A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease

Autores
Torrico, Faustino; Gascón, Joaquim; Ortiz, Lourdes; Pinto, Jimy; Rojas, Gimena; Palacios, Alejandro; Barreira, Fabiana; Blum, Bethania; Schijman, Alejandro Gabriel; Vaillant, Michel; Strub Wourgaft, Nathalie; Pinazo, Maria Jesus; Graeme, Bilbe; Ribeiro, Isabela
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-To-Treat (ITT) population. Follow-up was extended to 12 months. Results: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P =. 0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.
Fil: Torrico, Faustino. Universidad Mayor de San Simón; Bolivia
Fil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España
Fil: Ortiz, Lourdes. Universidad Juan Misael Saracho de Tarija; Bolivia
Fil: Pinto, Jimy. Universidad Mayor de San Simón; Bolivia
Fil: Rojas, Gimena. Universidad Mayor de San Simón; Bolivia
Fil: Palacios, Alejandro. Universidad Juan Misael Saracho de Tarija; Bolivia
Fil: Barreira, Fabiana. Drugs For Neglected Diseases Initiative; Suiza
Fil: Blum, Bethania. Drugs For Neglected Diseases Initiative; Suiza
Fil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vaillant, Michel. Centre National de la Recherche Scientifique; Francia
Fil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; Suiza
Fil: Pinazo, Maria Jesus. Drugs For Neglected Diseases Initiative; Suiza
Fil: Graeme, Bilbe. Drugs For Neglected Diseases Initiative; Suiza
Fil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; Suiza
Materia
CHAGAS DISEASE
FEXINIDAZOLE
NEGLECTED TROPICAL DISEASES
TRYPANOSOMA CRUZI
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/211744
Acceder
id CONICETDig_a430a1ba8968c0889652db1f8d3937ba
oai_identifier_str oai:ri.conicet.gov.ar:11336/211744
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas DiseaseTorrico, FaustinoGascón, JoaquimOrtiz, LourdesPinto, JimyRojas, GimenaPalacios, AlejandroBarreira, FabianaBlum, BethaniaSchijman, Alejandro GabrielVaillant, MichelStrub Wourgaft, NathaliePinazo, Maria JesusGraeme, BilbeRibeiro, IsabelaCHAGAS DISEASEFEXINIDAZOLENEGLECTED TROPICAL DISEASESTRYPANOSOMA CRUZIhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-To-Treat (ITT) population. Follow-up was extended to 12 months. Results: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P =. 0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.Fil: Torrico, Faustino. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; EspañaFil: Ortiz, Lourdes. Universidad Juan Misael Saracho de Tarija; BoliviaFil: Pinto, Jimy. Universidad Mayor de San Simón; BoliviaFil: Rojas, Gimena. Universidad Mayor de San Simón; BoliviaFil: Palacios, Alejandro. Universidad Juan Misael Saracho de Tarija; BoliviaFil: Barreira, Fabiana. Drugs For Neglected Diseases Initiative; SuizaFil: Blum, Bethania. Drugs For Neglected Diseases Initiative; SuizaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vaillant, Michel. Centre National de la Recherche Scientifique; FranciaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Pinazo, Maria Jesus. Drugs For Neglected Diseases Initiative; SuizaFil: Graeme, Bilbe. Drugs For Neglected Diseases Initiative; SuizaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaOxford University Press2023-02-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/211744Torrico, Faustino; Gascón, Joaquim; Ortiz, Lourdes; Pinto, Jimy; Rojas, Gimena; et al.; A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease; Oxford University Press; Clinical Infectious Diseases; 76; 3; 1-2-2023; E1186-E11941058-48381537-6591CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/cid/article/76/3/e1186/6655743info:eu-repo/semantics/altIdentifier/doi/10.1093/cid/ciac579info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:27:45Zoai:ri.conicet.gov.ar:11336/211744instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:27:46.119CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
title A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
