Efficacy and Safety of Acoziborole (SCYX-7158) in Patients With Human African Trypanosomiasis Due to T.b. Gambiense

Phase 2

Completed

Conditions: Trypanosomiasis, African
Gambiense Trypanosomiasis
Sleeping Sickness

Interventions: Drug: Acoziborole

Registration Number: NCT03087955

Lead Sponsor: Drugs for Neglected Diseases

Brief Summary: The goal of this study is to assess efficacy and safety of acoziborole in adult participants with Trypanosoma brucei gambiense (T.b. gambiense) HAT, either early- or intermediate-stage HAT (first arm) or late-stage HAT (second arm). Participants will receive 3 tablets of 320 mg as a single oral dose of acoziborole in the fasting state on Day 1. Participants will stay in the hospital for observation for 15 days. In total, participants will be followed for 18 months.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 208

Inclusion Criteria

Male or female patient
15 years of age or older
Signed informed consent form (as well as assent from illiterate and under-age patients, and those unable to give consent)
Karnofsky Performance Status above 50
Able to ingest oral tablets
Having a permanent address or being traceable by other persons
Able to comply with the schedule of follow-up visits and requirements of the study
Agreement to be hospitalised in order to receive treatment
For patients with late-stage HAT:
- Confirmation of g-HAT by detection of the parasite in the blood and/or the lymph and/or the CSF, at the investigational centre
- If trypanosomes are found in the blood or lymph, but not in the CSF, the CSF WBC, measured at the investigational centre, must be above 20/μL for the patient to be included in the cohort of patients with late-stage HAT
For patients with early- or intermediate-stage HAT:
- Confirmation of g-HAT by detection of the parasite in the blood and/or the lymph, at the investigational centre
- Absence of parasites in the CSF
- The CSF WBC, measured at the investigational centre, must be between 6 and 20/μL for the patient to be included in the cohort of patients with intermediate-stage HAT and equal to or below 5/μL for the patient to be included in the cohort of patients with early-stage HAT.

Exclusion Criteria

Severe malnourishment, defined as body-mass index (BMI) below 16
Pregnancy or breastfeeding (for women of child-bearing potential, confirmed pregnancy on a urine pregnancy test performed within 24 hours prior to administration of acoziborole)
Clinically significant medical condition that could, in the opinion of the Investigator, jeopardise the patient's safety or interfere with participation in the study, including, but not limited to significant liver or cardiovascular disease, suspected or proven active infection, central nervous system trauma or seizure disorder, coma or consciousness disturbances
Severely deteriorated health status, e.g. due to cardiovascular shock, respiratory distress syndrome or end-stage disease
Previously treated for HAT (except prior treatment with pentamidine)
Prior enrolment in the study
Foreseeable difficulty complying with follow-up, including migrant worker, refugee status, itinerant trader etc.
Current alcohol abuse or drug addiction
Not tested for malaria and/or not having received appropriate treatment for malaria
Not having received appropriate treatment for soil-transmitted helminthiasis
Clinically significant abnormal laboratory values including aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN), total bilirubin more than 1.5 ULN, severe leukopenia at less than 2000/mm^3, Potassium below 3.5 mmol/L, any other clinically significant abnormal laboratory value

