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

HAT, or sleeping sickness, is a neglected tropical disease which is endemic in sub Saharan Africa. This vector-borne parasitic disease is transmitted by the bite of the tsetse fly and can be fatal without diagnosis and treatment. The parasites responsible for HAT are the protozoa T.b. gambiense and T.b. rhodesiense. In 2021-2022, HAT due to T.b. gambiense (g-HAT) represented 94% of all HAT cases detected.

Between 2018 and 2022, approximately 1.5 million people lived in areas (mainly rural areas of sub-Saharan Africa) considered to be at moderate to very high risk of HAT and where the disease is still considered as a public health problem. Thanks to efforts from national control programs, supported by the World Health Organization (WHO), non-governmental organizations, bilateral cooperations, the private sector (including pharmaceutical companies) and philanthropic organizations, the number of cases of g-HAT is consistently falling. With respectively 799 and 675 cases of g-HAT reported in 2022 and 2023, the global goal of sustainable disease elimination by 2030, including the interruption of g HAT transmission, is achievable. As the numbers of reported cases diminish, resources for surveillance and specialized screening also taper. This decrease, coupled with the loss of diagnostic skills and disease management expertise, could lead to a weak and less specialized HAT technical environment.

Several therapeutic options are currently available to treat g-HAT at either the hemolymphatic (early) stage or meningoencephalitic (late) stage. In December 2018, fexinidazole was registered for the treatment of g-HAT in DRC. Since then, all other endemic countries authorized the use of fexinidazole for the treatment of g-HAT. Fexinidazole is administered as a 10 day oral treatment to patients with early- or late-stage g-HAT. In patients with very advanced g-HAT, nifurtimox eflornithine combination therapy (NECT) remains the first line treatment, due to the increased risk of relapse in these patients when treated with fexinidazole. Children with g-HAT who have a body weight below 20 kg and/or are under 6 years of age are treated with pentamidine (early stage) or NECT (late stage). Pentamidine and NECT are administered as intravenous (IV) infusions performed daily, over 7 days.

Whilst the delivery of fexinidazole has simplified the management of g-HAT and has facilitated the integration of g-HAT treatment into general health systems, it is expected that the current investment in acoziborole as an oral, single-dose treatment will help boost elimination efforts envisioned for all stages of g-HAT. Indeed, treatment with NECT and fexinidazole are conditioned by the demonstration of the parasite in any body fluid via microscopy. However, factors such as low parasitemia as well as the complexity of parasitological diagnostic methods make this demonstration difficult.

Acoziborole, as a single-dose oral administration, was studied in the open-label pivotal Phase II/III study (DNDi-OXA-02-HAT). The study was conducted in patients with g-HAT (all stages) in the DRC and Guinea. The results of the study showed the high efficacy of acoziborole in any stage of g-HAT, which was comparable to the efficacy of the reference treatment NECT used as a yardstick. Safety data collected during this study did not identify any new safety signals. Based on these data, the benefit-risk balance for treating g-HAT patients (regardless of the disease stage) with acoziborole administered as a single oral dose of 960 mg appeared favorable.

The present study (DNDi-OXA-04-HAT) was conducted in g-HAT seropositive individuals who were unconfirmed parasitologically. It was designed with the objective of assessing the safety and tolerability of a single 960-mg dose of acoziborole compared with placebo during a follow-up period of 4 months.

This study included an exploratory Sub-Study named "TrypSkin" which had the main objective of assessing the presence of extravascular dermal T.b. gambiense in the enrolled population. Participation in this Sub-Study was optional.

