Oral Fexinidazole Dosing Regimens for the Treatment of Adults With Chronic Indeterminate Chagas Disease

Summary

This study focuses on the evaluation of low doses (600 and 1200 mg) and short treatment duration (at 3, 7 and 10 days) of fexinidazole (Fexi) to determine the minimal efficacious and safe dose for the treatment of adult patients with chronic indeterminate Chagas Disease (CD).

Timeline

Start

2017-11-13

Primary completion

2018-12-19

Completion

2019-08-28

Outcome

Missed primary endpoint

paper Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. PMID 38218194 ↗

paper The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. PMID 38218194 ↗

Publications

• Background WHO | Chagas disease (American trypanosomiasis) [Internet]. WHO. [cited 2013 Aug 22]. Available from: http://www.who.int/mediacentre/factsheets/fs340/en/index.html
• Background Bern C, Montgomery SP. An estimate of the burden of Chagas disease in the United States. Clin Infect Dis. 2009 Sep 1;49(5):e52-4. doi: 10.1086/605091.
• Background Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazue G, Bray MA, Pecoul B. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis. 2010 Dec 21;4(12):e923. doi: 10.1371/journal.pntd.0000923.
• Background Raether W, Seidenath H. The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Ann Trop Med Parasitol. 1983 Feb;77(1):13-26. doi: 10.1080/00034983.1983.11811668.
• Background Moraes CB, Giardini MA, Kim H, Franco CH, Araujo-Junior AM, Schenkman S, Chatelain E, Freitas-Junior LH. Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development. Sci Rep. 2014 Apr 16;4:4703. doi: 10.1038/srep04703.
• Background Bahia MT, de Andrade IM, Martins TA, do Nascimento AF, Diniz Lde F, Caldas IS, Talvani A, Trunz BB, Torreele E, Ribeiro I. Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Negl Trop Dis. 2012;6(11):e1870. doi: 10.1371/journal.pntd.0001870. Epub 2012 Nov 1.
• Background Caldas S, Caldas IS, Cecilio AB, Diniz LF, Talvani A, Ribeiro I, Bahia MT. Therapeutic responses to different anti-Trypanosoma cruzi drugs in experimental infection by benznidazole-resistant parasite stock. Parasitology. 2014 Oct;141(12):1628-1637. doi: 10.1017/S0031182014000882.
• Background Munoz J, Gomez i Prat J, Gallego M, Gimeno F, Trevino B, Lopez-Chejade P, Ribera O, Molina L, Sanz S, Pinazo MJ, Riera C, Posada EJ, Sanz G, Portus M, Gascon J. Clinical profile of Trypanosoma cruzi infection in a non-endemic setting: immigration and Chagas disease in Barcelona (Spain). Acta Trop. 2009 Jul;111(1):51-5. doi: 10.1016/j.actatropica.2009.02.005. Epub 2009 Mar 5.
• Background Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz. 2002 Jan;97(1):3-24. doi: 10.1590/s0074-02762002000100001.
• Background Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010 Apr 17;375(9723):1388-402. doi: 10.1016/S0140-6736(10)60061-X.
• Background Pinto Dias JC. The treatment of Chagas disease (South American trypanosomiasis). Ann Intern Med. 2006 May 16;144(10):772-4. doi: 10.7326/0003-4819-144-10-200605160-00012. No abstract available.
• Background Castro AM, Luquetti AO, Rassi A, Rassi GG, Chiari E, Galvao LM. Blood culture and polymerase chain reaction for the diagnosis of the chronic phase of human infection with Trypanosoma cruzi. Parasitol Res. 2002 Oct;88(10):894-900. doi: 10.1007/s00436-002-0679-3. Epub 2002 Jun 15.
