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

Study Overview
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Brief Summary
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This study evaluates the effectiveness of fexinidazole administered to patients with 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. Participants receiving treatment at home will also complete questionnaires to check that instructions for fexinidazole administration are clear enough and followed correctly.

Official Title
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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

Conditions
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Trypanosomiasis, African, Sleeping Sickness, Trypanosomiasis; Gambian

Intervention / Treatment
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* Drug: Fexinidazole


Participation Criteria
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Eligibility Criteria
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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 jeopardise patient safety or interfere with participation in the study, including but not limited to significant liver or cardiovascular diseases, HIV infection, 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 ALT, 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 stabilisation; 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 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 centre, 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.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inpatients<br>Participants received fexinidazole orally for 10 days as inpatients (at the hospital) | Drug: Fexinidazole<br>* 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 (1 tablet) for 6 days (with food)<br>|
| Experimental: Outpatients<br>Participants received fexinidazole orally for 10 days as outpatients (at home) | Drug: Fexinidazole<br>* 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 (1 tablet) for 6 days (with food)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants whose treatment outcome at Month 18 is a success | Treatment outcome at Month 18 is categorised 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. | Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants whose treatment outcome at Month 12 is a success | Treatment outcome at Month 12 is categorised 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. | Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months) | 
| Occurrence of grade ≥ 3 adverse events (AEs) including laboratory and haematological abnormalities (if considered clinically significant) | Occurrence is presented as the number of participants with any AE of grade ≥ 3. 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. 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. | 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 | 
| Occurrence of any serious adverse event (SAE) | Occurrence is presented as the number of participants with any SAE. | Between the first intake of fexinidazole (Day 1) and the end of the follow-up period (18 months) | 
| Occurrence of temporary or permanent treatment discontinuation (inpatient or outpatient) for reasons related to safety | Number of patients who prematurely discontinued treatment (temporarily or permanently) for reasons related to safety (including overdose). | Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred) | 
| Occurrence of hospitalization (outpatient only) for reasons related to safety | 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. | Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred) | 
| Occurrence of permanent treatment discontinuation (inpatient or outpatient) for reasons related to safety | Number of patients who prematurely discontinued treatment permanently for reasons related to safety (including overdose). | Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred) | 
| Pharmacokinetic measure to assess patient compliance | Number of outpatients with a concentration of fexinidazole sulfone (M2, one of the metabolite of fexinidazole) in dried blood spot higher than 10 µg/mL at Day 11 (24 hours after last fexinidazole administration on Day 10). Concentrations of M2 are determined using a validated analytical method. | End-of-treatment visit (Day 11, 24 hours after last treatment administration) | 
| Outpatients compliance to the full course of the 10-day treatment | 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 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. | Between the first intake (Day 1) and last intake of fexinidazole (Day 10, or Day 11 if re-administration occurred) | 
| Outpatients compliance to 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 | 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) | End-of-treatment visit (Day 11) | 
| Feasibility of self-management of treatment intake in outpatients: occurrence of temporary treatment discontinuation | 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. | End-of-treatment visit (Day 11) | 
| Feasibility of self-management of treatment intake in outpatients: occurrence of permanent treatment discontinuation | 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. | End-of-treatment visit (Day 11) | 
| Feasibility of self-management of treatment intake in outpatients: delayed treatment start | 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. | End-of-treatment visit (Day 11) | 
| Feasibility of self-management of treatment intake in outpatients: hospitalization during the treatment period due to non-compliance | 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 hospitalisation. Occurrence of hospitalization is presented as the number of outpatients who had to be hospitalized during the treatment period due to non-compliance. | End-of-treatment visit (Day 11) | 
| 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 asks the participant and caregiver 8 questions about posology. To each of these 8 questions, the study personnel ticks '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. | Before treatment (Day 0) | 
| 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 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?). | End-of-treatment visit (Day 11) | 
| Acceptability of packaging in outpatients: instructions found helpful | Acceptability of packaging is assessed at Day 11 (end-of-treatment visit) by a questionnaire filled out by the participant and 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?). | End-of-treatment visit (Day 11) | 
| Whole blood concentration of fexinidazole from dry blood spot, measured 24 hours after the last dose of fexinidazole | Concentrations of fexinidazole is determined using a validated analytical method, in all patients with available PK data. | End-of-treatment visit (Day 11, 24 hours after last treatment administration) | 
| Whole blood concentration of fexinidazole metabolite M1 from dry blood spot, measured 24 hours after the last dose of fexinidazole | Concentrations of fexinidazole metabolite M1 (fexinidazole sulfoxide) is determined using a validated analytical method, in all patients with available PK data. | End-of-treatment visit (Day 11, 24 hours after last treatment administration) | 
| Whole blood concentration of fexinidazole metabolite M2 from dry blood spot, measured 24 hours after the last dose of fexinidazole | Concentrations of fexinidazole metabolite M2 (fexinidazole sulfone) is determined using a validated analytical method, in all patients with available PK data. | End-of-treatment visit (Day 11, 24 hours after last treatment administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T.b gambiense, HAT, outpatients