Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Subjects

Study Overview
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Brief Summary
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Acoziborole as an oral, single-dose treatment was studied in an open-label pivotal Phase II/III trial (DNDi-OXA-02-HAT) in DRC and Guinea. The safety and efficacy results on g-HAT confirmed cases (all disease stages) from the pivotal study provided data, that allows to envision the treatment of confirmed g-HAT cases but there is still a gap in the management of g-HAT seropositive non-parasitologically confirmed individuals. Indeed, the standard g-HAT case definition implies the demonstration of the parasite in any body fluid via microscopy. However, there are factors such as low parasitaemia and the complexity and low sensitivity of parasitological methods that make such demonstration difficult. It has been demonstrated that a variable proportion (mainly depending on the prevalence) of such g-HAT sero-suspects are confirmed cases and, therefore, remaining as potential reservoirs of the parasite and a source of new infections hindering the efforts to eliminate the disease. The present clinical trial intends to expand the safety data of acoziborole and complement the safety profile obtained from the pivotal trial by assessing the safety and tolerability of a single dose of acoziborole compared with placebo in seropositive individuals who are not confirmed parasitologically. In addition to this study, an exploratory sub-study named 'TrypSkin' is planned to assess the presence of extravascular dermal T.b. gambiense in the population enrolled.

Detailed Description
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HAT is a neglected tropical disease, transmitted by the bite of a tsetse fly, affecting sub-Saharan African countries. Without prompt diagnosis and treatment, it is usually fatal, as the parasites responsible for HAT (Trypanosoma brucei gambiense [T.b. gambiense or g-HAT] or Trypanosoma brucei rhodesiense [T.b. rhodesiense]) invade the central nervous system (late stage of the disease) causing neurological changes which include among other symptoms sleep disorder, aggression, sensory disturbances, psychosis, seizures, coma, and ultimately death. Eight and a half million people, living mainly in rural parts of East, West, and Central Africa, are situated in areas where g-HAT is still considered a public health problem. Whereas, fifty-three million people are estimated to be at risk of infection on the African continent. Few therapeutic options are currently available to treat g-HAT at either the haemolymphatic (early) stage or meningoencephalitic (late) stage. When early stage g-HAT is diagnosed, patients can be treated in their villages with intramuscular injections of pentamidine for 7 days. In patients with late-stage g-HAT, nifurtimox-eflornithine combination therapy (NECT), a combination of oral nifurtimox for 10 days plus eflornithine, two 2-hour intravenous (IV) infusions daily for 7 days, was found to provide similar cure rates to the standard regimen with eflornithine for 14 days, but with obvious practical advantages, including ease of administration and a shorter duration of treatment. In December 2018, Fexinidazole was approved for the treatment of g-HAT in the Democratic Republic of Congo (DRC), which is an effective 10-day oral treatment, able to cure early and late stage patients, although an increased risk of relapse on very advanced patients keeps NECT as first line treatment for patients showing more than 100 white blood cells (WBC)/µL of cerebrospinal fluid on diagnosis. Whilst the delivery of fexinidazole has improved the management of g-HAT cases and facilitates the integration of HAT treatment into the general health system, Acoziborole (studied in an open-label pivotal Phase II/III trial) as an oral, single-dose treatment envisioned for all stages of g-HAT is expected to improve further the management of g-HAT cases. However, there is still a gap in the management of g-HAT seropositive non-parasitologically confirmed individuals. Indeed, the standard g-HAT case definition implies the demonstration of the parasite in any body fluid via microscopy. But, there are factors such as low parasitaemia and the complexity and low sensitivity of parasitological methods that make such demonstration difficult. It has been demonstrated that a variable proportion (mainly depending on the prevalence) of such g-HAT sero-suspects are confirmed cases and, therefore, remaining as potential reservoirs of the parasite and a source of new infections hindering the efforts to eliminate the disease. The present clinical trial intends to expand the safety data of acoziborole and complement the safety profile obtained from the pivotal trial by assessing the safety and tolerability of a single dose of acoziborole compared with placebo in seropositive individuals who are not confirmed parasitologically. In addition to this study, an exploratory sub-study named 'TrypSkin' is planned to assess the presence of extravascular dermal T.b. gambiense in the population enrolled. Indeed, in an observational cohort study conducted in Guinea, the presence of extravascular dermal trypanosomes has been observed in individuals presenting with CATT positive results in plasma dilution ≥1:4 but not confirmed by parasitological examination of blood and lymph. If these dermal trypanosomes correspond to T.b. gambiense subspecies and are able to infect vectors, these individuals could act as reservoirs for the transmission of g-HAT, hampering the elimination goal.

