Fexinidazole in Human African Trypanosomiasis Due to T.b. Gambiense at Any Stage

An Open-label Study Assessing Effectiveness, Safety and Compliance With Fexinidazole in Patients With Human African Trypanosomiasis Due to T.b. Gambiense at Any Stage

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03025789

Enrollment

174

Registered

2017-01-20

Start date

2016-11-10

Completion date

2021-02-01

Last updated

2025-01-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Trypanosomiasis, African, Sleeping Sickness, Trypanosomiasis; Gambian

Keywords

T.b gambiense, HAT, outpatients

Brief summary

This study evaluates the effectiveness of fexinidazole administered to patients with human African trypanosomiasis due to T. b. gambiense (g-HAT) at all stages of the disease. The aim of the present study is to provide additional information on the effectiveness and safety of fexinidazole and to assess its use under conditions as close as possible to those in real life, both in patients treated on an out-patient basis and in the hospital setting, depending on clinical status. Participants will receive fexinidazole oral treatment for 10 days. Regular blood draws and lumbar punctures will be performed over 18 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. Treatment compliance, feasibility, and packaging acceptability will be thoroughly assessed in the participants receiving treatment at home. Those participants will complete questionnaires to check that instructions for fexinidazole administration are clear enough and followed correctly.

Detailed description

See attached protocol.

Interventions

DRUGFexinidazole

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)

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

6 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male or female patient, including breastfeeding or pregnant women in the second or third trimester. * ≥ 6 years of age. * ≥ 20 kg body weight. * Signed Informed Consent Form and Assent Form for patients less than 18 years of age * Trypanosomes detected in any body fluid. * Physically able to ingest at least one solid meal per day. * Able to take oral medication. * Karnofsky Performance Status \> 40%. * Able to comply with the schedule of follow-up visits and with the study constraints. * Easily reachable during the out-patient follow-up period. * Willing to undergo lumbar punctures.

Exclusion criteria

* Active clinically relevant medical conditions other than HAT that, in the Investigator's opinion, could jeopardize patient safety or interfere with participation in the study, including but not limited to significant liver or cardiovascular diseases, human immunodeficiency virus (HIV) infection, central nervous system (CNS) trauma or seizure disorders, coma or altered consciousness not related to HAT. * Severe renal or hepatic impairment defined as: elevated creatinine at \> 3 times the upper limit of normal (ULN); elevated alanine aminotranferase (ALT), aspartate aminotransferase (AST), or bilirubin at \> 3 ULN * Severely deteriorated general condition, such as cardiovascular shock, respiratory distress or terminal illness. * Any condition (except symptoms of HAT) that compromises ability to communicate with the Investigator as required for completion of the study. * Any contraindication to imidazole products (known hypersensitivity to imidazoles). * Treatment for HAT within 2 years prior to inclusion. * Prior enrolment in the study or prior intake of fexinidazole. * Foreseeable difficulty in complying with the schedule of follow-up visits (migrants, refugees, itinerant traders, etc.). Temporary Non-inclusion Criteria: * Recovery period after antimalarial treatment and/or treatment of helminthiasis (at least 3 days). * Uncontrolled diabetes or hypertension or any patients requiring clinical stabilization; wait until appropriate treatment to control the disease has been initiated. * First trimester of pregnancy. * Traumatic lumbar puncture at Screening i.e. red blood cells visible in cerebrospinal fluid (CSF); wait for 48 hours before repeating lumbar puncture. Eligibility Criteria for Out-patient Treatment * Accepting to be treated on an out-patient basis; * Karnofsky Performance Status \> 50%; * Good understanding of the method of administration of fexinidazole by the patient and/or caregiver\* (checked using a questionnaire at the time of dispensing fexinidazole); * Residing close to the investigational center, i.e. approximately one hour by road and/or boat, during the treatment period\*\*; * Easily reachable during the treatment period; * No medical or psychiatric contraindications for treatment as out-patient; * No pregnancy or breastfeeding; * No neurological symptoms.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Whose Treatment Outcome at Month 18 is a Success	Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months)	Treatment outcome at Month 18 is categorized as success or failure. Success is defined as a cure, according to the criteria adapted from the World Health Organization (WHO) update of the methodological framework for clinical trials in Sept 2014 (WHO/HTM/NTD/IDM/2015.5). Failure is defined as a relapse, probable relapse, death, use of rescue medication, loss to follow-up, refusal of all post-treatment lumbar puncture, and, in the absence of lumbar puncture at the Month 18 visit, an unfavorable outcome earlier than Month 18, or signs and symptoms evoking a relapse at Month 18. Success rate at Month 18 is defined as the percentage of participants (regardless of g-HAT stage) whose treatment outcome is a success at Month 18. An estimate of the success rate at Month 18 and the 95% exact Clopper-Pearson confidence interval (CI) of the estimate are provided.

