Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial

Abstract

<strong>Background </strong>More than six million people worldwide, particularly in vulnerable communities in Latin America, areinfected with <em>Trypanosoma cruzi</em>, the causative agent of Chagas disease. Only a small portion have access to diagnosisand treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, weredeveloped more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% ofpatients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the dosesevaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatmentdurations.<strong>Methods </strong>In this randomised, double-blind, phase 2 trial, we included adult patients (18–60 years old) with confirmed<em>T cruzi </em>infection by serology and PCR and without signs of organ involvement. We evaluated three regimens offexinidazole—600 mg once daily for 10 days (6∙0 g total dose), 1200 mg daily for 3 days (3∙6 g), and 600 mg daily for3 days followed by 1200 mg daily for 4 days (6∙6 g)—and compared them with a historical placebo control group(n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to fourmonths of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15.<strong>Findings </strong>Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completedthe study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%)of 46 in the historical control group. Mean parasite load decreased sharply following treatment but reboundedbeginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, deviceinfection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinuedtreatment due to adverse events unrelated to fexinidazole.<strong>Interpretation </strong>The fexinidazole regimens in this study had an acceptable safety profile but did not prove effectiveagainst <em>T cruzi </em>infection. Development of fexinidazole monotherapy for treating <em>T cruzi</em> infection has been stopped.