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

Abstract

Background 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. Methods 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. Discussion 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. Trial registration ClinicalTrials.gov NCT03640377. Registered on 21 Aug 2018.

Baseline Liver Ultrasound Findings in Preschool Children From the Praziquantel in Preschoolers Trial in Lake Albert, Uganda

“…Urine samples from potential participants were tested with circulating cathodic antigen testing 25 by field staff in villages following informed consent for initial screening. 24 Children with eggs in stool by Kato–Katz test who were otherwise healthy, were eligible for the study.…”

“…At the enrollment visit, children meeting eligibility criteria were admitted for up to 24 hours for administration of PZQ and assessment of pharmacokinetic parameters. 24 Information was collected on demographics, anthropometry, water exposure, biochemistry, full blood count, HIV and malaria. Ultrasound was performed by trained ultrasound technicians, following the Niamey Protocol 14 to assess baseline presence or absence of any schistosomiasis-related pathology.…”

“…22 Another study found left lobe hepatomegaly and splenomegaly to be associated with S. mansoni infection, but not liver fibrosis. 23 As part of a phase II trial of PZQ exploring different dosing regimens in children 12-47 months of age in Uganda (the praziquantel in preschoolers trial), 24 we assessed baseline liver US findings among a group of S. mansoni infected children.…”

Safety of integrated preventive chemotherapy for neglected tropical diseases

“…The availability of oral suspension for trachoma, the new chewable, rapidly disintegrating, mebendazole tablet (donated by Johnson & Johnson), and the forthcoming pediatric formulation of praziquantel open new possibilities for safe coadministration of NTD drugs in young children, specifically with respect to choking [55][56][57][58][59][60][61]. However, other questions remain.…”

Drugs for neglected tropical diseases: availability of age-appropriate oral formulations for young children

“…The clinical development programme to support the planned 2022 submission for a scientific opinion from the EMA for the enantiomer pure formulation (arpraziquantel) by Merck [ 106 ] included: two relative bioavailability studies [ 107 ], a randomised control phase 2 pharmacokinetic-pharmacodynamic (PK PD) dose finding study in S. mansoni - and S. japonicum -infected children and infants (clinicaltrials.gov identifier NCT02806263)[ 108 ], a palatability study [ 103 ] and a phase 3 efficacy and safety study in 3-month- to 6-year-old schistosoma-infected children, including a 4–6-year-old S. mansoni -infected cohort randomised to arpraziquantel or the currently available formulation (clinicaltrials.gov identifier NCT03845140) completed in November 2021 in Côte d’Ivoire and Kenya [ 106 ].…”