Conference Material > Abstract
Baudin E, Mordt OV, Alves D, Seixas J, Lemerani M, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/6ss9-0934
INTRODUCTION
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Conference Material > Slide Presentation
Baudin E, Mordt OV, Alves D, Seixas J, Lemerani M, et al.
MSF Scientific Day International 2024. 16 May 2024; DOI:10.57740/eoc91a
Conference Material > Abstract
Signorell A, Hetzel M, Tshefu AK, Omoluabi E, Awor P, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/16vw-z635
INTRODUCTION
In sub-Saharan Africa, over 400,000 children die annually from malaria and other preventable illnesses. Little is known about where these children die, from which causes, and under which circumstances. A better understanding of these factors is crucial to effectively address the remaining burden of preventable childhood diseases and mortality. Rectal artesunate (RAS) is a potentially life-saving pre-referral treatment for children with severe malaria. However, limited evidence is available regarding the operational feasibility of incorporating RAS into the continuum of care for severe malaria, and the unanticipated consequences, like inappropriate use as artemisinin monotherapy or treatment of uncomplicated malaria, this could have on overall case management.
METHODS
The Community Access to Rectal Artesunate for Malaria (CARAMAL) study accompanied the implementation of RAS as a pre-referral treatment in DRC, Nigeria and Uganda. 8,563 children aged <5 years with severe febrile illnesses were detected and enrolled at primary care level, and 6,348 at referral health facilities. The children were followed up during admission and after 28 days to assess healthcare-seeking patterns, RAS use and acceptance, anti-malarial treatment received at the various points of contact with the health system, and health outcomes at day 28.
ETHICS
This study was approved by the World Health Organization’s Research Ethics Review Committee; the University of Kinshasa School of Public Health Ethics Committee; the Health Research Ethics Committee of the Adamawa State Ministry of Health and the National Health Research Ethics Committee, Nigeria; the Research and Ethics Committee of the Makerere University School of Public Health and the Uganda National Council for Science and Technology; and CHAI’s Scientific and Ethical Review Committee.
RESULTS
Post-RAS introduction, RAS was administered to 88% of eligible patients in DRC, 52% in Nigeria, and 70% in Uganda. We followed up 93% of enrolled children (13,870/14,911) 28 days after enrolment at home to determine status and healthcare trajectory. After roll-out, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase in DRC (adjusted odds ratio, aOR: 0.48) and Uganda (aOR: 0.72). Postreferral treatment with parenteral artesunate was high (above 80%), but the administration of a full course of artemisinin-based combination therapy to complete treatment as per WHO guidelines was variable (from virtually zero in Nigeria to 65% in DRC). Hence, many children were in fact treated with artemisinin monotherapy. Case fatality rates (CFR) varied largely by country and place of initial presentation (range: 0.3% to 15%). RAS was associated with reduced likelihood of being dead or sick on day 28 only in Uganda (aOR: 0.61, p<0.05) where overall CFR was lowest. No protective effect was found in DRC and Nigeria. Most children were considered healthy on day 28, but over 60% had detectable malaria antigenaemia.
CONCLUSION
For RAS to be an effective pre-referral treatment for children with severe malaria in hard-to-reach locations, underlying health system factors need to be addressed to ensure a functional continuum of care.
CONFLICTS OF INTEREST
None declared
In sub-Saharan Africa, over 400,000 children die annually from malaria and other preventable illnesses. Little is known about where these children die, from which causes, and under which circumstances. A better understanding of these factors is crucial to effectively address the remaining burden of preventable childhood diseases and mortality. Rectal artesunate (RAS) is a potentially life-saving pre-referral treatment for children with severe malaria. However, limited evidence is available regarding the operational feasibility of incorporating RAS into the continuum of care for severe malaria, and the unanticipated consequences, like inappropriate use as artemisinin monotherapy or treatment of uncomplicated malaria, this could have on overall case management.
METHODS
The Community Access to Rectal Artesunate for Malaria (CARAMAL) study accompanied the implementation of RAS as a pre-referral treatment in DRC, Nigeria and Uganda. 8,563 children aged <5 years with severe febrile illnesses were detected and enrolled at primary care level, and 6,348 at referral health facilities. The children were followed up during admission and after 28 days to assess healthcare-seeking patterns, RAS use and acceptance, anti-malarial treatment received at the various points of contact with the health system, and health outcomes at day 28.
ETHICS
This study was approved by the World Health Organization’s Research Ethics Review Committee; the University of Kinshasa School of Public Health Ethics Committee; the Health Research Ethics Committee of the Adamawa State Ministry of Health and the National Health Research Ethics Committee, Nigeria; the Research and Ethics Committee of the Makerere University School of Public Health and the Uganda National Council for Science and Technology; and CHAI’s Scientific and Ethical Review Committee.
RESULTS
Post-RAS introduction, RAS was administered to 88% of eligible patients in DRC, 52% in Nigeria, and 70% in Uganda. We followed up 93% of enrolled children (13,870/14,911) 28 days after enrolment at home to determine status and healthcare trajectory. After roll-out, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase in DRC (adjusted odds ratio, aOR: 0.48) and Uganda (aOR: 0.72). Postreferral treatment with parenteral artesunate was high (above 80%), but the administration of a full course of artemisinin-based combination therapy to complete treatment as per WHO guidelines was variable (from virtually zero in Nigeria to 65% in DRC). Hence, many children were in fact treated with artemisinin monotherapy. Case fatality rates (CFR) varied largely by country and place of initial presentation (range: 0.3% to 15%). RAS was associated with reduced likelihood of being dead or sick on day 28 only in Uganda (aOR: 0.61, p<0.05) where overall CFR was lowest. No protective effect was found in DRC and Nigeria. Most children were considered healthy on day 28, but over 60% had detectable malaria antigenaemia.
CONCLUSION
For RAS to be an effective pre-referral treatment for children with severe malaria in hard-to-reach locations, underlying health system factors need to be addressed to ensure a functional continuum of care.
CONFLICTS OF INTEREST
None declared
Conference Material > Slide Presentation
Signorell A, Hetzel M, Tshefu AK, Omoluabi E, Awor P, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/3jc0-8f15
Conference Material > Video
Signorell A
MSF Scientific Days International 2022. 7 June 2022; DOI:10.57740/2emb-sy61