Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial

• Autores: Pinazo, Maria Jesus; Forsyth, Colin; Losada, Irene; Esteban, Elena Trigo; García Rodríguez, Magdalena; Villegas, Maria Luz; Molina, Israel; Crespillo Andújar, Clara; Gállego, Montserrat; Ballart, Cristina; Ramirez Gomez, Juan Carlos; Aden, Tilman; Hoerauf, Achim; Pfarr, Kenneth; Vaillant, Michel; Marques, Tayná; Fernandes, Jayme; Blum, Bethania; Ribeiro, Isabela; Sosa Estani, Sergio Alejandro; Barreira, Fabiana; Gascón, Joaquim
• Año de publicación: 2024
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: CHAGAS DISEASE; TRYPANOCIDAL DRUGS; CLINICAL TRIALS; BENZNIDAZOLE
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Background More than six million people worldwide, particularly in vulnerable communities in Latin America, are infected with Trypanosoma cruzi, the causative agent of Chagas disease. Only a small portion have access to diagnosis and treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, were developed more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% of patients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the doses evaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatment durations. Methods In this randomised, double-blind, phase 2 trial, we included adult patients (18–60 years old) with confirmed T cruzi infection by serology and PCR and without signs of organ involvement. We evaluated three regimens of fexinidazole—600 mg once daily for 10 days (6∙0 g total dose), 1200 mg daily for 3 days (3∙6 g), and 600 mg daily for 3 days followed by 1200 mg daily for 4 days (6∙6 g)—and compared them with a historical placebo control group (n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to four months of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15. Findings Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completed the study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. Mean parasite load decreased sharply following treatment but rebounded beginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, device infection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinued treatment due to adverse events unrelated to fexinidazole. Interpretation The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. Development of fexinidazole monotherapy for treating T cruzi infection has been stopped. Funding The Drugs for Neglected Diseases initiative.
Fil: Pinazo, Maria Jesus. Drugs For Neglected Diseases Initiative; Brasil. Universidad de Barcelona; España. Instituto de Salud Carlos III; España
Fil: Forsyth, Colin. Drugs For Neglected Diseases Initiative; Brasil
Fil: Losada, Irene. Universidad de Barcelona; España
Fil: Esteban, Elena Trigo. Hospital Universitario La Paz; España
Fil: García Rodríguez, Magdalena. Consorcio Hospital General Universitario de Valencia; España
Fil: Villegas, Maria Luz. Complex Hospitalari Universitari Moisès Broggi; España
Fil: Molina, Israel. Hospital Universitari Vall D'hebron; España. Instituto de Salud Carlos III; España
Fil: Crespillo Andújar, Clara. National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital; Argentina. Hospital Universitario La Paz; España. Instituto de Salud Carlos III; España
Fil: Gállego, Montserrat. Universidad de Barcelona; España. Instituto de Salud Carlos III; España
Fil: Ballart, Cristina. Universidad de Barcelona; España. Instituto de Salud Carlos III; España
Fil: Ramirez Gomez, Juan Carlos. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
Fil: Aden, Tilman. University Hospital Bonn; Alemania
Fil: Hoerauf, Achim. University Hospital Bonn; Alemania. German Center for Infection Research; Alemania
Fil: Pfarr, Kenneth. University Hospital Bonn; Alemania. German Center for Infection Research; Alemania
Fil: Vaillant, Michel. Luxembourg Institute of Health; Alemania
Fil: Marques, Tayná. Drugs For Neglected Diseases Initiative; Brasil
Fil: Fernandes, Jayme. Drugs For Neglected Diseases Initiative; Brasil
Fil: Blum, Bethania. Drugs For Neglected Diseases Initiative; Brasil
Fil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; Brasil
Fil: Sosa Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina
Fil: Barreira, Fabiana. Drugs For Neglected Diseases Initiative; Brasil
Fil: Gascón, Joaquim. Drugs For Neglected Diseases Initiative; Brasil. Instituto de Salud Carlos III; España