Fexinidazole Treatment was found to be effective for patients with Chagas disease and was associated with fewer adverse events when administered at lower doses and in shorter durations, according to results of a study published in Clinical Infectious Diseases.
Researchers performed a double-blind, randomized, placebo-controlled, proof-of-concept phase 2 study among adults in Bolivia with polymerase chain reaction-confirmed Chagas disease. Patients were randomly assigned to receive either a 1200- or 1800-mg dose of fexinidazole or placebo daily, at a duration of 2, 4, or 8 weeks. The primary outcome was the effectiveness of each regimen of fexinidazole vs placebo in eliminating Trypanosoma cruzi parasitemia. The primary endpoint was the achievement of sustained parasitic clearance for up to 12 months following the end of treatment.
The study population initially comprised 47 patients, 14 of whom were men. The mean patient age was 34.2 years.
Fexinidazole treatment was discontinued in 4 patients due to the occurrence of severe neutropenia at approximately day 63; all 4 patients had received treatment for more than 2 weeks. A total 24 severe adverse events were reported among patients who received fexinidazole, 16 of which were deemed treatment related. Of note, symptoms of severe depression leading to subsequent suicide occurred in 1 patient who received fexinidazole. Neuropsychiatric-related adverse events occurred between days 2 and 7 among 30 (75%) patients who received fexinidazole, with insomnia noted in 18, anxiety in 10, depression in 15, and neuropathy in 15.
Concentrations of alanine aminotransferase and aspartate aminotransferase 3 times above the upper limit of normal were observed in 16 patients. Of these patients, acute hepatocellular liver injury was observed in 6 and acute cholestatic liver injury or mixed liver injury was observed in 2. No liver-related events were observed among patients who received placebo, nor in those who received fexinidazole at a cumulative dose of less than 12.6 g.
All patients with complete follow-up data (n=42) who received fexinidazole achieved sustained parasitic clearance for 12 months after the end of treatment, including those who received less than 5 (n=9) or less than 7 (n=11) days of treatment. Owing to this finding, the researchers noted that “… shorter treatment regimens and lower [fexinidazole] doses may improve safety outcomes” in patients with Chagas disease.
The researchers noted that “the unexpected adverse events recorded in this study indicate the fexinidazole treatment regimens tested are not sufficiently safe for treating chronic [Chagas disease].” However, they concluded that “… efficacy findings and exposure-response analyses suggest further proof-of-concept trials of fexinidazole at lower doses and shorter durations are warranted.”
Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Torrico F, Gascón J, Ortiz L, et al. A phase-2, randomized, multicenter, placebo-controlled, proof-of-concept trial of oral fexinidazole in adults with chronic indeterminate Chagas disease. Clin Infect Dis. Published online August 4, 2022. doi: 10.1093/cid/ciac579