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

Abstract

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. MethodsWe 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 perprotocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661.

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy

“…Our data showed that suboptimal dose of Bz decreased parasitemia and heart parasite load, corroborating previous findings ( Vilar-Pereira et al., 2016 ). Indeed, compared with the therapeutic dose (100 mg/kg/day), lower doses of Bz are able to control parasite burden in vivo and in vitro ( Cevey et al., 2016 ), raising the question that the Bz dosing regimen currently used should be revised and optimized ( Almeida et al., 2019 ; DNDi, 2019 ; Molina-Morant et al., 2020a ; Torrico et al., 2021 ). Although Bz therapy has controversial data as a therapeutic approach to hamper progression of Chagas heart disease when used in chronically infected patients ( Machado-de-Assis et al., 2013 ; Morillo et al., 2015 ; Rassi et al., 2017 ; Nunes et al., 2018 ), our data support that therapy with the suboptimal Bz dose, which was able to partially reverse pivotal electrical abnormalities (bradycardia, P duration, QTc).…”

“…The BENEFIT study, the most extensive clinical trial with patients with CCC performed to date, showed that 192 (13.4%) of patients interrupted treatment during the study due to drug adverse events (AEs) ( Morillo et al., 2015 ). Thus, in recent years, new clinical studies are making efforts to find new strategies to decrease Bz dosage and even increase its efficacy ( Almeida et al., 2019 ; Molina-Morant et al., 2020a ; Torrico et al., 2021 ) to reduce the occurrence of adverse events, thus enhancing treatment compliance ( Ciapponi et al., 2020 ). On the other hand, efficacy of Bz treatment in progression of severity of CCC is still on debate ( Rassi et al., 2017 ).…”

A Rapid Review on the Efficacy and Safety of Pharmacological Treatments for Chagas Disease

“…Finally, the present study only captures literature available by December 2020. Torrico et al [ 41 ] published the BENDITA study on April 2021 and it was therefore not included in our analysis. Future reviews should include this important study.…”

“…In fact, a recent RCT published right after the completion of the present rapid review, the BENDITA study, by Torrico, et al, found that variations in BNZ dosing, duration, and combination therapy of BNZ with fosravucanazole were similar in efficacy regardless of the treatment duration, dose or combination therapy. The implications of this study are groundbreaking: shorter durations or lower doses of BNZ could have the same efficacy and potentially a lower risk of AEs and treatment discontinuation [ 41 ]. Future RCTs should be conducted to confirm these findings.…”

Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

“…A recent study conducted by Torrico and colleagues evaluated patients with chronic indeterminate Chagas disease [26]. They found that treatment in the chronic phase with a lower dose and shorter treatment duration have similar efficacy when compared to the standard treatment, in addition to higher safety.…”