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

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