Official Title
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Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Non-parasitologically Confirmed Subjects: a Multicentre Randomised Double-blind Placebo-controlled Study

Conditions
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Trypanosomiasis, African, Trypanosoma Brucei Gambiense; Infection, Sleeping Sickness

Intervention / Treatment
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* Drug: Acoziborole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed the informed consent form Male or female 15 years of age or older CATT test or HAT sero-K-set RDT positive Parasitology negative (in blood and/or lymph if lymphadenopathy is present) Karnofsky Performance Status above 70 Able to ingest oral tablets Known address and/or contact details provided Must be able to comply with the schedule of follow-up visits and other requirements of the study Agreement to be hospitalised upon enrolment for at least 5 days (in order to receive in-ward post-treatment observational follow-up through the first 5 days after treatment) Agreement to not take part in any other clinical trials during the participation in this study For women of childbearing potential: Must agree to have protected sexual relations to avoid becoming pregnant from enrolment up to 3 months after dosing Negative urine pregnancy tests Exclusion Criteria: Individuals parasitologically confirmed in blood and/or lymph Previously treated for g-HAT Severe malnutrition, defined as body mass index (BMI) <16 kg/m2 Pregnant or breast-feeding women For women of childbearing potential: Urine pregnancy test positive Do not accept contraceptive protection from enrolment up to 3 months after dosing Clinically significant medical condition and/or abnormal laboratory results that could, in the opinion of the Investigator, jeopardise the subject's safety or participation in the study Additional exclusion criteria for the TrypSkin exploratory sub-study: Rejection to participate in the exploratory sub-study in the signed ICF Known diabetes Known haemophilia

Ages Eligible for Study
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Minimum Age: 15 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 arms (acoziborole and placebo, ratio 3:1); 5 days post drug administration of hospitalization; follow-up visits at Month 1 and Month 4 (End of Study Visit)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acoziborole<br>Single dose administration of 3 tablets of 320 mg | Drug: Acoziborole<br>* Acoziborole tablets<br>|
| Placebo Comparator: Placebo<br>Single dose administration of 3 tablets of 320 mg | Drug: Placebo<br>* matching placebo of acoziborole tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of treatment-emergent adverse events (TEAEs) | Occurrence of any Treatment Emergent Adverse Event from investigational product administration to 4 month follow-up visit | From Investigational Product administration to 4 months follow up visit (End of Study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events (AEs) | Occurrence of any Adverse Event from Inform Consent signature to 4 month follow-up visit | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Alanine Aminotransferase | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Albumin | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Alkaline Phosphatase | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Aspartate Aminotransferase | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Calcium | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Chloride | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Creatinine | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Glucose | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Potassium | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Sodium | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Total Bilirubin | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Total Carbon Dioxide | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Total Protein | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in biochemistry parameter: Blood Urea Nitrogen | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in hematology parameter: hemoglobin | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in hematology parameter: Platelets | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in hematology parameter: white blood cells | Changes from baseline at D5, M1 and M4 will be will be presented by treatment group and summarized using mean, standard deviation, median, interquartile range (Q1-Q2) and range (minimum - maximum). Changes from baseline will also be presented as shift table expressed by % of subjects with low, normal or high value for each parameter and each timepoint. | From Inform Consent signature to 4 months follow up visit (End of Study) | 
| Change from baseline in ECG (Electrocardiogram) parameter: heart rate (HR) | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Change from baseline in ECG (Electrocardiogram) parameter: RR interval | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Change from baseline in ECG (Electrocardiogram) parameter: PR interval | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Change from baseline in ECG (Electrocardiogram) parameter: QRS interval | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Change from baseline in ECG (Electrocardiogram) parameter: QT interval | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Change from baseline in ECG (Electrocardiogram) parameter: QTc interval | change from baseline (Δ) at D5 will be summarized by treatment group and Placebo -corrected change from baseline (ΔΔ) will be calculated using an analysis of covariance model adjusting for sex and age. | From Inform Consent signature to Day 5 (end of Hospitalization) | 
| Blood concentration of acoziborole at Day 5 and Month 1 | Concentration of acoziborole in whole blood at Day 5 and Month 1 | Day 5 and 1 month follow-up visit | 
| Correlation between ΔQTc measurements and acoziborole concentrations in blood at Day 5 |  | Day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human African Trypanosomiasis, Trypanosoma Brucei Gambiense, Sleeping sickness, g-HAT, g-HAT seropositive individuals