Praziquantel in Children Under Age 4

Learn more about:
Related Clinical Trial
Correlating Protection Against Malaria With Serum Profiles Against Plasmodium Falciparum Antigen Repertoires Prevalence of Chronic Kidney Disease (CKD) and Risk Factors in Sub-Saharan Africa S. Japonicum and Pregnancy Outcomes Artemisinin-based Combination Therapy-Intermittent Preventive Treatment (ACT-IPT) Trial Among Schoolchildren in Kassena-Nankana, Ghana Study of Safety and Immune Response of the Sm14 Vaccine in Adults of Endemic Regions L-praziquantel Orodispersible Tablets (L-PZQ ODT) in Schistosoma Infected Children The Effect of Praziquantel Treatment on Schistosoma Mansoni Morbidity and re-Infection Along Lake Victoria, Uganda Praziquantel in Children Under Age 4 Schistosoma Haematobium Infections and Praziquantel Antioxidant Supplements in the Reversal of Schistosomal Peri-portal Fibrosis Single-sex Controlled Human Schistosomiasis Infection: Safety and Dose Finding A Phase Ib Study of the Safety, Reactogenicity, and Immunogenicity of Sm-TSP-2/Alhydrogel)(R) With or Without AP 10-701 for Intestinal Schistosomiasis in Healthy Exposed Adults Single-sex Female Controlled Human Schistosomiasis Mansoni Infection An Open Label Dose Finding Safety and Efficacy in Children and Infants Infected With Schistosomiasis (S.Mansoni) Schistosomiasis Effect on Response to Vaccines, Anaemia and Nutritional Status of Children of Northern Senegal Praziquantel-Pharmacokinetic Study Schistosomiasis in Women of Reproductive Age in Burkina Faso: Implications for Control Iron Supplementation in Schistosomiasis and Soil Transmitted Helminths Control Programmes in Zambia Schistosomiasis in Formal and Non-Formal Schools in Uganda: Implications for Control Programmes Using Community-Based Volunteers to Reach Non-Enrolled School Aged Children Through Community-Directed Treatment of Schistosomiasis in School-Aged Children in Rural Northern Ghana Sm-TSP-2 Schistosomiasis Vaccine in Healthy Ugandan Adults Clinical Trial of Bilhvax,a Vaccine Candidate Against Schistosomiasis A Phase I Study of the Safety, Reactogenicity, and Immunogenicity of Sm-TSP-2/Alhydrogel® With or Without GLA-AF for Intestinal Schistosomiasis in Healthy Adults Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study Schistosomiasis in Senegal Repeated Doses of Praziquantel in Schistosomiasis Treatment (RePST) Childhood Schistosomiasis: a Novel Strategy Extending the Benefits/Reach of Antihelminthic Treatment Anti-Schistosomiasis Vaccine: Sm14 Phase 2b-Sn in School Children Study to Evaluate the Safety of the Vaccine Prepared sm14 Against Schistosomiasis Arachidonic Acid Treatment Against Schistosomiasis Infection in Children Detection of Schistosomiasis CAA in Travellers After High-risk Water Contact Evaluation of Strategies for Improved Uptake of Preventive Treatment for Intestinal Schistosomiasis Health Benefits of Repeated Treatment in Pediatric Schistosomiasis Seropositivity and Adverse Birth Events in Migrants From Bilharzia-endemic Areas Women and Children as the Focus for Control of Schistosomiasis Infections in the Irrigations Area of Burkina Faso

Brief Title

Praziquantel in Children Under Age 4

Official Title

Phase II PK/PD Driven Dose Finding Trial of Praziquantel in Children Under Four

Brief 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.
    

Detailed Description

      Over 200 million individuals worldwide are infected with one of three predominant species of
      schistosomes, with over half of infections occurring in children.1 Recent studies have
      highlighted the fact that many children experience their first infections before the age of
      two, with the prevalence of infection among children under four mirroring the prevalence of
      older children and adults from the same community.2 Importantly, schistosomiasis has been
      implicated as a cause of linear growth stunting, undernutrition, anemia, and deficits in
      neurodevelopment among children over the age of four, representing a significant proportion
      of the global burden of disease due to schistosomiasis.3 Little is known with respect to the
      impact of schistosomiasis on key morbidities among the highly vulnerable group of children
      under four.

