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

TORRICO, FAUSTINO; GASCÓN, JOAQUIM; BARREIRA, FABIANA; BLUM, BETHANIA; ALMEIDA, IGOR C; ALONSO-VEGA, CRISTINA; BARBOZA, TAYNÁ; BILBE, GRAEME; CORREIA, ERIKA; GARCIA, WILSON; ORTIZ, LOURDES; PARRADO, RUDY; RAMIREZ, JUAN CARLOS; RIBEIRO, ISABELA; STRUB-WOURGAFT, NATHALIE; VAILLANT, MICHEL; SOSA-ESTANI, SERGIO; ARTEAGA, ROGER; DE LA BARRA, ANABELLE; CAMACHO BORJA, JHONNY; MARTINEZ, IVANA; FERNANDES, JAYME; GARCIA, LINETH; LOZANO, DANIEL; PALACIOS, ALEJANDRO; SCHIJMAN, ALEJANDRO; PINAZO, MARIA JESUS; PINTO, JIMMY; ROJAS, GIMENA; ESTEVAO, IGOR; ORTEGA-RODRIGUEZ, URIEL; MENDES, MARIA TAYS; SCHUCK, EDGAR; HATA, KATSURA; MAKI, NORITSUGU; ASADA, MAKOTO

LANCET INFECTIOUS DISEASES

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2021

1473-3099

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