Secondary

Measure	Time frame	Description
Number of Participants With Any Grade ≥ 3 Treatment-emergent Adverse Events (AEs) Including Laboratory and Hematological Abnormalities (if Considered Clinically Significant)	Between the first intake of fexinidazole (Day 1) and the end of the observation period, or the end of the follow-up period (18 months) for non-serious AEs assessed as related to fexinidazole	AE severity is graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for AEs (CTCAE), Version 4.03 and, for certain laboratory parameters, modified CTCAE is used. Grade ≥3 AEs include the following events: Grade 3 events (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living), Grade 4 events (life-threatening consequences; urgent intervention indicated), and Grade 5 events (death related to AE). The observation period extends from the first intake of fexinidazole (Day 1) until the end-of-hospitalization visit (between Day 13 and Day 18) for inpatients and until the end-of-treatment visit (on Day 11) for outpatients.
Number of Participants With Any Treatment-emergent Serious Adverse Event (SAE)	Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months)	An SAE was defined as any AE that: resulted in death; was life-threatening; required inpatient hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was an important medical event that was not immediately life-threatening or did not result in death, but that jeopardised the patient's safety or required an intervention to prevent one of the outcomes above. Patients treated on an outpatient basis who required hospitalisation, for whatever reason, underwent the same procedures as patients initially treated in hospital, up to the end of the hospitalisation period. During this period, and up to Day 13 or Day 18, the reasons for hospitalisation were not to be considered to be SAEs solely based on the criterion of hospitalisation, but could be considered to be SAEs based on other criteria.
Number of Participants With Any Temporary or Permanent Treatment Discontinuation (Inpatient or Outpatient) for Reasons Related to Safety	Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred)	Number of patients who prematurely discontinued treatment (temporarily or permanently) for reasons related to safety (including overdose).
Number of Participants With Any Hospitalization for Reasons Related to Safety (Outpatients Only)	Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred)	Number of outpatients who are hospitalized for reasons related to safety (including overdose). An outpatient is considered as hospitalized for reasons related to safety if he/she is initially planned to be treated as an outpatient but experiences an AE during the treatment period (Day 1 to Day 10) and is hospitalized during the treatment period.
Number of Participants With Any Permanent Treatment Discontinuation (Inpatient or Outpatient) for Reasons Related to Safety	Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred)	Number of patients who prematurely discontinued treatment permanently for reasons related to safety (including overdose).
Number of Outpatients Who Were Compliant With the Full Course of the 10-day Treatment	Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred)	Number of outpatients who completed the full course of the 10-day treatment. Full completion can be either completing the 10-day treatment in the outpatient setting, or starting treatment as an outpatient but finishing treatment at the hospital, for those who have to be hospitalized (for any reason). At Day 11, the participant and/or caregiver have to present the treatment packaging they received at study inclusion, and the investigator has to record if the treatment calendar was fully completed or not.
Number of Outpatients Who Were Compliant With the 10-day Treatment Posology, Including Taking the Correct Number of Tablets During the 2 Phases of Treatment and Taking Tablets All at Once Every Day, With Food and Without Any Interruption of Treatment	End-of-treatment visit (Day 11)	Number of patients whose response to the question How did you take your treatment? is correct, as determined by the study personnel leading the compliance interview at Day 11 (end-of-treatment visit). The expected answer for participants weighing 35 kg or more is: 2 phases. Day 1 to 4 = 3 tablets. Day 5 to 10 = 2 tablets. Tablets to be taken all at once during a meal. The expected answer for participants weighing less than 35 kg is: 2 phases. Day 1 to 4 = 2 tablets. Day 5 to 10 = 1 tablet. Tablets to be taken all at once during a meal. The answer is considered correct if the 4 key messages have been understood (treatment period composed of 2 phases, each with a different number of tablets to be taken; treatment to be taken for 10 days without interruption; tablets to be taken all at once every day; treatment to be taken during a meal)
Feasibility of Self-management of Treatment Intake in Outpatients: Occurrence of Temporary Treatment Discontinuation	End-of-treatment visit (Day 11)	The occurrence of temporary treatment discontinuation is recorded at Day 11 (end-of-treatment visit) in the case report form by the study personnel (Section on feasibility, question Was the treatment temporarily discontinued?). Occurrence is presented as the number of outpatients who temporarily discontinued their treatment.