• Acoziborole (Drug): Single dose administration of acoziborole (3 tablets of 320 mg) on Day 1
• Placebo (Drug): Single dose administration of placebo (3 tablets of 320 mg) on Day 1

Primary outcomes

• Occurrence of Any TEAEs [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of any TEAEs.
• Occurrence of TEAEs - Malaria [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Acarodermatitis [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Abdominal Pain [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Enteritis [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Nausea [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Gastritis [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Headache [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Fatigue [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs - Blood Potassium Increased [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of common TEAEs (by PT, for PTs reported in ≥1% of participants in either arm).
• Occurrence of TEAEs by Period of Occurrence [During hospitalization: from investigational product administration (Day 1) to Day 5 (End of Hospitalization); After hospitalization: from Day 5 (discharge) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of any TEAEs, by period of occurrence.
• Occurrence of Serious TEAEs [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of any serious TEAEs.
• Occurrence of Severe Treatment-related TEAEs [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence and excess rate (95% CI) of any serious TEAEs.
• Occurrence of Any Treatment-related TEAEs [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence of any treatment-related TEAEs by arm
• Occurrence of Treatment-related TEAEs by PT [From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).]: Occurrence of any treatment-related TEAEs by PT and by arm

Secondary outcomes

• Occurrence of Adverse Events (AEs) [From Inform Consent signature (up to 2 days before treatment) to the Month 4 follow up visit (End of Study)]: Occurrence of any Adverse Event from Inform Consent signature to 4 month follow-up visit. Of note, all AEs reported during this study were TEAEs.
• Change From Baseline in Biochemistry Parameter: Alanine Aminotransferase [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Albumin [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Aspartate Aminotransferase [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Calcium [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Chloride [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Creatinine [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Glucose [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Potassium [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Sodium [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Total Bilirubin [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Bicarbonate [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Total Protein [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Biochemistry Parameter: Blood Urea Nitrogen [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Hematology Parameter: Hemoglobin [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Hematology Parameter: Platelet Count [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in Hematology Parameter: Leukocytes [From baseline to the Month 4 follow-up visit (End of Study).]: Changes from baseline to Day 5, Month 1 and Month 4; presented by treatment arm.
• Change From Baseline in ECG (Electrocardiogram) Parameter: Heart Rate (HR) [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an analysis of covariance (ANCOVA) model adjusted for sex and age.
• Change From Baseline in ECG Parameter: RR Interval [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusted for sex and age.
• Change From Baseline in ECG Parameter: PR Interval [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusted for sex and age.
• Change From Baseline in ECG Parameter: QRS Interval [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusting for sex and age.
• Change From Baseline in ECG Parameter: QT Interval [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusted for sex and age.
• Change From Baseline in ECG Parameter: QTcF [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusted for sex and age.
• Change From Baseline in ECG Parameter: QTcB [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Actual values at baseline (Day 1 pre-dose) and Day 5. Change from baseline at Day 5 (Δ). Placebo-corrected change from baseline (ΔΔ), calculated using an ANCOVA model adjusted for sex and age.
• Placebo-corrected Baseline-adjusted QTcF (ΔΔQTcF), Computed From a Concentration-response (C-R) Model Between Dry Blood Spot Concentration and Changes From Baseline in QTcF Parameter [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Mixed linear model developed based on the model defined by Garnett et al (2017). The fixed effect parameters of the pre-specified model were intercept, slope for acoziborole concentrations, influence of baseline (centered on mean), and a treatment specific intercept (0=acoziborole, 1=Placebo). Sex and age were included in the model as fixed covariates.
• Incidence of Abnormal Values for PR, QRS, QTcB and QTcF According to Pre-defined Thresholds [From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)]: Incidence of abnormal values for PR, QRS, QTcB and QTcF at Day 1 and/or Day 5, according to pre-defined thresholds

Sex: All, ages: 15 Years to any

Inclusion Criteria:

* Signed the informed consent form (ICF)
* Male or female
* 15 years of age or older
* Card agglutination test for trypanosomiasis (CATT) test or HAT sero-K-set rapid diagnostic test (RDT) positive
* Parasitology negative (in blood and/or lymph node aspirate \[if lymphadenopathy is present\])
* Karnofsky performance status above 70
* Able to ingest oral tablets
* Known address and/or contact details provided
* Able to comply with the schedule of follow-up visits and other requirements of the study
* Agreement to be hospitalized 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:

