Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study
Summary: Background: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood–brain barrier for late-stage infection. These procedures are inconvenien...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-07-01
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| Series: | The Lancet Global Health |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214109X21002084 |
| _version_ | 1818891987679444992 |
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| author | Victor Kande Betu Ku Mesu, DPH Wilfried Mutombo Kalonji, MD Clélia Bardonneau, MSc Olaf Valverde Mordt, MSc Digas Ngolo Tete, MPH Séverine Blesson, MSc François Simon, MSc Sophie Delhomme, MSc Sonja Bernhard, PhD Hélène Mahenzi Mbembo, MD Christian Mpia Moke, MD Steven Lumeya Vuvu, MMed Junior Mudji E'kitiak, MD Felix Akwaso Masa, MD Melchias Mukendi Ilunga, MD Dieudonné Mpoyi Muamba Nzambi, MD Tim Mayala Malu, MD Serge Kapongo Tshilumbwa, MD Franck Botalema Bolengi, MD Mathieu Nkieri Matsho, MD Crispin Lumbala, MPH Bruno Scherrer, PhD Nathalie Strub-Wourgaft, MD Antoine Tarral, MD |
| author_facet | Victor Kande Betu Ku Mesu, DPH Wilfried Mutombo Kalonji, MD Clélia Bardonneau, MSc Olaf Valverde Mordt, MSc Digas Ngolo Tete, MPH Séverine Blesson, MSc François Simon, MSc Sophie Delhomme, MSc Sonja Bernhard, PhD Hélène Mahenzi Mbembo, MD Christian Mpia Moke, MD Steven Lumeya Vuvu, MMed Junior Mudji E'kitiak, MD Felix Akwaso Masa, MD Melchias Mukendi Ilunga, MD Dieudonné Mpoyi Muamba Nzambi, MD Tim Mayala Malu, MD Serge Kapongo Tshilumbwa, MD Franck Botalema Bolengi, MD Mathieu Nkieri Matsho, MD Crispin Lumbala, MPH Bruno Scherrer, PhD Nathalie Strub-Wourgaft, MD Antoine Tarral, MD |
| author_sort | Victor Kande Betu Ku Mesu, DPH |
| collection | DOAJ |
| description | Summary: Background: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood–brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. Methods: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1–4 then 1200 mg fexinidazole on days 5–10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11–18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). Findings: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2–99·7): 186 (98%) of 189 patients (95·4–99·7) with stage 1 and 41 (100%) of 41 patients (91·4–100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. Interpretation: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. Funding: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign. Translation: For the French translation of the abstract see Supplementary Materials section. |
| first_indexed | 2024-12-19T17:49:32Z |
| format | Article |
| id | doaj.art-fc53e144d24e4957ad24602246c04574 |
| institution | Directory Open Access Journal |
| issn | 2214-109X |
| language | English |
| last_indexed | 2024-12-19T17:49:32Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Global Health |
| spelling | doaj.art-fc53e144d24e4957ad24602246c045742022-12-21T20:11:57ZengElsevierThe Lancet Global Health2214-109X2021-07-0197e999e1008Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort studyVictor Kande Betu Ku Mesu, DPH0Wilfried Mutombo Kalonji, MD1Clélia Bardonneau, MSc2Olaf Valverde Mordt, MSc3Digas Ngolo Tete, MPH4Séverine Blesson, MSc5François Simon, MSc6Sophie Delhomme, MSc7Sonja Bernhard, PhD8Hélène Mahenzi Mbembo, MD9Christian Mpia Moke, MD10Steven Lumeya Vuvu, MMed11Junior Mudji E'kitiak, MD12Felix Akwaso Masa, MD13Melchias Mukendi Ilunga, MD14Dieudonné Mpoyi Muamba Nzambi, MD15Tim Mayala Malu, MD16Serge Kapongo Tshilumbwa, MD17Franck Botalema Bolengi, MD18Mathieu Nkieri Matsho, MD19Crispin Lumbala, MPH20Bruno Scherrer, PhD21Nathalie Strub-Wourgaft, MD22Antoine Tarral, MD23Ministry of Health, Kinshasa, Democratic Republic of the CongoNational HAT Control Programme, Programme National de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the CongoDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Kinshasa, Democratic Republic of the CongoDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandSwiss Tropical and Public Health Institute, Basel, SwitzerlandBandundu Hospital, Kwilu Province, Democratic Republic of the CongoBandundu Hospital, Kwilu Province, Democratic Republic of the CongoVanga Hospital, Kwilu Province, Democratic Republic of the CongoVanga Hospital, Kwilu Province, Democratic Republic of the CongoMasi Manimba Hospital, Kwilu Province, Democratic Republic of the CongoDipumba Hospital (MIBA), Mbuji Mayi, Kasaï Oriental Province, Democratic Republic of the CongoDipumba Hospital (MIBA), Mbuji Mayi, Kasaï Oriental Province, Democratic Republic of the CongoMushie Hospital, Maï Ndombe Province, Democratic Republic of the CongoKatanda Hospital, Kasaï Oriental Province, Democratic Republic of the CongoIsangi Hospital, Tshopo Province, Democratic Republic of the CongoBagata Hospital, Kwilu Province, Democratic Republic of the CongoNational HAT Control Programme, Programme National de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the CongoBruno Scherrer Conseil, Saint Arnoult en Yvelines, FranceDrugs for Neglected Diseases Initiative, Geneva, SwitzerlandDrugs for Neglected Diseases Initiative, Geneva, Switzerland; Correspondence to: Dr Antoine Tarral, Drugs for Neglected Diseases initiative, 1202 Geneva, SwitzerlandSummary: Background: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood–brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. Methods: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1–4 then 1200 mg fexinidazole on days 5–10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11–18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). Findings: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2–99·7): 186 (98%) of 189 patients (95·4–99·7) with stage 1 and 41 (100%) of 41 patients (91·4–100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. Interpretation: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. Funding: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign. Translation: For the French translation of the abstract see Supplementary Materials section.http://www.sciencedirect.com/science/article/pii/S2214109X21002084 |
| spellingShingle | Victor Kande Betu Ku Mesu, DPH Wilfried Mutombo Kalonji, MD Clélia Bardonneau, MSc Olaf Valverde Mordt, MSc Digas Ngolo Tete, MPH Séverine Blesson, MSc François Simon, MSc Sophie Delhomme, MSc Sonja Bernhard, PhD Hélène Mahenzi Mbembo, MD Christian Mpia Moke, MD Steven Lumeya Vuvu, MMed Junior Mudji E'kitiak, MD Felix Akwaso Masa, MD Melchias Mukendi Ilunga, MD Dieudonné Mpoyi Muamba Nzambi, MD Tim Mayala Malu, MD Serge Kapongo Tshilumbwa, MD Franck Botalema Bolengi, MD Mathieu Nkieri Matsho, MD Crispin Lumbala, MPH Bruno Scherrer, PhD Nathalie Strub-Wourgaft, MD Antoine Tarral, MD Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study The Lancet Global Health |
| title | Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study |
| title_full | Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study |
| title_fullStr | Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study |
| title_full_unstemmed | Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study |
| title_short | Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study |
| title_sort | oral fexinidazole for stage 1 or early stage 2 african trypanosoma brucei gambiense trypanosomiasis a prospective multicentre open label cohort study |
| url | http://www.sciencedirect.com/science/article/pii/S2214109X21002084 |
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