• Background de Castro AM, Luquetti AO, Rassi A, Chiari E, Galvao LM. Detection of parasitemia profiles by blood culture after treatment of human chronic Trypanosoma cruzi infection. Parasitol Res. 2006 Sep;99(4):379-83. doi: 10.1007/s00436-006-0172-5. Epub 2006 Mar 29.
• Background Britto C, Cardoso MA, Vanni CM, Hasslocher-Moreno A, Xavier SS, Oelemann W, Santoro A, Pirmez C, Morel CM, Wincker P. Polymerase chain reaction detection of Trypanosoma cruzi in human blood samples as a tool for diagnosis and treatment evaluation. Parasitology. 1995 Apr;110 ( Pt 3):241-7. doi: 10.1017/s0031182000080823.
• Background Solari A, Ortiz S, Soto A, Arancibia C, Campillay R, Contreras M, Salinas P, Rojas A, Schenone H. Treatment of Trypanosoma cruzi-infected children with nifurtimox: a 3 year follow-up by PCR. J Antimicrob Chemother. 2001 Oct;48(4):515-9. doi: 10.1093/jac/48.4.515.
• Background Galvao LM, Chiari E, Macedo AM, Luquetti AO, Silva SA, Andrade AL. PCR assay for monitoring Trypanosoma cruzi parasitemia in childhood after specific chemotherapy. J Clin Microbiol. 2003 Nov;41(11):5066-70. doi: 10.1128/JCM.41.11.5066-5070.2003.
• Background Schijman AG, Altcheh J, Burgos JM, Biancardi M, Bisio M, Levin MJ, Freilij H. Aetiological treatment of congenital Chagas' disease diagnosed and monitored by the polymerase chain reaction. J Antimicrob Chemother. 2003 Sep;52(3):441-9. doi: 10.1093/jac/dkg338. Epub 2003 Aug 13.
• Background Flores-Chavez M, Bosseno MF, Bastrenta B, Dalenz JL, Hontebeyrie M, Revollo S, Breniere SF. Polymerase chain reaction detection and serologic follow-up after treatment with benznidazole in Bolivian children infected with a natural mixture of Trypanosoma cruzi I and II. Am J Trop Med Hyg. 2006 Sep;75(3):497-501.
• Background Duffy T, Bisio M, Altcheh J, Burgos JM, Diez M, Levin MJ, Favaloro RR, Freilij H, Schijman AG. Accurate real-time PCR strategy for monitoring bloodstream parasitic loads in chagas disease patients. PLoS Negl Trop Dis. 2009;3(4):e419. doi: 10.1371/journal.pntd.0000419. Epub 2009 Apr 21.
• Background Ramirez JD, Guhl F, Umezawa ES, Morillo CA, Rosas F, Marin-Neto JA, Restrepo S. Evaluation of adult chronic Chagas' heart disease diagnosis by molecular and serological methods. J Clin Microbiol. 2009 Dec;47(12):3945-51. doi: 10.1128/JCM.01601-09. Epub 2009 Oct 21.
• Background Diez M, Favaloro L, Bertolotti A, Burgos JM, Vigliano C, Lastra MP, Levin MJ, Arnedo A, Nagel C, Schijman AG, Favaloro RR. Usefulness of PCR strategies for early diagnosis of Chagas' disease reactivation and treatment follow-up in heart transplantation. Am J Transplant. 2007 Jun;7(6):1633-40. doi: 10.1111/j.1600-6143.2007.01820.x.
• Pinazo MJ, Forsyth C, Losada I, Esteban ET, Garcia-Rodriguez M, Villegas ML, Molina I, Crespillo-Andujar C, Gallego M, Ballart C, Ramirez JC, Aden T, Hoerauf A, Pfarr K, Vaillant M, Marques T, Fernandes J, Blum B, Ribeiro I, Sosa-Estani S, Barreira F, Gascon J; FEXI-12 Study Team. Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2024 Apr;24(4):395-403. doi: 10.1016/S1473-3099(23)00651-5. Epub 2024 Jan 11.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Fexinidazole	Small molecule	600 mg	Oral
Subject	Fexinidazole	Small molecule	1200 mg	Oral

Indications