Brief Title
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
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.
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.
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.
Study Phase
Phase 2/Phase 3
Study Type
Interventional
Primary Outcome
Occurrence of treatment-emergent adverse events (TEAEs)
Secondary Outcome
Occurrence of adverse events (AEs)
Condition
Trypanosomiasis, African
Intervention
Acoziborole
Study Arms / Comparison Groups
Acoziborole
Description: Single dose administration of 3 tablets of 320 mg
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
1200
Start Date
December 30, 2021
Completion Date
May 1, 2023
Primary Completion Date
May 1, 2023
Eligibility Criteria
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
Gender
All
Ages
15 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Victor Kande Betu Ku Mesu, Dr., +41 22 906 92 60, [email protected]
Location Countries
Congo, The Democratic Republic of the
Location Countries
Congo, The Democratic Republic of the
Administrative Informations
NCT ID
NCT05256017
Organization ID
DNDi-OXA-04-HAT
Responsible Party
Sponsor
Study Sponsor
Drugs for Neglected Diseases
Study Sponsor
Victor Kande Betu Ku Mesu, Dr., Principal Investigator, Ministry of Public Health, Hygiene and Prevention, Kinshasa
Verification Date
February 2022