The praziquantel in preschoolers (PIP) trial: study protocol for a phase II PK/PD-driven randomised controlled trial of praziquantel in children under 4 years of age

摘要

Over 200 million individuals worldwide are infected with Schistosoma species, with over half of infections occurring in children. Many children experience first infections early in life and this impacts their growth and development; however praziquantel (PZQ), the drug used worldwide for the treatment of schistosomiasis, only has regulatory approval among adults and children over the age of four, although it is frequently used “off label” in endemic settings. Furthermore, pharmacokinetic/pharmacodynamics (PK/PD) evidence suggests the standard PZQ dose of 40?mg/kg is insufficient in preschool-aged children (PSAC). Our goal is to understand the best approaches to optimising the treatment of PSAC with intestinal schistosomiasis. We will conduct a randomised, controlled phase II trial in a Schistosoma mansoni endemic region of Uganda and a Schistosoma japonicum endemic region of the Philippines. Six hundred children, 300 in each setting, aged 12–47?months with Schistosoma infection will be randomised in a 1:1:1:1 ratio to receive either (1) 40?mg/kg PZQ at baseline and placebo at 6 months, (2) 40?mg/kg PZQ at baseline and 40?mg/kg PZQ at 6 months, (3) 80?mg/kg PZQ at baseline and placebo at 6 months, or (4) 80?mg/kg PZQ at baseline and 80?mg/kg PZQ at 6 months. Following baseline treatment, children will be followed up for 12?months. The co-primary outcomes will be cure rate and egg reduction rate at 4 weeks. Secondary outcomes include drug efficacy assessed by novel antigenic endpoints at 4 weeks, actively collected adverse events and toxicity for 12?h post-treatment, morbidity and nutritional outcomes at 6 and 12?months, biomarkers of inflammation and environmental enteropathy and PZQ PK/PD parameters. The trial will provide valuable information on the safety and efficacy of the 80?mg/kg PZQ dose in PSAC, and on the impact of six-monthly versus annual treatment, in this vulnerable age group. ClinicalTrials.gov NCT03640377 . Registered on 21 Aug 2018.