Percentage of Participants Whose Treatment Outcome at Month 12 is a Success	Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months)	Treatment outcome at Month 12 is categorized as success or failure. Success is defined as a cure, according to the criteria adapted from the World Health Organization (WHO) update of the methodological framework for clinical trials in Sept 2014 (WHO/HTM/NTD/IDM/2015.5). Failure is defined as a relapse, probable relapse, death, use of rescue medication, loss to follow-up, refusal of all post-treatment lumbar puncture, and, in the absence of lumbar puncture at the Month 12 visit, an unfavorable outcome earlier than Month 12, or signs and symptoms evoking a relapse at Month 12 (data collected at Month 18 are considered, if available). Success rate at Month 12 is defined as the percentage of participants (regardless of g-HAT stage) whose treatment outcome is a success at Month 12. An estimate of the success rate at Month 12 and the 95% exact Clopper-Pearson confidence interval (CI) of the estimate are provided.
Feasibility of Self-management of Treatment Intake in Outpatients: Delayed Treatment Start	End-of-treatment visit (Day 11)	The occurrence of delayed treatment start is recorded at Day 11 (end-of-treatment visit) in the case report form by the study personnel (Section on feasibility, date of first administration \[Day 1\] minus date of dispensing \[Day 0\] \> 1 day). The occurrence of delayed treatment start is presented as the number of outpatients who had their planned treatment start delayed by at least 1 day.
Feasibility of Self-management of Treatment Intake in Outpatients: Hospitalization During the Treatment Period Due to Non-compliance	End-of-treatment visit (Day 11)	The occurrence of hospitalization is recorded at Day 11 (end-of-treatment visit) in the case report form by the study personnel (Section on feasibility, question Did the patient finish his/her treatment in hospital?), with non-compliance as the reason for hospitalization. Occurrence of hospitalization is presented as the number of outpatients who had to be hospitalized during the treatment period due to non-compliance.
Acceptability of Packaging in Outpatients: Full Understanding of Instructions Concerning Dosing Regimen	Before treatment (Day 0)	Full understanding of the instructions concerning the dosing regimen of fexinidazole is assessed at Day 0 (day of treatment dispensing) by the study personnel. During the interview, the study personnel ask the participant and/or caregiver 8 questions about posology. To each of these 8 questions, the study personnel tick 'Yes' if the immediate answer is consistent with the expected answer. Full understanding of the instructions requires all 8 questions to be answered correctly. Full understanding is presented as the number of patients who correctly answered all 8 questions.
Acceptability of Packaging in Outpatients: Help Requested to Follow the Treatment	End-of-treatment visit (Day 11)	Acceptability of packaging is assessed at Day 11 (end-of-treatment visit) by a questionnaire filled out by the participant and/or caregiver. The occurrence of help needed is presented as the number of outpatients who indicate at the end of treatment that they had to request help to follow the treatment (Section on acceptability, question Did you have to request help to follow the treatment?).
Acceptability of Packaging in Outpatients: Instructions Found Helpful	End-of-treatment visit (Day 11)	Acceptability of packaging is assessed at Day 11 (end-of-treatment visit) by a questionnaire filled out by the participant and/or caregiver. The number of patients who found the instructions helpful is recorded (Section on acceptability, question Did you find the instruction sheet provided with the medication helpful / Did it help you to remember the important information?).
Whole Blood Concentration of Fexinidazole From Dry Blood Spot, Measured 24 Hours After the Last Dose of Fexinidazole	End-of-treatment visit (Day 11, 24 hours after last treatment administration)	Concentrations of fexinidazole is determined using a validated analytical method, in all patients with available PK data.
Whole Blood Concentration of Fexinidazole Metabolite M1 From Dry Blood Spot, Measured 24 Hours After the Last Dose of Fexinidazole	End-of-treatment visit (Day 11, 24 hours after last treatment administration)	Concentrations of fexinidazole metabolite M1 (fexinidazole sulfoxide) is determined using a validated analytical method, in all patients with available PK data.
Whole Blood Concentration of Fexinidazole Metabolite M2 From Dry Blood Spot, Measured 24 Hours After the Last Dose of Fexinidazole	End-of-treatment visit (Day 11, 24 hours after last treatment administration)	Concentrations of fexinidazole metabolite M2 (fexinidazole sulfone) is determined using a validated analytical method, in all patients with available PK data.
Feasibility of Self-management of Treatment Intake in Outpatients: Occurrence of Permanent Treatment Discontinuation	End-of-treatment visit (Day 11)	The occurrence of permanent treatment discontinuation is recorded at Day 11 (end-of-treatment visit) in the case report form by the study personnel (Section on feasibility, question Was the treatment stopped permanently?). Occurrence is presented as the number of outpatients who prematurely (prior to Day 10) discontinued their treatment permanently.

