A Pharmacokinetic and Tolerability Study of Fexinidazole in a Single Oral Dose in Adult Participants With Mild and Moderate Hepatic Impairment

Study Overview
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Brief Summary
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In human, metabolic hepatic clearance represents a significant part of the total clearance of fexinidazole and could be decreased in patients with liver impairment, leading to some overexposure, and conversely, the formation of the 2 active metabolites could be decreased, leading to decreased exposure in hepatic impairment (HI). As there is no experience of use in patients with hepatic impairment, in fexinidazole summary of product characteristics (SmPC) approved by the European Medicines Agency (EMA), fexinidazole is contra-indicated in patients with clinical signs of cirrhosis or jaundice, and in the proposed USA product information, fexinidazole is contra-indicated in patients with liver impairment. Therefore, FDA requested a study with the objective to evaluate the effect of mild and moderate hepatic impairment (HI) on the pharmacokinetics (PK) of fexinidazole and its 2 metabolites, as a post-marketing requirement.

Detailed Description
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The duration of the study for 1 participant will be of 38 days maximum, including: A screening period from Day (D)-28 to D-2 Baseline assessments on D-1 Single dose administration on D1 and institutionalization for 6 days End of study (EOS): D10, or to be organized as soon as possible in case of early withdrawal

Official Title
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A Multicentric, Open-label, Non-randomized, Pharmacokinetic and Tolerability Study of Fexinidazole Given as an Oral Single 1200 mg Dose in Participants With Mild and Moderate Hepatic Impairment, and in Matched Participants With Normal Hepatic Function

Conditions
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Hepatic Function Abnormal

Intervention / Treatment
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* Drug: Fexinidazole (HOE239)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants, between 18 and 75 years of age, inclusive 12-lead ECG without clinically significant abnormality, in the judgment of the Investigator; normal QT interval confirmed Contraception (with double contraception methods) for male and female (unless postmenopausal) participants; not pregnant or breastfeeding for female participants; no sperm donation for male participants. Having given written informed consent prior to any procedure related to the study Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research Not under any administrative or legal supervision Participants with HI Body weight between 50.0 and 125.0 kg, inclusive if male, and between 40.0 and 110.0 kg, inclusive if female, body mass index (BMI) between 18.00 and 34.99 kg/m2, inclusive Stable chronic liver disease assessed by medical history, physical examination, laboratory values Vital signs after 10 minutes resting in supine position within the following range [or if out of range, considered not clinically significant (NCS) by the Investigator]: 95 mmHg < systolic blood pressure (SBP) < 180 mmHg 45 mmHg < diastolic blood pressure (DBP) < 100 mmHg 40 bpm < HR < 100 bpm Laboratory parameters within the acceptable range for participants with HI; however, serum creatinine should be strictly below the upper laboratory normal For moderate HI cohort: Child-Pugh total score ranging from 7 to 9, inclusive For mild HI cohort: Child-Pugh total score ranging from 5 to 6, inclusive Matched participants with normal hepatic function Body weight within 15% of the mean body weight of the participants with HI to be matched, and BMI between 18.00 and 34.99 kg/m2, inclusive Certified as healthy by a comprehensive clinical assessment Vital signs after 10 minutes resting in the supine position within the following range: 95 mmHg < SBP < 160 mmHg 45 mmHg < DBP < 90 mmHg 40 bpm < HR < 100 bpm Laboratory parameters within the normal range, excluding specific exceptions allowed per protocol. Exclusion Criteria: Participant has clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, loss of taste and smell, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening. Participant who had severe course of COVID-19 Positive test for SARS-CoV-2 Blood donation within 2 months before inclusion Postural hypotension - symptomatic or asymptomatic (decrease in SBP ≥ 30 mmHg within 3 minutes). Excessive consumption of beverages with xanthine bases COVID-19 vaccination: last administration of a vaccine within 1 week (symptom free) to 2 weeks before inclusion Any participant who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental development Any participant in the exclusion period of a previous study according to applicable regulations Any participant who cannot be contacted in case of emergency Positive alcohol breath test Any consumption of citrus fruits or their juices within 5 days before inclusion Unable or not agreeing to self-complete the hospital anxiety and depression scale (HADS) Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. Positive result on anti-human immunodeficiency virus 1 and/or 2 antibodies Cockayne Syndrome Participants with HI Uncontrolled clinically relevant cardiovascular, pulmonary, gastrointestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illness Hepatocarcinoma Acute hepatitis Hepatic encephalopathy grade 2, 3, and 4 Presence or history of drug hypersensitivity, or allergic disease, including active seasonal rhinitis, diagnosed and treated by a physician History or presence of regular use of recreational drugs or alcohol abuse within 2 years before inclusion Smoking more than 15 cigarettes or equivalent per day, unable to refrain from smoking over 5 cigarettes per day from D-1 and throughout the entire institutionalization Any significant change in chronic treatment medication within 14 days before inclusion Consumption of CYP450 potent inducers or inhibitors that could impact the pharmacokinetics of the investigational product Positive results on urine drug screen outside documented medical prescription Pre-existing cardiac disease, long QT syndrome, or use of drugs known to block potassium channels, prolong the QT interval and/or induce bradycardia Matched participants with normal hepatic function Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illness Frequent headaches and/or migraine, recurrent nausea and/or vomiting Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician, except seasonal rhinitis History or presence of regular use of recreational drugs or alcohol abuse Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking from D-1 and throughout the entire institutionalization Any medication (including CYP450 inducers or inhibitors, or omeprazole) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic (PD) half-life of the medication (except HRT and contraception when applicable), any vaccination within the last 28 days (except COVID-19 vaccination) and any biologics (antibody or its derivatives) given within 4 months before inclusion Positive result on any of the following tests: hepatitis B surface antigen, antihepatitis B core antibodies, anti-hepatitis C virus antibodies Positive result on urine drug screen The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants with mild HI<br>Mild HI is defined as a total score ranging from 5 to 6, inclusive (Child-Pugh score A) | Drug: Fexinidazole (HOE239)<br>* Route of administration: oral; pharmaceutical form: tablet<br>* Other names: Fexinidazole Winthrop®;|
| Experimental: Participants with moderate HI<br>Moderate HI is defined as a total score ranging from 7 to 9, inclusive (Child-Pugh score B) | Drug: Fexinidazole (HOE239)<br>* Route of administration: oral; pharmaceutical form: tablet<br>* Other names: Fexinidazole Winthrop®;|
| Experimental: Participants with normal hepatic function<br>Participants with normal hepatic function matched to participants | Drug: Fexinidazole (HOE239)<br>* Route of administration: oral; pharmaceutical form: tablet<br>* Other names: Fexinidazole Winthrop®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax for fexinidazole and metabolites M1, M2 | Maximum plasma concentration observed (Cmax) | Day 1 to Day 6 | 
| AUC for fexinidazole and metabolites M1, M2 | Area under the plasma concentration versus time curve extrapolated to infinity (AUC) | Day 1 to Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tmax for fexinidazole and metabolites M1, M2 | Time to reach Cmax (tmax) | Day 1 to Day 6 | 
| Fexinidazole unbound fraction |  | Day 1 and Day 2 | 
| Fexinidazole unbound Cmaxu | Unbound maximum plasma concentration observed (Cmaxu) | Day 1 and Day 6 | 
| Fexinidazole unbound AUCu | Unbound area under the plasma concentration versus time curve extrapolated to infinity | Day 1 and Day 6 | 
| Number of subjects with Adverse Events (AEs) |  | Day 1 to Day 10 |