OXA004: Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Subjects

Sponsor

Drugs for Neglected Diseases (Other)

Overall Status

Recruiting

CT.gov ID

NCT05256017

Collaborator

(none)

1,200

Enrollment

Locations

Arms

Anticipated Duration (Months)

300

Patients Per Site

18.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Trypanosomiasis, African Trypanosoma Brucei Gambiense; Infection Sleeping Sickness	Drug: Acoziborole Drug: Placebo	Phase 2/Phase 3

Detailed Description

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.

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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)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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 30, 2021

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Acoziborole Single dose administration of 3 tablets of 320 mg	Drug: Acoziborole Acoziborole tablets
Placebo Comparator: Placebo Single dose administration of 3 tablets of 320 mg	Drug: Placebo matching placebo of acoziborole tablets

Arm

Intervention/Treatment

Active Comparator: Acoziborole

Single dose administration of 3 tablets of 320 mg

Drug: Acoziborole

Acoziborole tablets

Placebo Comparator: Placebo

Single dose administration of 3 tablets of 320 mg

Drug: Placebo

matching placebo of acoziborole tablets

Outcome Measures

Primary Outcome Measures

Occurrence of treatment-emergent adverse events (TEAEs) [From Investigational Product administration to 4 months follow up visit (End of Study)]
Occurrence of any Treatment Emergent Adverse Event from investigational product administration to 4 month follow-up visit

Secondary Outcome Measures

Occurrence of adverse events (AEs) [From Inform Consent signature to 4 months follow up visit (End of Study)]
Occurrence of any Adverse Event from Inform Consent signature to 4 month follow-up visit
Change from baseline in biochemistry parameter: Alanine Aminotransferase [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Albumin [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Alkaline Phosphatase [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Aspartate Aminotransferase [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Calcium [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Chloride [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Creatinine [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Glucose [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Potassium [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Sodium [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Total Bilirubin [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Total Carbon Dioxide [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Total Protein [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in biochemistry parameter: Blood Urea Nitrogen [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in hematology parameter: hemoglobin [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in hematology parameter: Platelets [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in hematology parameter: white blood cells [From Inform Consent signature to 4 months follow up visit (End of Study)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: heart rate (HR) [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: RR interval [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: PR interval [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: QRS interval [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: QT interval [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Change from baseline in ECG (Electrocardiogram) parameter: QTc interval [From Inform Consent signature to Day 5 (end of Hospitalization)]
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.
Blood concentration of acoziborole at Day 5 and Month 1 [Day 5 and 1 month follow-up visit]
Concentration of acoziborole in whole blood at Day 5 and Month 1
Correlation between ΔQTc measurements and acoziborole concentrations in blood at Day 5 [Day 5]

Other Outcome Measures

Exploratory outcome: occurrence of dermatitis and/or pruritus [From Inform Consent signature to 4 months follow up visit (End of Study)]
Exploratory outcome: occurrence of positive results on blood and skin samples analyzed by Immuno-Histochemistry (IHC), TBR- PCR and/or 18S-PCR [From Inform Consent signature to 4 months follow up visit (End of Study)]
Exploratory outcome: occurrence of positive results on blood and skin samples analyzed by qPCRs, multiplex qRT-PCRs and SHERLOCK (Specific High-sensitivity Enzymatic Reporter unlocking) [From Inform Consent signature to 4 months follow up visit (End of Study)]
Exploratory outcome: descriptive comparisons between groups and timepoints in occurrence of dermatitis, pruritus, positive results in skin and blood samples analyzed by IHC, qPCRs, multiplex qRT-PCRs and SHERLOCK [From Inform Consent signature to 4 months follow up visit (End of Study)]
Exploratory outcome: occurrence comparisons between all diagnostic methods alone or in combination [From Inform Consent signature to 4 months follow up visit (End of Study)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	Hospital of Dipumba	Mbuji-Mayi	Kasai-Oriental	Congo, The Democratic Republic of the
2	General Referral Hospital of Masi-Manimba	Masi-Manimba	Kwilu	Congo, The Democratic Republic of the
3	General Hospital of Bandundu	Bandundu		Congo, The Democratic Republic of the
4	General Referral Hospital of Dubreka	Dubréka	Dubreka	Guinea