Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial
| Autor: | Daniel Franz Lozano Beltran, Sandro Villarroel, Cristina Alonso-Vega, Nair Montano, Jimena Ramos Morales, Alejandro Palacios Lopez, Juan Carlos Ramirez, Tomás Duffy, Margarita Bisio, Alejandro G. Schijman, Lourdes Ortiz, Roxana Challapa Quechover, Silvia Sanz Sender, Paul Matthias Diderichsen, Eugene Cox, Nilce Mendoza, Michel Vaillant, Faustino Torrico, Fabiana Alves, Lineth Garcia, Igor C. Almeida, Gimena Rojas Delgadillo, Lizeth Rojas Panozo, Michael Everson, Maria Yurly Escobar Caballero, Fred Duncanson, Rudy Nelson Vasco Arenas, Isabel Gonzales, Helmut Ramon Magne Anzoleaga, Makoto Asada, Wladimiro Jimenez, Facundo Garcia-Bournisen, David Wesche, Carlos Florencio Hoyos Delfin, Letty Cardozo, Luis Izquierdo, Isabela Ribeiro, Erika Correia, Bethania Blum, Nathalie Strub-Wourgaft, María-Jesús Pinazo, Glaucia Santina, Manuel Morales, Albert Mendoza Zalabar, Joaquim Gascon, Rudy Parrado, Alexandre F. Marques, Antonia Daniels, Joan Carlos Reverter, Jimy Jose Pinto Rocha, Violeta Alejandra Fernandez Galvez, Anabelle de la Barra, Dunia Torrico Terceros, Gabriela Cuellar |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Placebo-controlled study Ciencias de la Salud Administration Oral Polymerase Chain Reaction Parasite Load law.invention Placebos Randomized controlled trial law Medicine Prospective Studies education.field_of_study Incidence Middle Aged Trypanocidal Agents E1224 Treatment Outcome Infectious Diseases Nitroimidazoles Benznidazole Female medicine.drug Adult Chagas disease Bolivia medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD Adolescent Drug-Related Side Effects and Adverse Reactions Trypanosoma cruzi 030106 microbiology Population Placebo Young Adult 03 medical and health sciences Double-Blind Method Internal medicine Humans Chagas Disease education business.industry Triazoles medicine.disease Treatment Enfermedades Infecciosas Clinical trial Thiazoles Regimen business |
| Zdroj: | The Lancet Infectious Diseases. 18:419-430 |
| ISSN: | 1473-3099 |
| DOI: | 10.1016/s1473-3099(17)30538-8 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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