A Non-Inferiority Randomized Single Blind Controlled Trial Comparing One and Two Dose Regimes of Oxfendazole versus a Two Dose Regime of Triclabendazole to Treat Chronic Fascioliasis

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Oxfendazole in Fascioliasis Principal Investigators/Program Directors: GARCIA, Hector H./ CABADA, Miguel M. A Non-Inferiority Randomized Single Blind Controlled Trial Comparing One and Two Dose Regimes of Oxfendazole versus a Two Dose Regime of Triclabendazole to Treat Chronic Fascioliasis ABSTRACT Fasciola hepatica infection causes human liver disease in wide endemic regions around the world. Triclabendazole is the only effective drug to treat human fascioliasis. However, it is not widely available and recently reports about resistance in livestock and decreased efficacy in humans raise concerns for the availability of effective treatment in human infections. Triclabendazole (TCBZ) resistance in human has been reported in The Netherlands, Turkey, Chile, Portugal, and Peru. In our experience in Cusco, Peru, more than 40% of children treated with one triclabendazole dose failed to achieve parasitological cure and 60% of these failed a second dose of treatment. Oxfendazole (OXF) is a veterinary benzimidazole with a wide anti-helminthic spectrum. Our group has demonstrated that OXF is highly efficacious against Taenia solium cysticercosis and other helminths. A preliminary study in naturally infected sheep showed that OXF is also highly efficacious against Fasciola hepatica. We have completed animal toxicology and phase 1 OXF studies in humans, confirming the high bioavailability of OXF and, importantly, its safety. These data strongly suggest that OXF is an excellent candidate for the treatment of human fascioliasis. Therefore, we propose to compare two oral OXF treatment regimens, a single 20 mg/kg dose and two 20 mg/kg doses, against the standard of care of two 10 mg/kg oral doses of TCBZ for the treatment of 336 children and adults with chronic Fasciola hepatica infection in endemic areas of Cusco, Peru. In addition, population PK modeling will be performed among subjects randomized to the OXF arms. This study will evaluate the efficacy, safety, and population pharmacokinetics of OXF in the groups most affected by fascioliasis. This application builds upon our 25-years of experience working with OXF and takes advantage of the solid expertise of the PIs in helminth infections, prior pivotal randomized clinical trials of anti- parasitic treatment in cysticercosis, and our continued work in a well-known Fasciola-endemic region in the Andes Mountains of Cusco. The investigators supported by the Oxfendazole Development Group will form a multidisciplinary team of accomplished experts in fascioliasis, field epidemiology, clinical trials, and new drug development that will ensure the successful completion of this study. This trial has the potential to provide a new standard of care for the treatment of chronic fascioliasis. In addition, it will be the first evaluation of OXF efficacy for a human tissue parasite and constitutes a significant step forward towards making this promising drug available for the treatment of human. It will provide additional pharmacokinetic and safety data to advance OXF development as a human drug.