  * Agreed to have protected sexual relations to avoid becoming pregnant from enrolment up to 3 months after dosing (contraceptive protection was advised and offered at no cost)
  * Negative urine pregnancy tests (before dosing at site level)

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/m\^2
* Pregnant or breast-feeding women
* For women of childbearing potential:

  * Urine pregnancy test positive
  * Did not accept contraceptive protection (i.e. condom or sexual abstinence) 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, jeopardize the participant'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 mellitus
* Known hemophilia

Participant flow

Outcome results

• Occurrence of Any TEAEs (Primary), Count of participants, Participants: Acoziborole 195; Placebo 69
• Occurrence of TEAEs - Malaria (Primary), Count of participants, Participants: Acoziborole 34; Placebo 14
• Occurrence of TEAEs - Acarodermatitis (Primary), Count of participants, Participants: Acoziborole 13; Placebo 3
• Occurrence of TEAEs - Abdominal Pain (Primary), Count of participants, Participants: Acoziborole 23; Placebo 9
• Occurrence of TEAEs - Enteritis (Primary), Count of participants, Participants: Acoziborole 7; Placebo 4
• Occurrence of TEAEs - Nausea (Primary), Count of participants, Participants: Acoziborole 7; Placebo 3
• Occurrence of TEAEs - Gastritis (Primary), Count of participants, Participants: Acoziborole 6; Placebo 3
• Occurrence of TEAEs - Headache (Primary), Count of participants, Participants: Acoziborole 53; Placebo 8
• Occurrence of TEAEs - Fatigue (Primary), Count of participants, Participants: Acoziborole 14; Placebo 5
• Occurrence of TEAEs - Blood Potassium Increased (Primary), Count of participants, Participants: Acoziborole 8; Placebo 6
• Occurrence of TEAEs by Period of Occurrence (Primary), Number, participants: Acoziborole 124; Placebo 38
• Occurrence of Serious TEAEs (Primary), Count of participants, Participants: Acoziborole 3; Placebo 4
• Occurrence of Adverse Events (AEs) (Secondary), Count of participants, Participants: Acoziborole 195; Placebo 69
• Change From Baseline in Biochemistry Parameter: Alanine Aminotransferase (Secondary), Mean, U/L: Acoziborole 20.6 +/- 7.90; Placebo 20.6 +/- 9.44
• Change From Baseline in Biochemistry Parameter: Albumin (Secondary), Mean, g/dL: Acoziborole 3.22 +/- 0.471; Placebo 3.23 +/- 0.433
• Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase (Secondary), Mean, U/L: Acoziborole 99.8 +/- 46.71; Placebo 101.8 +/- 52.59
• Change From Baseline in Biochemistry Parameter: Aspartate Aminotransferase (Secondary), Mean, U/L: Acoziborole 32.8 +/- 10.20; Placebo 32.7 +/- 12.41
• Change From Baseline in Biochemistry Parameter: Calcium (Secondary), Mean, mmol/L: Acoziborole 2.314 +/- 0.1341; Placebo 2.322 +/- 0.1216
• Change From Baseline in Biochemistry Parameter: Chloride (Secondary), Mean, mmol/L: Acoziborole 105.3 +/- 3.05; Placebo 105.3 +/- 2.74
• Change From Baseline in Biochemistry Parameter: Creatinine (Secondary), Mean, mg/dL: Acoziborole 0.84 +/- 0.238; Placebo 0.84 +/- 0.230
• 22 more outcome measures not shown.

Adverse events

Time frame: From ICF signature (up to 2 days prior treatment) to Month 4 (end of follow-up)

Serious adverse events by term

Other adverse events by term

Limitations and caveats: No limitations or caveats were identified.

• Study Protocol (PDF, 2023-06-13)
• Statistical Analysis Plan (PDF, 2024-02-09)

• Victor Kande Betu Kumeso, Dr., Principal investigator, Ministry of Public Health, Hygiene and Prevention, Kinshasa