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

Trypanosomiasis, African Clinical Trial

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

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Sleeping Sickness
• Trypanosoma Brucei Gambiense; Infection
• Trypanosomiasis
• Trypanosomiasis, African

• NCT number: NCT05256017
• Study type: Interventional
• Source: Drugs for Neglected Diseases
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: December 30, 2021
• Completion date: August 2, 2023