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

Faustino Torrico, Joaquim Gascón, Lourdes Ortiz, Jimy Pinto, Gimena Rojas, Alejandro Palacios, Fabiana Barreira, Bethania Blum, Alejandro Gabriel Schijman, Michel Vaillant, Nathalie Strub-Wourgaft, Maria Jesus Pinazo, Graeme Bilbe, Isabela Ribeiro*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Background: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods: This double-blind, randomized, 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 1 of 6 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 (ITT) population. 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 treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). 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 =. 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 <10 days. Clinical Trials Registration: NCT02498782.

Original languageEnglish
Pages (from-to)e1186-e1194
JournalClinical Infectious Diseases
Volume76
Issue number3
Early online date4 Aug 2022
DOIs
Publication statusPublished - 1 Feb 2023

Keywords

  • Chagas disease
  • fexinidazole
  • neglected tropical diseases
  • Trypanosoma cruzi

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