Dried blood spot technique-based liquid chromatography-tandem mass spectrometry method as a simple alternative for benznidazole pharmacokinetic assessment

Chagas disease (CD) is recognized as one of the major neglected global tropical diseases. Benznidazole (BNZ) is the drug of choice for the treatment of adults, young infants, and newborns with CD. However, the pharmacokinetics (PK) of BNZ have been poorly evaluated in all age groups, with consequent gaps in knowledge about PK-pharmacodynamic relationships in CD. The purpose of this study was to develop and validate a bioanalytical method to quantify BNZ levels in small-volume whole-blood samples collected as dried blood spots (DBS). The analysis was performed using high-performance liquid chromatography-positive electrospray tandem mass spectrometry. PK evaluation in healthy male volunteers was conducted to verify the correlation between DBS and plasma BNZ concentrations. The calibration curve was linear from 50 to 20,000 ng · ml1. Intra- and interday precision and bias values were less than 14.87% (n 9) and 9.81% (n 27), respectively. The recovery rates ranged from 94 to 100% with no matrix effect. There was no hematocrit level effect in a range of 20 to 70%. The PK results obtained from DBS and plasma were comparable (r2 0.8295) and equivalent to previously published information on BNZ. BNZ in DBS was stable at room temperature for more than one year. This article describes the first microsampling method for measuring BNZ levels in DBS that has the potential to facilitate broad implementation of PK in clinical trials involving adult and pediatric patients in remote areas and helps to address existing knowledge gaps in the treatment of CD.Fil: Galindo Bedor, Danilo César. Universidade Federal de Pernambuco; BrasilFil: Tavares Cavalcanti Bedor, Noely Camila. No especifíca;Fil: Wellithom Viturino da Silva, José. Universidade Federal de Pernambuco; BrasilFil: Damasceno Sousa, Giovana. Universidade Federal de Pernambuco; BrasilFil: Pereira de Santana, Davi. Universidade Federal de Pernambuco; BrasilFil: Garcia Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blum, Bethania. No especifíca;Fil: Alves, Fabiana. No especifíca;Fil: Ribeiro, Isabela. No especifíca

New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial

Background: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. Methods: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18–50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. Findings: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73–99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73–99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64–95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65–95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67–97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64–95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. Interpretation: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. Funding: Drugs for Neglected Diseases initiative (DNDi). Translation: For the Spanish translation of the abstract see Supplementary Materials section.Fil: Torrico, Faustino. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; Bolivia. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España. Universidad de Barcelona; EspañaFil: Barreira, Fabiana. DNDi Latin America; BrasilFil: Blum, Bethania. DNDi Latin America; BrasilFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alonso Vega, Cristina. DNDi Latin America; Brasil. Instituto de Salud Global de Barcelona; EspañaFil: Barboza, Tayná. DNDi Latin America; BrasilFil: Bilbe, Graeme. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. DNDi Latin America; BrasilFil: Garcia, Wilson. Universidad Mayor de San Simón; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente ; BoliviaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Vaillant, Michel. Luxembourg Institute Of Health; LuxemburgoFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. DNDi Latin America; Brasi

Inquiries of access to medicines in home level: a comparative study of initiatives carried out in Brazil between 2002 and 2004

Made available in DSpace on 2012-09-06T01:12:18Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 939.pdf: 1123120 bytes, checksum: 2624e43df70cf27fff1851892f0a96ae (MD5) Previous issue date: 2007Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Este trabalho tem como foco a investigação do acesso aos medicamentos por meio deinquéritos domiciliares realizados entre 2002 e 2004 no Brasil. O eixo da investigação foi a Pesquisa Domiciliar para a medida de Acesso e Uso de Medicamentos (PDAUM 2004) proposta pela OMS para avaliar a situação farmacêutica nos países e ser aplicadaa um baixo custo e com facilidade operacional. Além disso, selecionaram-se estudos realizados no período, com abrangência nacional, em que foi abordada a questão dos medicamentos. As demais pesquisas investigadas foram: Pesquisa de Orçamentos Familiares (POF 2002-2003), e Pesquisa Nacional de Amostra por Domicílios, Suplemento Saúde (PNAD-Saúde 2003), realizadas pelo IBGE; e Pesquisa Mundial de Saúde (PMS-2003), iniciativa da OMS para avaliar a saúde nos países. (...) Para cotejar os estudos, elegeu-se um modelo de abordagem ao acesso a medicamentos em dimensões mensuráveis. Apesar de as pesquisas avaliadas nesse trabalho terem abordado dimensões em comum, ficou claro que as pesquisas que não têm como foco a saúde, como a POF, deixam de prover importantes informações sobre o acesso amedicamentos. A PNAD-saúde, mesmo sendo uma pesquisa feita em conjunto com o Ministério da Saúde, tratou a questão do acesso aos medicamentos de forma secundária. A PMS constituiu uma pesquisa ampla e eficaz na abordagem dos aspectos relacionados à saúde e aos medicamentos, assim como para a avaliação das desigualdades. Da mesmaforma, apresentou um plano amostral mais abrangente que a PDAUM. (...) Ademais, sua aplicação em conjunto com o módulo de serviços, dispondo de, praticamente, os mesmos recursos, proporcionou um conjunto deinformações úteis para a orientação das políticas públicas, uma vez que, por meio de uma metodologia barata e rápida, são disponibilizados, dados de estrutura, processo e resultados nos serviços, assim como os resultados medidos fora do ambiente do serviço

