TY - JOUR
T1 - A phase-2, randomized, multicenter, placebo-controlled, proof-of-concept trial of oral fexinidazole in adults with chronic indeterminate Chagas disease
AU - Torrico, Faustino
AU - Gascón, Joaquim
AU - Ortiz, Lourdes
AU - Pinto, Jimy
AU - Rojas, Gimena
AU - Palacios, Alejandro
AU - Barreira, Fabiana
AU - Blum, Bethania
AU - Schijman, Alejandro Gabriel
AU - Vaillant, Michel
AU - Strub-Wourgaft, Nathalie
AU - Pinazo, Maria Jesus
AU - Bilbe, Graeme
AU - Ribeiro, Isabela
N1 - Funding
This work was supported by the Drugs for Neglected Diseases initiative through funding by the following donors: Associação Bem-Te-Vi Diversidade, Brazil; UK aid, UK; Federal Ministry of Education and Research (BMBF) through KfW, Germany; Médecins Sans Frontières (MSF) International; Rockefeller Foundation, USA; Swiss Agency for Development and Cooperation (SDC), Switzerland; and other private foundations and individuals.
The Platform for a Comprehensive Care of Patients with Chagas disease in Bolivia is a collaborative project between CEADES of Health and Environment; Universidad Mayor de San Simon in Cochabamba, Bolivia; Juan Misael University Saracho, Tarija, Bolivia; and ISGLOBAL (Barcelona Institute for Global Health, Spain), and supported by the National Chagas Control Program in Bolivia. The Platform is funded by the Spanish Agency for Cooperation and Development (AECID) (grant number 10-CO1-039). ISGLOBAL Research group receives funds from the Agència de Gestiód’ Ajuts Universitarisi de Recerca (AGAUR) [grant number 2017SGR924], and from ISCIII, subprogram RETICS co-funded by FEDER (grant number RD16/0027/0004). DNDi, CEADES and ISGLOBAL are members of the Ibero-American NHEPACHA network (New tools for patients with Chagas disease). ICA is supported by NIH/NIMHD grant 2G12MD007592, and is a Special Visiting Researcher of the Science Without Borders Program, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
PY - 2023/2/8
Y1 - 2023/2/8
N2 - 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.
AB - 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.
UR - https://pubmed.ncbi.nlm.nih.gov/35925555
U2 - 10.1093/cid/ciac579
DO - 10.1093/cid/ciac579
M3 - Article
C2 - 35925555
SN - 1058-4838
VL - 76
SP - e1186-e1194
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 3
ER -