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Late-stage HAT	Acoziborole	Participants with confirmation of HAT by detection of the parasite in the blood and/or lymph and/or cerebrospinal fluid (CSF) at the investigational center. If testing for parasites in CSF was negative, the CSF white blood cell count, measured at the investigational center, had to be above 20 cells/µL for classification as late-stage HAT. Participants received 960 mg acoziborole as a single oral dose.
Early- and intermediate-stage HAT	Acoziborole	Participants with confirmation of HAT by detection of the parasite in the blood and/or lymph at the investigational center. Parasites had to be absent from the CSF. The CSF white blood cell count, measured at the investigational center, had to be between 6 and 20 cells/µL for classification as intermediate stage HAT and equal to or below 5 cells/µL for classification as early-stage HAT. Participants received 960 mg acoziborole as a single oral dose.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Late-stage HAT Whose Treatment Outcome Was a Success at Month 18 According to Adapted World Health Organization (WHO) Criteria	18 months post-dose	Success was defined according to an algorithm based on the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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. An estimate of the percentage of participants whose treatment outcome was a success at Month 18 and the 95% Jeffreys confidence interval (CI) of the estimate were provided.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Late-stage HAT Whose Treatment Outcome Was a Success at Month 12 According to Adapted WHO Criteria	12 months post-dose	Success was defined according to an algorithm based on the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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 end of Month 12, an unfavorable outcome earlier than end of Month 12, or signs and symptoms evoking a relapse at end of Month 12. For participants who continued after Month 12, data after Month 12 were considered in the algorithm. An estimate of the percentage of participants whose treatment outcome was a success at Month 12 and the 95% Jeffreys CI of the estimate were provided.
Percentage of Participants With Late-stage HAT Whose Treatment Outcome Was a Success at Month 6 According to Adapted WHO Criteria	6 months post-dose	Success was defined according to an algorithm based on to the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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 end of Month 6, an unfavorable outcome earlier than end of Month 6, or signs and symptoms evoking a relapse at end of Month 6. For participants who continued after Month 6, data after Month 6 were considered in the algorithm. An estimate of the percentage of participants whose treatment outcome was a success at Month 6 and the 95% Jeffreys CI of the estimate were provided.
Percentage of Participants With Early- and Intermediate-stage HAT Whose Treatment Outcome Was a Success at Month 18 According to Adapted WHO Criteria	18 months post-dose	Success was defined according to an algorithm based on the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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 end of Month 18, an unfavorable outcome earlier than end of Month 18, or signs and symptoms evoking a relapse at end of Month 18. An estimate of the percentage of participants whose treatment outcome was a success at Month 18 and the 95% Jeffreys CI of the estimate were provided.
Percentage of Participants With Early- and Intermediate-stage HAT Whose Treatment Outcome Was a Success at Month 12 According to Adapted WHO Criteria	12 months post-dose	Success was defined according to an algorithm based on the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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 end of Month 12, an unfavorable outcome earlier than end of Month 12, or signs and symptoms evoking a relapse at end of Month 12. For participants who continued after Month 12, data after Month 12 were considered in the algorithm. An estimate of the percentage of participants whose treatment outcome was a success at Month 12 and the 95% Jeffreys CI of the estimate were provided.
Percentage of Participants With Early- and Intermediate-stage HAT Whose Treatment Outcome Was a Success at Month 6 According to Adapted WHO Criteria	6 months post-dose	Success was defined according to an algorithm based on the criteria adapted from the WHO Recommendations of the Informal Consultation on Issues for Clinical Product Development for Human African Trypanosomiasis 2007 (WHO/CDS/NTD/IDM/2007.1). Success was defined as a cure or a probable cure. Failure was 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 end of Month 6, an unfavorable outcome earlier than end of Month 6, or signs and symptoms evoking a relapse at end of Month 6. For participants who continued after Month 6, data after Month 6 were considered in the algorithm. An estimate of the percentage of participants whose treatment outcome was a success at Month 6 and the 95% Jeffreys CI of the estimate were provided.
