A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease

Abstract

Background Chagas disease (CD) has significant global health impact, but safe and effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods This double-blind, randomised, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically-confirmed chronic indeterminate CD and positive PCR were randomly assigned to one of six fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat population (ITT). Follow-up was extended to 12 months. Results Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade-3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received from 3 days to 8 weeks of treatment with fexinidazole. Delayed onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients, versus none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (“1200mg-2week”) and 100.0% (“1800mg-2week”). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (p = 0.0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions Further evaluation is needed to establish fexinidazole’s minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens of <10 days.

Monotherapy and combination chemotherapy for Chagas disease treatment: a systematic review of clinical efficacy and safety based on randomized controlled trials

“…Conversely, BNZ (150 mg −1 kg per 60 days) showed better results compared to posaconazole (100 or 400 mg −1 kg per 60 days), returning a higher negative seroconversion rate (94.1%) for BNZ compared to posaconazole (10-20%) (Molina et al, 2014). Torrico et al (2018) identified a similar response in patients with chronic ChD receiving ravuconazole. Accordingly, this drug (4000 or 2000 mg for 65 days) determined lower negative seroconversion rates (28.9% or 8.3%) compared to BNZ (82.2%, 5 mg −1 kg per 60 days).…”

“…In this review, we identified that the evidence provided by randomized controlled clinical trials targeting ChD treatment is based on BNZ (De Andrade et al, 1996;Sosa Estani et al, 1998;Andrade et al, 2004;Marin-Neto et al, 2008;Chippaux et al, 2010;Morillo et al, 2015;Vallejo et al, 2016;Molina-Morant et al, 2020), NFx (Coura et al, 1997, allopurinol (Rassi et al, 2007), posaconazole (Molina et al, 2014;Morillo et al, 2017), ravuconazole (Torrico et al, 2018) and fosravuconazole (Torrico et al, 2021); administered in monotherapy, as well as BNZ combined with thioctic acid (Sosa-Estani et al, 2004), posaconazole (Morillo et al, 2017) and fosravuconazole (Torrico et al, 2021).…”

“…2003; Muñoz et al, 2011;Nogueira et al, 2018). Despite clinical evidence generated in recent decades supporting BNZ-based treatment for indeterminate chronic ChD (Molina et al, 2014;Morillo et al, 2017;Torrico et al, 2018), more efficient and safer drugs are still needed. Thus, several studies reviewed were based on repositioning strategies involving drugs with trypanocidal potential, such as allopurinol (Rassi et al, 2007), posaconazole (Molina et al, 2014;Morillo et al, 2017), ravuconazole (Torrico et al, 2018) and fosravuconazole (Torrico et al, 2021).…”

“…Studies prior to 2014 were unable to meet all criteria. However, 4 studies (26.66%) after 2014 met all the methodological criteria analysed (Molina et al, 2014;Morillo et al, 2017;Torrico et al, 2018Torrico et al, , 2021. Considering the items evaluated in the D&B checklist, criteria 8 and 10 were the least observed by the authors, namely: were the statistical tests used to assess the main outcomes appropriate?…”

“…All treatments were associated with a low frequency of altered liver function estimated from alanine aminotransferase levels (2.2-38%) and reduced white blood cell counts (0.1-43%). Altered liver function, estimated from serum transaminase levels, was identified in patients treated with BNZ (Molina et al, 2014;Morillo et al, 2015Morillo et al, , 2017Vallejo et al, 2016;Torrico et al, 2018Torrico et al, , 2021, posaconazole (Molina et al, 2014;Morillo et al, 2017) and E1224 (Torrico et al, 2018) alone, as well as BNZ combined with thioctic acid (Sosa-Estani et al, 2004), posaconazole (Morillo et al, 2017) or fosravuconazole (Torrico et al, 2021). Leucopenia, neutropenia and/or lymphopenia were identified in patients treated with allopurinol, BNZ alone or combined with fosravuconazole (Rassi et al, 2007;Morillo et al, 2015;Torrico et al, 2021) (Table 3).…”