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Praziquantel in Children Under Age 4 (PIPS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03640377
Recruitment Status : Not yet recruiting
First Posted : August 21, 2018
Last Update Posted : August 21, 2018
Sponsor:
Collaborators:
London School of Hygiene and Tropical Medicine
University of Liverpool
Research Institute for Tropical Medicine, Philippines
Medical Research Council
Information provided by (Responsible Party):
Jennifer Friedman, MD, PhD, Rhode Island Hospital

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.


Condition or disease Intervention/treatment Phase
Schistosomiasis Schistosomiasis Mansoni Schistosoma Japonicum Infection Drug: Praziquantel Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Children ages 12-48 months who are infected with S. japonicum (Philippines) or S. mansoni (Uganda) will be randomized to receive either 40 or 60 mg/kg of praziquantel at baseline. Six months later, half of each group will receive second treatment at same dose or placebo.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Tablets will be crushed and given with orange juice
Primary Purpose: Treatment
Official Title: Phase II PK/PD Driven Dose Finding Trial of Praziquantel in Children Under Four
Estimated Study Start Date : January 1, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Praziquantel 40 mg/kg dose only baseline treatment
150 children will receive 40 mg/kg Praziquantel at baseline as single treatment and placebo six months following baseline
Drug: Praziquantel
Praziquantel given as crushed tablets (40 or 60 mg/kg)

Active Comparator: Praziquantel 60 mg/kg dose only baseline treatment
150 children will receive 60 mg/kg Praziquantel at baseline as single treatment and placebo six months following baseline
Drug: Praziquantel
Praziquantel given as crushed tablets (40 or 60 mg/kg)

Active Comparator: Praziquantel 40 mg/kg dose at baseline and 6 months
150 children will receive 40 mg/kg Praziquantel at baseline and again six months later.
Drug: Praziquantel
Praziquantel given as crushed tablets (40 or 60 mg/kg)

Active Comparator: Praziquantel 60 mg/kg dose at baseline and 6 months
150 children will receive 60 mg/kg Praziquantel at baseline and again six months later.
Drug: Praziquantel
Praziquantel given as crushed tablets (40 or 60 mg/kg)




Primary Outcome Measures :
  1. Treatment efficacy [ Time Frame: Four weeks post treatment ]
    Treatment efficacy as captured by egg reduction rate

  2. Treatment efficacy [ Time Frame: Four weeks post treatment ]
    Treatment efficacy as captured by cure rate


Secondary Outcome Measures :
  1. Iron status [ Time Frame: Six and 12 months following treatment ]
    Assess impact of varying doses and frequency of dosing on iron status

  2. Hemoglobin [ Time Frame: Six and 12 months following treatment ]
    Assess impact of varying doses and frequency of dosing on hemoglobin

  3. Age and gender adjusted linear growth [ Time Frame: Six and 12 months following treatment ]
    Assess impact of varying doses and frequency of dosing on linear growth

  4. Age and gender adjusted nutritional status [ Time Frame: Six and 12 months following treatment ]
    Assess impact of varying doses and frequency of dosing on nutritional status

  5. Biomarker of inflammation-CRP [ Time Frame: Six and 12 months following treatment ]
    CRP

  6. Biomarker of inflammation-IL-6 [ Time Frame: Six and 12 months following treatment ]
    serum IL-6

  7. Biomarker of inflammation-TNF-alpha [ Time Frame: Six and 12 months following treatment ]
    serum TNF-alpha

  8. Fecal Calprotectin [ Time Frame: Six and 12 months following treatment ]
    A measure of gut inflammation

  9. Urine Lactulose-Mannitol Ratio [ Time Frame: 12 months following treatment ]
    A measure of environmental enteropathy


Other Outcome Measures:
  1. Pharmacokinetic profile of Praziquantel [ Time Frame: up to 24 hours post treatment ]
    Area under the curve will be measured at discrete intervals from time 0 to 24 hours following treatment

  2. Pharmacokinetic profile of Praziquantel [ Time Frame: up to 24 hours post treatment ]
    Maximum plasma concentration (CMax) will be captured by measure Praziquantel at discrete intervals from time 0 to 24 hours following treatment

  3. Pharmacodynamic profile of Praziquantel [ Time Frame: 4 weeks post treatment ]
    The number of participants who achieve an egg reduction rate of 90% or greater

  4. Pharmacodynamic profile of Praziquantel [ Time Frame: 4 weeks post treatment ]
    The number of participants who achieve complete cure as defined by 0 eggs per gram of feces at 4 weeks post treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Months to 48 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03640377


Contacts
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Contact: Jennifer F Friedman, MD, PhD 401 444 7449 Jennifer_Friedman@Brown.edu

Sponsors and Collaborators
Rhode Island Hospital
London School of Hygiene and Tropical Medicine
University of Liverpool
Research Institute for Tropical Medicine, Philippines
Medical Research Council
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Responsible Party: Jennifer Friedman, MD, PhD, Director, Center for International Health Research, Rhode Island Hospital
ClinicalTrials.gov Identifier: NCT03640377    
Other Study ID Numbers: 403818
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data from the trial will be made available to interested investigators following IRB approval to provide these de-identified data. Specifically, after research data set has been cleaned, finalized, and all identifiers removed, the PIs will provide timely release and sharing of the final research data for use by other researchers. In addition, this study will generate samples collected young children. Upon discussion with the Principal Investigators and based on availability of samples, residual stored samples may be shared following IRB approval to provide these de-identified samples to interested researchers.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Within one year of trial completion and up to five years after.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Schistosomiasis
Schistosomiasis mansoni
Schistosomiasis japonica
Trematode Infections
Helminthiasis
Parasitic Diseases
Praziquantel
Anthelmintics
Antiparasitic Agents
Anti-Infective Agents