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

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; 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; Suiz

In vitro and in vivo experimental models for drug screening and development for Chagas disease

Submitted by Nuzia Santos ([email protected]) on 2012-11-12T19:20:36Z No. of bitstreams: 1 100.2010.pdf: 628329 bytes, checksum: e376150db1b041e55dd80e513a9798f8 (MD5)Made available in DSpace on 2012-11-12T19:20:36Z (GMT). No. of bitstreams: 1 100.2010.pdf: 628329 bytes, checksum: e376150db1b041e55dd80e513a9798f8 (MD5)Fiocruz, DNDiFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil/Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Drugs for Neglected Disease Initiative.Geneva, SwitzerlandUniversidade Federal de Ouro Preto. Departamento de Ciências Biológicas. Ouro Preto, MG, Brasil.Drugs for Neglected Disease Initiative. Geneva, Switzerland.Drugs for Neglected Disease Initiative, Geneva, Switzerland.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.Instituto de Investigaciones Científicas y Servicios de Alta Tecnologia- AIP. Clayton, Panamá.Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil.Drugs for Neglected Disease Initiative.Geneva, SwitzerlandMédecins sans Frontières. Geneva, Switzerland.Instituto Conmemorativo Gorgas de Estudios de la Salud. Panamá, Panamá.University of Georgia. Center for Tropical and Emerging Global Disease. GA, USA..Institute Pasteur-Korea. Center for Neglected Diseases Drug Discovery. Gyeonggi-do, Korea.Instituto de Investigaciones Científicas y Servicios de Alta Tecnologia-AIP. Clayton, Panamá.Universidade Federal de Ouro Preto. Departamento de Ciências Biológicas. Ouro Preto, MG, Brasil.Drugs for Neglected Disease Initiative. Geneva, Switzerland.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Murdoch University. Murdoch, AustráliaPrograma Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Al¬though the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been as¬sayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

In vitro and in vivo experimental models for drug screening and development for Chagas disease.

Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Al?though the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been as?sayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

In vitro and in vivo experimental models for drug screening and development for Chagas disease.

Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Al¬though the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been as¬sayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial

Background: Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. Method: In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18–50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228. Findings: Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4–44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4–20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9–92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity. Interpretation: E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224. Funding: Drugs for Neglected Diseases initiative.Fil: Torrico, Faustino. Universidad Mayor de San Simon Bolivia; Bolivia. Fundación Ceades; BoliviaFil: Gascon, Joaquim. Instituto de Salud Global de Barcelona; EspañaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho de Tarija; BoliviaFil: Alonso Vega, Cristina. Drugs For Neglected Diseases Initiative; SuizaFil: Pinazo, María-Jesús. Instituto de Salud Global de Barcelona; EspañaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alves, Fabiana. Drugs For Neglected Diseases Initiative; SuizaFil: Strub-Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Santina, Glaucia. Drugs For Neglected Diseases Initiative; SuizaFil: Blum, Bethania. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. Drugs For Neglected Diseases Initiative; SuizaFil: García Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Vaillant, Michel. Competence Center in Methodology and Statistics; LuxemburgoFil: Ramos Morales, Jimena. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Pinto Rocha, Jimy Jose. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Rojas Delgadillo, Gimena. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Magne Anzoleaga, Helmut Ramon. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Mendoza, Nilce. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Quechover, Roxana Challapa. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Caballero, Maria Yurly Escobar. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Lozano Beltran, Daniel Franz. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Zalabar, Albert Mendoza. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Rojas Panozo, Lizeth. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Palacios Lopez, Alejandro. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Torrico Terceros, Dunia. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Fernandez Galvez, Violeta Alejandra. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Cardozo, Letty. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Cuellar, Gabriela. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Vasco Arenas, Rudy Nelson. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Gonzales, Isabel. Platform for Comprehensive Care of Patients with Chagas Disease; BoliviaFil: Hoyos Delfin, Carlos Florencio. Universidad Juan Misael Saracho; BoliviaFil: Garcia, Lineth. Universidad Mayor de San Simón; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: de la Barra, Anabelle. Universidad Mayor de San Simón; BoliviaFil: Montaño, Nair. Universidad Mayor de San Simón; BoliviaFil: Villarroel, Sandro. Universidad Mayor de San Simón; BoliviaFil: Duffy, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bisio, Margarita María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Duncanson, Fred. Eisai; JapónFil: Everson, Michael. Eisai; JapónFil: Daniels, Antonia. Eisai; JapónFil: Asada, Makoto. Eisai; JapónFil: Cox, Eugene. Quantitative Solutions; Países BajosFil: Wesche, David. Quantitative Solutions; Países BajosFil: Diderichsen, Paul Matthias. Quantitative Solutions; Países BajosFil: Marques, Alexandre F. Universidade Federal de Minas Gerais; BrasilFil: Izquierdo, Luis. ISGlobal; EspañaFil: Sender, Silvia Sanz. ISGlobal; EspañaFil: Reverter, Joan Carlos. Hospital Clinic Barcelona; EspañaFil: Morales, Manuel. Hospital Clinic Barcelona; EspañaFil: Jimenez, Wladimiro. Hospital Clinic Barcelona; Españ