Estimated Percentage of Participants With Late-stage HAT Whose Treatment Outcome Was Not a Proven Failure at Month 18, Based on the Kaplan-Meier Analysis of Time to Proven and Definitive Failure	18 months post-dose	Failure was defined as the first objective evidence of proven and definitive (sustainable) failure, defined as death; rescue medication use; trypanosomes in any body fluid at Month 6, 12, or 18; a cerebrospinal fluid (CSF) white blood cell count (WBC) of \>50 cells/μL at Month 6 followed by confirmation of failure (defined as CSF WBC \>20 cells/μL at Month 12 and/or Month 18 and/or signs and symptoms evoking a relapse at Month 12 and/or Month 18); a CSF WBC \>20 cells/μL at Month 12 followed by confirmation of failure (defined as CSF WBC \>20 cells/μL at Month 18 and/or signs and symptoms evoking a relapse at Month 18); or a CSF WBC \>20 cells/μL at Month 18. This outcome was analyzed using a Kaplan-Meier approach to estimate the cumulative rate of proven and definitive failures. The proven failure-free probability was estimated as an alternative (more liberal) success rate (95% CI) at Month 18 based on the Kaplan-Meier estimate of the rate of participants who were not proven failures
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From the single dose acoziborole administration until 6 months post-dose for non-serious AEs and 18 months post-dose for serious AEs	Occurrence of any AEs, during the observation period and until 6 months post-dose (for non-serious AEs) and until 18 months post-dose for SAEs. Analysis of AEs was based on the concept of TEAEs, defined as any AEs occurring on or after the date of study-drug administration or worsening in intensity on or after the date of study-drug administration.
Number of Participants With Serious TEAEs	From the single dose acoziborole administration until 18 months post-dose	Occurrence of any serious TEAEs during the observation period and until 18 months post-dose.
Acoziborole Area Under the Curve From Time Zero to 240 Hours Post Dose (AUC0-240h) in Whole Blood Considering Concentration-time Data up to 240 Hours After a Single Administration	Pre-dose and 4, 9, 24, 48, 72, 96, and 240 hours post-dose	Participants received a single dose of 960 mg acoziborole on Day 1. Acoziborole in whole blood was assessed pre-dose and 4, 9, 24, 48, 72, 96, and 240 hours after the single administration, (on Days 1, 2, 3, 4, 5, and 11). Data up to 240 hours post dose were considered for this analysis. Descriptive statistics of the AUC0-240h were presented. The activity of acoziborole is more exposure-dependent than concentration-dependent, therefore the exposure (AUC) was used as the main PK data for efficacy purposes.
Mean Acoziborole Concentration in CSF After 240 Hours in Participants With Late-stage HAT	240 hours post-dose	Participants received a single dose of 960 mg acoziborole on Day 1. Acoziborole in CSF of participants with late-stage HAT was assessed 240 hours after the single administration (on Day 11). Descriptive statistics of the acoziborole concentration were presented.
Mean Acoziborole Concentration in CSF After 240 Hours in Participants With Early- and Intermediate-stage HAT	240 hours post-dose	Participants received a single dose of 960 mg acoziborole on Day 1. Acoziborole in CSF of participants with early- and intermediate-stage HAT was assessed 240 hours after the single administration (on Day 11). Descriptive statistics of the acoziborole concentration were presented.

Trial Locations

Locations (12): Centre de Traitement de Nkara
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Nkara, Bandundu, Democratic Republic of the Congo
Centre de Traitement de Kimpese
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Kimpese, Bas-Congo Province, Democratic Republic of the Congo
Hôpital Général de Référence de Ngandajika
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Gandajika, East Kasai, Democratic Republic of the Congo
Hôpital Secondaire de Katanda
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Katanda, East Kasai, Democratic Republic of the Congo
Hôpital de Dipumba
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Mbuji-Mayi, East Kasai, Democratic Republic of the Congo
Hôpital Général de Référence de Bagata
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Bagata, Kwilu, Democratic Republic of the Congo
Hôpital Général de Référence de Masi-Manimba
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Masi-Manimba, Kwilu, Democratic Republic of the Congo
Hôpital Général de Référence de Kwamouth
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Kwamouth, Mai Ndombe, Democratic Republic of the Congo
Hopital Général de Réference de Bandundu
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Bandundu Province, Democratic Republic of the Congo
Hôpital de Référence d'Isangi
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Isangi, Democratic Republic of the Congo
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Centre de Traitement de Nkara
🇨🇩Nkara, Bandundu, Democratic Republic of the Congo