      In the 1980s, Praziquantel (PZQ) was approved for the treatment of schistosomiasis among
      adults and children ages four and older, and remains FDA approved only for this age group. In
      2008, the WHO funded studies to address the safety and parasitologic efficacy of PZQ in the
      context of S. haematobium and S. mansoni in young children. Based on these and other studies,
      the WHO in 2011 issued a report recommending that pre-school age children be treated as part
      of "regular health services."4 This recommendation was based on studies that did not a)
      evaluate pharmaco-kinetics/dynamics (PK-PD) in this age group, b) evaluate parasitologic
      efficacy in S. japonicum or c) evaluate the impact of treatment on key
      schistosomiasis-related morbidities. Since that time, co-PI Bustinduy led the first study of
      the PK-PD of PZQ at both 40 and 60 mg/kg dosing among children ages 3-8. Results from that
      study, albeit small, showed that higher doses are likely needed, particularly for younger
      children. Authors urged further study of higher doses in this age group, the causes of the
      significant inter-subject variability in PK-PD, better PD indices linking drug exposure to
      treatment effects, and enantiomer activity across all three species before introduction of
      monoenantiomeric formulations.5

      Thus, significant lacunae remain with respect to treatment of pre-school age children, which
      contribute to the persistent exclusion of this vulnerable age group from preventive
      chemotherapy campaigns, with none of the 28 schistosomiasis endemic African nations or The
      Philippines currently including children under the age of four in control programs.2 In this
      application, we propose a trial to investigate the off label use of PZQ in children under the
      age of four. The trial will be conducted at two sites, with high prevalence of intestinal
      schistosomiasis due to S. mansoni (Uganda) and S. japonicum (The Philippines) employing a two
      arm single blind, placebo controlled modified cross-over trial design among N=600 children
      ages 1-4. Children who are infected with schistosomiasis will be randomized at baseline to
      receive 40 or 60 mg/kg of PZQ. At six months, we will re-randomize half of each baseline
      group to receive a treatment at the same dose or placebo. This will allow us to evaluate the
      impact of 6 versus 12 month treatment intervals on key measures of morbidity which,
      importantly, will inform frequency of treatment needed in this young age group. Successful
      execution of the following specific aims for this trial will address the significant
      aforementioned gaps:

      SA1 To assess the PK/PD of PZQ administered at different dose regimens. SA1a To measure drug
      efficacy as per standard parasitological endpoints (Cure Rate and Egg Reduction Rate) at 4
      +/- 1 weeks post-PZQ.

      SA1b To expand PD endpoints for drug efficacy to include state-of-the art antigen tests to
      accurately capture residual worm burden (Circulating Cathodic and Anodic Antigens (CCA and
      CAA)).

      SA1c To evaluate the PK/PD of both PZQ enantiomers given the concern that this varies across
      species and has varied in studies of S. mansoni.

      SA1d To assess the role of environmental enteropathy in inter-individual variability in PZQ
      area under the curve (AUC) demonstrated in this age group.

      SA2 To assess the safety and impact of PZQ treatment (dose and interval) on key measures of
      morbidity 6 and 12 months after initial treatment and mechanisms mediating morbidity.

      SA2a To further evaluate the safety of higher PZQ dosing (60 mg/kg), particularly among the
      unstudied group of very young children ages 1-2.

      SA2b To evaluate the impact of different doses (40 vs. 60 mg/kg) and varying dosing intervals
      (every 6 or 12 months) on iron status, hemoglobin, and age and gender adjusted longitudinal
      growth and nutritional status as captured by height and weight for age, and weight for height
      z-scores as determined by WHO Anthro.

      SA2c To evaluate the mechanistic role of environmental enteropathy (EE) in the pathogenesis
      of schistosomiasis related morbidities. We will capture state of the art biomarkers of EE
      including fecal calprotectin, urine lactulose:mannitol ratio, serum endotoxin, serum
      endotoxin core antibody, and pro-inflammatory cytokines and employ Path Modeling techniques
      to identify mechanistic pathways.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Treatment efficacy

Secondary Outcome

 Iron status

Condition

Schistosomiasis

Intervention

Praziquantel

Study Arms / Comparison Groups

 Praziquantel 40 mg/kg dose only baseline treatment
Description:  150 children will receive 40 mg/kg Praziquantel at baseline as single treatment and placebo six months following baseline

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

600

Start Date

January 1, 2019

Completion Date

June 30, 2022

Primary Completion Date

June 30, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  S. japonicum or S. mansoni infection by urine CCA

          -  Otherwise healthy as determined by history and physical examination conducted by the
             study physician at the second stage screening

          -  Age 12-48 months inclusive

          -  Parental consent to participate.

        Exclusion Criteria:

          -  Parental inability to provide informed consent

          -  Significant disease/illness as determined by history or physical exam. This includes a
             severe acute illness or chronic disease as defined by greater than 3 months duration
             and significantly impacting a child's daily activities.

          -  Severe wasting as defined by WHZ < -3,

          -  Severe anemia (hemoglobin < 7 g/dL)

          -  Exposure to immuno-modulatory therapeutics.
      

Gender

All

Ages

12 Months - 48 Months

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

, 401 444 7449, [email protected]



Administrative Informations


NCT ID

NCT03640377

Organization ID

403818


Responsible Party

Principal Investigator

Study Sponsor

Rhode Island Hospital

Collaborators

 London School of Hygiene and Tropical Medicine

Study Sponsor

, , 


Verification Date

August 2018