Phase II PK/PD driven dose finding trial of Praziquantel in children under four

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Project Summary The overall goals of this proposal are to conduct a trial to address the significant gaps with respect to our understanding of best approaches to treatment of children ages 1-4 with intestinal schistosomiasis. Over 200 million individuals worldwide are infected with one of three predominant species of schistosomes, with over half of infections occurring in children. Recent studies have highlighted the fact that many children experience first infections before the age of two, with the prevalence of infection among children under four mirroring the prevalence of older children from the same community. Importantly, praziquantel (PZQ), the drug used worldwide for the treatment of schistosomiasis, is only FDA approved among adults and children over the age of four. Only one small study led by co-PI Bustinduy has evaluated the pharmacokinetic/pharmacodynamics (PK/PD) of PZQ in children. That study, conducted among children ages 3-8, strongly suggests that the current dose of 40 mg/kg is insufficient, with lower cure rates than found at 60 mg/kg. In endemic settings, PZQ is most often administered as part of school based, or community wide preventive chemotherapy campaigns. Currently, none of the 28 schistosomiasis endemic African nations or The Philippines includes children under the age of four in control programs. The reasons for this are multifactorial and include a) lack of sufficient PK/PD data in this age group, with none in children under three, b) lack of safety data at a dose of 60 mg/kg, c) lack of data addressing the impact of treatment on key growth and nutritional outcomes in this vulnerable age group hampering prioritization of treatment, d) no PK/PD studies conducted in the context of pediatric S. japonicum and e) FDA labeling that does not include young children. The goals of this proposal are to conduct a randomized, controlled Phase II trial to be conducted in an S. mansoni endemic region of Uganda and an S. japonicum endemic region of The Philippines with N=600 children ages 1-4, that will address many of the current gaps that are hindering treatment of young children. Specifically in SA1 we will 1) assess PK/PD of PZQ dosing among children under the age of 4 at doses of 40 versus 60 mg/kg, 2) expand PD endpoints to include state of the art antigen tests and morbidity outcomes, 3) assess the PK/PD of both PZQ enantiomers, and 4) address the innovative hypothesis that environmental enteropathy (EE) contributes to the significant inter-individual variability observed in PZQ PK/PD. In SA2, we will 1) assess the safety of PZQ administered at 60 mg/kg in two large cohorts of very young children, 2) assess the impact of two different treatment intervals (6 vs 12 months) on nutritional status, growth, and anemia risk, and 3) address innovative hypotheses regarding mechanisms through which schistosomiasis contributes to morbidity in this age group including EE and gut microbial translocation with consequent systemic immune activation.