Pathogenesis of Adverse Drug Reactions

• 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: Children's Mercy Hospital Kansas City
• 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

Tracking Information

• First Submitted Date: September 21, 2005
• First Posted Date: September 23, 2005
• Results First Submitted Date: April 18, 2017
• Results First Posted Date: August 14, 2017
• Last Update Posted Date: August 14, 2017
• Study Start Date: July 2002
• Actual Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 11, 2017)

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).

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: August 11, 2017)

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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pathogenesis of Adverse Drug Reactions
• Official Title: The Role of Drug Metabolizing Enzymes in the Pathogenesis Adverse Drug Reactions in Children
• 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.

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 Type: Observational
• Study Design: Observational Model: Case-Only; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Urine DNA (source: blood or saliva)

• 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
• Condition: Seizures

Intervention

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

Study Groups/Cohorts

Patients receiving Carbamazepine or Valproic Acid

Intervention: Other: No intervention; Urine Collection

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 11, 2017): 274
• Original Enrollment (submitted: September 21, 2005): 120
• Actual Study Completion Date: March 2010
• Actual Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 16 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00224952
• Other Study ID Numbers: PPRU 10606; NIH Grant HD044239
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Steve Leeder, Children's Mercy Hospital Kansas City
• Study Sponsor: Children's Mercy Hospital Kansas City

Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• University of Utah
• University of Louisville

Investigators

• Principal Investigator: J. Steven Leeder, Pharm.D., Ph.D.,; Children's Mercy Hospital Kansas City

• PRS Account: Children's Mercy Hospital Kansas City
• Verification Date: August 2017