. IPD Sharing Statement

Citations:
PubMed Identifier
29113731
Citation
Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, Delhomme S, Bernhard S, Kuziena W, Lubaki JF, Vuvu SL, Ngima PN, Mbembo HM, Ilunga M, Bonama AK, Heradi JA, Solomo JLL, Mandula G, Badibabi LK, Dama FR, Lukula PK, Tete DN, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018 Jan 13;391(10116):144-154. doi: 10.1016/S0140-6736(17)32758-7. Epub 2017 Nov 4. Erratum In: Lancet. 2018 Jan 13;391(10116):124.
Results Reference
derived
Links:
URL
http://www.dndi.org
Description
Sponsor Website

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Pivotal Study of Fexinidazole for Human African Trypanosomiasis in Stage 2

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