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

ORTIZ LOURDES; ALEJANDRO G. SCHIJMAN,; STRUB- WOURGAFT N; GASCON J; PINAZO MJ; ALVES FABIANA; GASCON J; PINAZO MJ; ALVES FABIANA; FAUSTINO TORRICO; ALONSO-VEGA CRISTINA; ALMEIDA IGOR; ISABELA RIBEIRO; FAUSTINO TORRICO; ALONSO-VEGA CRISTINA; ALMEIDA IGOR; ISABELA RIBEIRO; ORTIZ LOURDES; ALEJANDRO G. SCHIJMAN,; STRUB- WOURGAFT N

LANCET INFECTIOUS DISEASES

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2018 p. 419 - 430

1473-3099

Background Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety andefficacy of three oral E1224 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 randomisedwith a computer-generated randomisation list, which was stratified by centre and used a block size of 10. 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 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were sustainabilityof 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 analysispopulation 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 treatmentphase, 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