TY - JOUR
T1 - New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA)
T2 - a phase 2, double-blind, randomised trial
AU - Torrico, Faustino
AU - Gascón, Joaquim
AU - Barreira, Fabiana
AU - Blum, Bethania
AU - Almeida, Igor C.
AU - Alonso-Vega, Cristina
AU - Barboza, Tayná
AU - Bilbe, Graeme
AU - Correia, Erika
AU - Garcia, Wilson
AU - Ortiz, Lourdes
AU - Parrado, Rudy
AU - Ramirez, Juan Carlos
AU - Ribeiro, Isabela
AU - Strub-Wourgaft, Nathalie
AU - Vaillant, Michel
AU - Sosa-Estani, Sergio
AU - Arteaga, Roger
AU - de la Barra, Anabelle
AU - Camacho Borja, Jhonny
AU - Martinez, Ivana
AU - Fernandes, Jayme
AU - Garcia, Lineth
AU - Lozano, Daniel
AU - Palacios, Alejandro
AU - Schijman, Alejandro
AU - Pinazo, Maria Jesus
AU - Pinto, Jimmy
AU - Rojas, Gimena
AU - Estevao, Igor
AU - Ortega-Rodriguez, Uriel
AU - Mendes, Maria Tays
AU - Schuck, Edgar
AU - Hata, Katsura
AU - Maki, Noritsugu
AU - Asada, Makoto
AU - BENDITA study group
N1 - Funding Information:
We would like to thank the BENDITA study group: Roger Arteaga, Alejandro Palacios, Jimmy Pinto, and Gimena Rojas (Plataforma de Atenci?n al Paciente con Enfermedad de Chagas, Bolivia), Anabelle de la Barra and Lineth Garcia (Universidad de San Sim?n, Cochabamba, Bolivia), Daniel Lozano (CEADES, Cochabamba, Bolivia); Jayme Fernandes and Ivana Martinez (DNDi Latin America, Rio de Janeiro, Brazil); Igor Estevao, Uriel Ortega-Rodriguez, and Maria Tays Mendes (Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA); and Edgar Schuck, Katsura Hata, Noritsugu Maki, and Makoto Asada (Eisai). We thank Mike Muller, senior medical writer at Scinopsis, for her efforts in creating the manuscript. We would also like to thank Brittany Maguire of the Infectious Diseases Data Observatory for help with the literature search, and Louise Burrows and Colin Forsyth of DNDi for help with editing and revising the manuscript. We would like to thank all trial participants and study site personnel. DNDi is grateful to its donors, public and private, who have provided funding for all DNDi activities since its inception in 2003. DNDi would also like to thank the Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente Foundation, Barcelona Institute for Global Health, Servicio Departamental de Salud Chuquisaca, Universidad Aut?noma Juan Misael Saracho Tarija, and Universidad Mayor de San Sim?n Cochabamba. The Platform of Comprehensive Care for Patients with Chagas Disease is funded by Agencia Espa?ola de Cooperaci?n Internacional para el Desarrollo (grant 10-COI-039). JG was supported by the Departament d'Universitats i Recerca de la Generalitat de Catalunya, Spain (grant 2017SGR924). For this study, DNDi received financial support from the following donors: Global Health Innovative Technology Fund, Japan; Department for International Development (UK Aid), UK; German Federal Ministry of Education and Research through Kreditanstalt f?r Wiederaufbau, Germany; Dutch Ministry of Foreign Affairs, Netherlands; Brazilian Ministry of Health, Brazil; Associa??o Bem-Te-Vi Diversidade, Brazil; Funda??o Oswaldo Cruz (Fiocruz), Brazil; Starr International Foundation, Switzerland. For its overall mission, DNDi also receives funding from the Swiss Agency for Development and Cooperation, Switzerland and M?decins Sans Fronti?res. Non-conventional serology assays were done at the Biomolecule Analysis Core Facility (currently known as Biomolecule Analysis and Omics Unit) at Border Biomedical Research Center, University of Texas at El Paso, supported by grant 5U54MD007592 from the National Institute on Minority Health and Health Disparities, a component of the National Institutes of Health. DNDi would also like to thank Eisai and Elea laboratories for providing study supplies.
Funding Information:
We would like to thank the BENDITA study group: Roger Arteaga, Alejandro Palacios, Jimmy Pinto, and Gimena Rojas (Plataforma de Atención al Paciente con Enfermedad de Chagas, Bolivia), Anabelle de la Barra and Lineth Garcia (Universidad de San Simón, Cochabamba, Bolivia), Daniel Lozano (CEADES, Cochabamba, Bolivia); Jayme Fernandes and Ivana Martinez (DNDi Latin America, Rio de Janeiro, Brazil); Igor Estevao, Uriel Ortega-Rodriguez, and Maria Tays Mendes (Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA); and Edgar Schuck, Katsura Hata, Noritsugu Maki, and Makoto Asada (Eisai). We thank Mike Muller, senior medical writer at Scinopsis, for her efforts in creating the manuscript. We would also like to thank Brittany Maguire of the Infectious Diseases Data Observatory for help with the literature search, and Louise Burrows and Colin Forsyth of DNDi for help with editing and revising the manuscript. We would like to thank all trial participants and study site personnel. DNDi is grateful to its donors, public and private, who have provided funding for all DNDi activities since its inception in 2003. DNDi would also like to thank the Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente Foundation, Barcelona Institute for Global Health, Servicio Departamental de Salud Chuquisaca, Universidad Autónoma Juan Misael Saracho Tarija, and Universidad Mayor de San Simón Cochabamba. The Platform of Comprehensive Care for Patients with Chagas Disease is funded by Agencia Española de Cooperación Internacional para el Desarrollo (grant 10-COI-039). JG was supported by the Departament d'Universitats i Recerca de la Generalitat de Catalunya, Spain (grant 2017SGR924). For this study, DNDi received financial support from the following donors: Global Health Innovative Technology Fund, Japan; Department for International Development (UK Aid), UK; German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; Dutch Ministry of Foreign Affairs, Netherlands; Brazilian Ministry of Health, Brazil; Associação Bem-Te-Vi Diversidade, Brazil; Fundação Oswaldo Cruz (Fiocruz), Brazil; Starr International Foundation, Switzerland. For its overall mission, DNDi also receives funding from the Swiss Agency for Development and Cooperation, Switzerland and Médecins Sans Frontières. Non-conventional serology assays were done at the Biomolecule Analysis Core Facility (currently known as Biomolecule Analysis and Omics Unit) at Border Biomedical Research Center, University of Texas at El Paso, supported by grant 5U54MD007592 from the National Institute on Minority Health and Health Disparities, a component of the National Institutes of Health. DNDi would also like to thank Eisai and Elea laboratories for providing study supplies.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY NC ND 4.0 license
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104932611&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/33836161
U2 - 10.1016/S1473-3099(20)30844-6
DO - 10.1016/S1473-3099(20)30844-6
M3 - Article
C2 - 33836161
AN - SCOPUS:85104932611
SN - 1473-3099
VL - 21
SP - 1129
EP - 1140
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 8
ER -