Clinical trial NCT05256017: Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Subjects
Official title: Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Non-parasitologically Confirmed Subjects: a Multicentre Randomised Double-blind Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Trypanosomiasis, African
Trypanosoma Brucei Gambiense; Infection
Sleeping Sickness
Keywords: Human African Trypanosomiasis
Trypanosoma Brucei Gambiense
Sleeping sickness
g-HAT
g-HAT seropositive individuals
Lead sponsor: Drugs for Neglected Diseases
Sponsor class: OTHER
First posted: 2022-02-25
Enrollment: 1208
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Unbalanced, randomized (ratio of 3:1 \[acoziborole:placebo\]) parallel-arm study. Study treatment (acoziborole or placebo) administered on Day 1. Post-treatment hospitalization of 5 days (up to Day 5). Follow-up visits scheduled at Month 1 and Month 4 (End of Study visit).
Primary purpose: TREATMENT

Brief summary: Human African trypanosomiasis (HAT) or sleeping sickness is a tropical disease which is endemic in sub-Saharan Africa. Most cases of HAT are due to the parasite Trypanosoma brucei gambiense (T.b. gambiense), which is transmitted by the bite of the tsetse fly. HAT can be fatal without diagnosis and treatment. Several treatment options are currently available to treat HAT caused by the T.b. gambiense parasite (g-HAT), but these treatments can be administered only after demonstrating via microscopy the presence of the parasite in a body fluid. 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, remain potential reservoirs of the parasite and a source of new infections hindering the efforts to eliminate the disease.

The drug acoziborole was evaluated in a study called "DNDi-OXA-02-HAT". During this study, patients with g-HAT from the DRC and Guinea took a single dose of acoziborole. This study showed that acoziborole has a high efficacy and is safe for treating patients with confirmed g-HAT .

The present study is called "DNDi-OXA-04-HAT". It included seropositive participants from the DRC and Guinea who did not have parasites detected via microscopy in a body fluid. Its objective was to collect data on the safety and tolerability of a single dose of acoziborole compared to a placebo (i.e. a dummy treatment). The results of this study would help decide if acoziborole can be used in the population of g-HAT seropositive individuals and help eliminate the HAT disease.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Occurrence of Any TEAEs
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Malaria
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Acarodermatitis
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Abdominal Pain
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Enteritis
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Nausea
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Gastritis
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Headache
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Fatigue
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs - Blood Potassium Increased
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of TEAEs by Period of Occurrence
timeFrame: 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).
measure: Occurrence of Serious TEAEs
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of Severe Treatment-related TEAEs
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of Any Treatment-related TEAEs
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
measure: Occurrence of Treatment-related TEAEs by PT
timeFrame: From the investigational product administration (Day 1) to the Month 4 follow-up visit (End of Study).
Secondary outcomes:
measure: Occurrence of Adverse Events (AEs)
timeFrame: From Inform Consent signature (up to 2 days before treatment) to the Month 4 follow up visit (End of Study)
measure: Change From Baseline in Biochemistry Parameter: Alanine Aminotransferase
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Albumin
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Aspartate Aminotransferase
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Calcium
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Chloride
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Creatinine
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Glucose
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Potassium
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Sodium
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Total Bilirubin
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Bicarbonate
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Total Protein
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Biochemistry Parameter: Blood Urea Nitrogen
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Hematology Parameter: Platelet Count
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in Hematology Parameter: Leukocytes
timeFrame: From baseline to the Month 4 follow-up visit (End of Study).
measure: Change From Baseline in ECG (Electrocardiogram) Parameter: Heart Rate (HR)
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: RR Interval
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: PR Interval
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: QRS Interval
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: QT Interval
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: QTcF
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Change From Baseline in ECG Parameter: QTcB
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: 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
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
measure: Incidence of Abnormal Values for PR, QRS, QTcB and QTcF According to Pre-defined Thresholds
timeFrame: From baseline (Day 1 pre-dose) to Day 5 (End of Hospitalization)
Other outcomes:
Locations:
city: Bagata
country: Congo, The Democratic Republic of the
facility: General Referral Hospital of Bagata
state: Bandundu
city: Mbuji-Mayi
country: Congo, The Democratic Republic of the
facility: Hospital of Dipumba
state: Kasai-Oriental
city: Idiofa
country: Congo, The Democratic Republic of the
facility: General Referral Hospital of Idiofa
state: Kwilu
city: Masi-Manimba
country: Congo, The Democratic Republic of the
facility: General Referral Hospital of Masi-Manimba
state: Kwilu
city: Kwamouth
country: Congo, The Democratic Republic of the
facility: General Referral Hospital of Kwamouth
state: Mai-Ndombe
city: Bandundu
country: Congo, The Democratic Republic of the
facility: General Referral Hospital of Bandundu
city: Dubreka
country: Guinea
facility: General Referral Hospital of Dubreka
Study officials:
affiliation: Ministry of Public Health, Hygiene and Prevention, Kinshasa
name: Victor Kande Betu Kumeso, Dr.
role: PRINCIPAL_INVESTIGATOR
References: