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

• Published in: The Lancet infectious diseases 2018-04, Vol.18 (4), p.419-430
• Main Authors: Torrico, Faustino, Gascon, Joaquim, Ortiz, Lourdes, Alonso-Vega, Cristina, Pinazo, María-Jesús, Schijman, Alejandro, Almeida, Igor C, Alves, Fabiana, Strub-Wourgaft, Nathalie, Ribeiro, Isabela, Santina, Glaucia, Blum, Bethania, Correia, Erika, Garcia-Bournisen, Facundo, Vaillant, Michel, Morales, Jimena Ramos, Pinto Rocha, Jimy Jose, Rojas Delgadillo, Gimena, Magne Anzoleaga, Helmut Ramon, Mendoza, Nilce, Quechover, Roxana Challapa, Caballero, Maria Yurly Escobar, Lozano Beltran, Daniel Franz, Zalabar, Albert Mendoza, Rojas Panozo, Lizeth, Palacios Lopez, Alejandro, Torrico Terceros, Dunia, Fernandez Galvez, Violeta Alejandra, Cardozo, Letty, Cuellar, Gabriela, Vasco Arenas, Rudy Nelson, Gonzales, Isabel, Hoyos Delfin, Carlos Florencio, Garcia, Lineth, Parrado, Rudy, de la Barra, Anabelle, Montano, Nair, Villarroel, Sandro, Duffy, Tomas, Bisio, Margarita, Ramirez, Juan Carlos, Duncanson, Fred, Everson, Michael, Daniels, Antonia, Asada, Makoto, Cox, Eugene, Wesche, David, Diderichsen, Paul Matthias, Marques, Alexandre F, Izquierdo, Luis, Sender, Silvia Sanz, Reverter, Joan Carlos, Morales, Manuel, Jimenez, Wladimiro
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adolescent; Adult; Adults; Benznidazole; Biosynthesis; Bolivia; Chagas disease; Chagas Disease - drug therapy; Chemotherapy; Chronic illnesses; Clinical trials; Deoxyribonucleic acid; DNA; Double-Blind Method; Drug dosages; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; Female; Humans; Immunoglobulins; Incidence; Infections; Infectious diseases; Male; Middle Aged; Nitroimidazoles - administration & dosage; Nitroimidazoles - adverse effects; Parasite Load; Parasites; Placebos - administration & dosage; Polymerase Chain Reaction; Prospective Studies; Protozoa; Thiazoles - administration & dosage; Thiazoles - adverse effects; Treatment Outcome; Triazoles - administration & dosage; Triazoles - adverse effects; Trypanocidal Agents - administration & dosage; Trypanosoma cruzi; Trypanosoma cruzi - genetics; Trypanosoma cruzi - isolation & purification; Vector-borne diseases; Young Adult
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(17)30538-8

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. 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. 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