Countries

Democratic Republic of the Congo, Guinea

Participant flow

Recruitment details

The study was conducted at 8 centers in the Democratic Republic of Congo and 1 center in Guinea. 200 participants were screened and signed informed consent. 3 patients had no trypanosomes in their blood and were not included since g-HAT positivity could not be confirmed. Of the 197 screened HAT-positive participants, 174 were included and treated, and 23 were not included, mainly due to inclusion/exclusion criteria not met. Participants were enrolled between 10 November 2016 and 10 August 2019.

Pre-assignment details

The pre-treatment period of up to 15 days included screening and treatment of concurrent malaria/soil-transmitted helminthiasis. At the end of this period, all participants (regardless of g-HAT stage and treatment setting) were treated with fexinidazole.

Participants by arm

Arm	Count
Inpatients Participants received fexinidazole orally for 10 days as inpatients (at the hospital) 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)	136
Outpatients Participants received fexinidazole orally for 10 days as outpatients (at home) 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)	38
Total	174

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	1	0
Overall Study	Lack of Efficacy	6	1
Overall Study	Withdrawal by Subject	0	2

Baseline characteristics

Characteristic	Inpatients	Outpatients	Total
Age, Continuous	26.0 years STANDARD_DEVIATION 15.5	27.9 years STANDARD_DEVIATION 18	26.4 years STANDARD_DEVIATION 16
g-HAT stage: Stage 1/intermediate, Stage 2 Stage 1/intermediate	53 Participants	17 Participants	70 Participants
g-HAT stage: Stage 1/intermediate, Stage 2 Stage 2	83 Participants	21 Participants	104 Participants
Race/Ethnicity, Customized Sub-Saharan African	136 Participants	38 Participants	174 Participants
Region of Enrollment Congo, The Democratic Republic of the	110 Participants	32 Participants	142 Participants
Region of Enrollment Guinea	26 Participants	6 Participants	32 Participants
Sex: Female, Male Female	78 Participants	18 Participants	96 Participants
Sex: Female, Male Male	58 Participants	20 Participants	78 Participants
White blood cell (WBC) in cerebrospinal fluid (CSF) 100 cells/µL or lower	80 Participants	20 Participants	100 Participants
White blood cell (WBC) in cerebrospinal fluid (CSF) Higher than 100 cells/µL	56 Participants	18 Participants	74 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 136	0 / 38
other Total, other adverse events	73 / 136	23 / 38
serious Total, serious adverse events	10 / 136	4 / 38

Outcome results

Primary

Percentage of Participants Whose Treatment Outcome at Month 18 is a Success

Treatment outcome at Month 18 is categorized as success or failure. Success is defined as a cure, according to the criteria adapted from the World Health Organization (WHO) update of the methodological framework for clinical trials in Sept 2014 (WHO/HTM/NTD/IDM/2015.5). Failure is defined as a relapse, probable relapse, death, use of rescue medication, loss to follow-up, refusal of all post-treatment lumbar puncture, and, in the absence of lumbar puncture at the Month 18 visit, an unfavorable outcome earlier than Month 18, or signs and symptoms evoking a relapse at Month 18. Success rate at Month 18 is defined as the percentage of participants (regardless of g-HAT stage) whose treatment outcome is a success at Month 18. An estimate of the success rate at Month 18 and the 95% exact Clopper-Pearson confidence interval (CI) of the estimate are provided.

Time frame: Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months)

Population: This population includes all patients in the mITT population (i.e. who received at least one table of fexinidazole), regardless of treatment setting (inpatients and outpatients). The efficacy of fexinidazole was not meant to be studied in inpatients and outpatients separately.

Arm	Measure	Value (NUMBER)
All Treated Patients, Regardless of Treatment Setting	Percentage of Participants Whose Treatment Outcome at Month 18 is a Success	93.1 percentage of participants

Secondary

Acceptability of Packaging in Outpatients: Full Understanding of Instructions Concerning Dosing Regimen

Full understanding of the instructions concerning the dosing regimen of fexinidazole is assessed at Day 0 (day of treatment dispensing) by the study personnel. During the interview, the study personnel ask the participant and/or caregiver 8 questions about posology. To each of these 8 questions, the study personnel tick 'Yes' if the immediate answer is consistent with the expected answer. Full understanding of the instructions requires all 8 questions to be answered correctly. Full understanding is presented as the number of patients who correctly answered all 8 questions.

Time frame: Before treatment (Day 0)

Population: All outpatients included in the mITT population (i.e. who received at least one table of fexinidazole).

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
All Treated Patients, Regardless of Treatment Setting	Acceptability of Packaging in Outpatients: Full Understanding of Instructions Concerning Dosing Regimen	30 Participants

Secondary

Acceptability of Packaging in Outpatients: Help Requested to Follow the Treatment

Acceptability of packaging is assessed at Day 11 (end-of-treatment visit) by a questionnaire filled out by the participant and/or caregiver. The occurrence of help needed is presented as the number of outpatients who indicate at the end of treatment that they had to request help to follow the treatment (Section on acceptability, question Did you have to request help to follow the treatment?).