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Pathogenesis of Adverse Drug Reactions

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00224952
Recruitment Status : Completed
First Posted : September 23, 2005
Results First Posted : August 14, 2017
Last Update Posted : August 14, 2017
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Utah
University of Louisville
Information provided by (Responsible Party):
Steve Leeder, Children's Mercy Hospital Kansas City

Study Description
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Brief Summary:
The purpose of the study is to examine the individual metabolic profiles of pediatric patients receiving carbamazepine or valproate therapy, in an attempt to determine identities of the reactive metabolites or, alternatively, the identities of those metabolites that serve as potential precursors to reactive species.

Condition or disease Intervention/treatment
Seizures Other: No intervention; Urine Collection

Detailed Description:

Adverse drug reactions can be broadly defined as any undesirable response associated with therapeutic drug use. A simple and clinically useful classification is to divide adverse events into those that are dose-dependent and largely predictable from the known pharmacologic properties of the compound in question, and those that are dependent on characteristics unique to susceptible individuals, or idiosyncratic in nature.

The long term objective of this research is to characterize the mechanisms responsible for the pathogenesis of idiosyncratic hypersensitivity reactions in children, particularly those involving carbamazepine and other aromatic anticonvulsants.

The study is divided into two phases. Phase 1 of the study involves collecting urine from 50 patients taking CBZ therapeutically. Participants will be asked to provide a spot urine sample during routine health visits. The urine will be analyzed for the presence of CBZ and its metabolites. In Phase 2 of the study, urine will be collected from patients taking either CBZ or VPA therapeutically. If blood samples are drawn from these patients for medical purposes not related to this study the residual blood sample will be recovered before it is discarded for use in genotyping analysis. Participants will be asked to provide a urine sample covering one complete dosing interval of CBZ or VPA (preferably overnight). Patients will also be followed longitudinally, with urine collections at each clinic visit over at least a two year period.

Study Design
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Study Type : Observational
Actual Enrollment : 274 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: The Role of Drug Metabolizing Enzymes in the Pathogenesis Adverse Drug Reactions in Children
Study Start Date : July 2002
Actual Primary Completion Date : March 2010
Actual Study Completion Date : March 2010

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Patients receiving Carbamazepine or Valproic Acid Other: No intervention; Urine Collection
Urine collected from children receiving carbamazepine or valproic acid as part of their clinical management
Other Names:
  • carbamazepine: Tegretol
  • valproic acid: Depakote


Outcome Measures
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Primary Outcome Measures :
  1. Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine [ Time Frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years ]
    1. To examine the individual metabolic profiles of pediatric patients receiving carbamazepine or valproate therapy, in an attempt to determine the identities of the reactive metabolites or, alternatively, the identities of those metabolites that serve as potential precursors to reactive species (e.g., through conjugation with detoxifying compounds such as glutathione).


Secondary Outcome Measures :
  1. Age-related Changes in Bioactivation [ Time Frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years ]
    2. To determine if age-related differences exist regarding the ability of pediatric patients to bioactivate carbamazepine or valproate to reactive metabolites. Data provided below reflect the slope of the least squares regression.


Biospecimen Retention:   Samples With DNA
Urine DNA (source: blood or saliva)

Eligibility Criteria
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Ages Eligible for Study:   1 Year to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Pediatric patients of both genders between 1 and 16 years of age receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy or polytherapy
Criteria

Inclusion Criteria:

  • Pediatric patients of both genders between 1 and 16 years of age receiving CBZ or VPA mono-therapy will be recruited for this study. Additionally, for those patients who are receiving drugs other than CBZ or VPA to control their seizures, if CBZ or VPA are subsequently added to their treatment regimen, then these patients will also be recruited for this study.

Exclusion Criteria:

  • None
Contacts and Locations
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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): NCT00224952


Locations
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United States, Kentucky
Kosair Children's Hospital
Louisville, Kentucky, United States, 40202
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
United States, Utah
Primary Children's Hospital, Pediatric Neurology
Salt Lake City, Utah, United States, 84113
Sponsors and Collaborators
Children's Mercy Hospital Kansas City
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Utah
University of Louisville
Investigators
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Principal Investigator: J. Steven Leeder, Pharm.D., Ph.D., Children's Mercy Hospital Kansas City
More Information
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Additional Information:

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Responsible Party: Steve Leeder, Pharm.D; Ph.D, Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier: NCT00224952    
Other Study ID Numbers: PPRU 10606
NIH Grant HD044239
First Posted: September 23, 2005    Key Record Dates
Results First Posted: August 14, 2017
Last Update Posted: August 14, 2017
Last Verified: August 2017
Keywords provided by Steve Leeder, Children's Mercy Hospital Kansas City:
seizures
Epilepsy
Additional relevant MeSH terms:
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Seizures
Drug-Related Side Effects and Adverse Reactions
Neurologic Manifestations
Nervous System Diseases
Chemically-Induced Disorders
Carbamazepine
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
 Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Sodium Channel Blockers
Membrane Transport Modulators
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers