Neutropenia

Multicenter trial

Intensive care medicine

Malaria

Pure mathematics

Surgery

Environmental health

Plasmodium falciparum

Parasitemia

Placebo

Immunology

Asymptomatic

Alternative medicine

Indeterminate

Multicenter study

Mathematics

Population

Internal medicine

Clinical endpoint

Chemotherapy

Medicine

Dose

Gastroenterology

Chagas disease

Randomized controlled trial

Pathology

Clinical Infectious Diseases

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 &amp;gt;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 &amp;lt;10 days. Clinical Trials Registration NCT02498782.

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