spellingShingle A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
Torrico, Faustino
CHAGAS DISEASE
FEXINIDAZOLE
NEGLECTED TROPICAL DISEASES
TRYPANOSOMA CRUZI
title_short A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
title_full A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
title_fullStr A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
title_full_unstemmed A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
title_sort A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease
dc.creator.none.fl_str_mv Torrico, Faustino
Gascón, Joaquim
Ortiz, Lourdes
Pinto, Jimy
Rojas, Gimena
Palacios, Alejandro
Barreira, Fabiana
Blum, Bethania
Schijman, Alejandro Gabriel
Vaillant, Michel
Strub Wourgaft, Nathalie
Pinazo, Maria Jesus
Graeme, Bilbe
Ribeiro, Isabela
author Torrico, Faustino
author_facet Torrico, Faustino
Gascón, Joaquim
Ortiz, Lourdes
Pinto, Jimy
Rojas, Gimena
Palacios, Alejandro
Barreira, Fabiana
Blum, Bethania
Schijman, Alejandro Gabriel
Vaillant, Michel
Strub Wourgaft, Nathalie
Pinazo, Maria Jesus
Graeme, Bilbe
Ribeiro, Isabela
author_role author
author2 Gascón, Joaquim
Ortiz, Lourdes
Pinto, Jimy
Rojas, Gimena
Palacios, Alejandro
Barreira, Fabiana
Blum, Bethania
Schijman, Alejandro Gabriel
Vaillant, Michel
Strub Wourgaft, Nathalie
Pinazo, Maria Jesus
Graeme, Bilbe
Ribeiro, Isabela
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CHAGAS DISEASE
FEXINIDAZOLE
NEGLECTED TROPICAL DISEASES
TRYPANOSOMA CRUZI
topic CHAGAS DISEASE
FEXINIDAZOLE
NEGLECTED TROPICAL DISEASES
TRYPANOSOMA CRUZI
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-To-Treat (ITT) population. Follow-up was extended to 12 months. Results: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P =. 0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.
Fil: Torrico, Faustino. Universidad Mayor de San Simón; Bolivia
Fil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España
Fil: Ortiz, Lourdes. Universidad Juan Misael Saracho de Tarija; Bolivia
Fil: Pinto, Jimy. Universidad Mayor de San Simón; Bolivia
Fil: Rojas, Gimena. Universidad Mayor de San Simón; Bolivia
Fil: Palacios, Alejandro. Universidad Juan Misael Saracho de Tarija; Bolivia
Fil: Barreira, Fabiana. Drugs For Neglected Diseases Initiative; Suiza
Fil: Blum, Bethania. Drugs For Neglected Diseases Initiative; Suiza
Fil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vaillant, Michel. Centre National de la Recherche Scientifique; Francia
Fil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; Suiza
Fil: Pinazo, Maria Jesus. Drugs For Neglected Diseases Initiative; Suiza
Fil: Graeme, Bilbe. Drugs For Neglected Diseases Initiative; Suiza
Fil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; Suiza
description Background: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-To-Treat (ITT) population. Follow-up was extended to 12 months. Results: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P =. 0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.
publishDate 2023
dc.date.none.fl_str_mv 2023-02-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/211744
Torrico, Faustino; Gascón, Joaquim; Ortiz, Lourdes; Pinto, Jimy; Rojas, Gimena; et al.; A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease; Oxford University Press; Clinical Infectious Diseases; 76; 3; 1-2-2023; E1186-E1194
1058-4838
1537-6591
CONICET Digital
CONICET
url http://hdl.handle.net/11336/211744
identifier_str_mv Torrico, Faustino; Gascón, Joaquim; Ortiz, Lourdes; Pinto, Jimy; Rojas, Gimena; et al.; A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults with Chronic Indeterminate Chagas Disease; Oxford University Press; Clinical Infectious Diseases; 76; 3; 1-2-2023; E1186-E1194
1058-4838
1537-6591
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/cid/article/76/3/e1186/6655743
info:eu-repo/semantics/altIdentifier/doi/10.1093/cid/ciac579
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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