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 80 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 80 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 80 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.
Phase:
Phase 2
Details
Lead Sponsor:
Rhode Island Hospital
Collaborators:
London School of Hygiene and Tropical Medicine Medical Research Council Research Institute for Tropical Medicine, Philippines University of Liverpool