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| ID | Type | Description | Link |
|---|---|---|---|
| NIH Grant HD044239 |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
| University of Utah | OTHER |
| University of Louisville | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients receiving Carbamazepine or Valproic Acid |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| No intervention; Urine Collection | Other | Urine collected from children receiving carbamazepine or valproic acid as part of their clinical management |
|
| Measure | Description | Time Frame |
|---|---|---|
| Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 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). | urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Age-related Changes in Bioactivation | 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. | urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years |
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Inclusion Criteria:
Exclusion Criteria:
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Pediatric patients of both genders between 1 and 16 years of age receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy or polytherapy
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| Name | Affiliation | Role |
|---|---|---|
| J. Steven Leeder, Pharm.D., Ph.D., | Children's Mercy Hospital Kansas City | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kosair Children's Hospital | Louisville | Kentucky | 40202 | United States | ||
| Children's Mercy Hospital |
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| ID | Title | Description |
|---|---|---|
| FG000 | Carbamazepine Phase 1 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management |
| FG001 | Carbamazepine Phase 2 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management |
| FG002 | Valporic Acid Phase 2 | No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Carbamazepine Phase 1 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management |
| BG001 | Carbamazepine Phase 2 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 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). | Carbamazepine detoxification product (MTHIS) was only measured in the Carbamazepine Phase I and 2 arms. Valproic Acid (NAC) detoxification products were only measured in the Valproic Acid Phase 2 arm. Units of measure for all analytes are nmol per mg creatinine. | Posted | Mean | Standard Deviation | nmol per mg creatinine | urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years |
|
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This was an observational study with no interventions. The study posed no significant risks to participants thus explaining 0 participants at risk.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Carbamazepine Phase 1 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| J. Steven Leeder Pharm D, PhD | The Children's Mercy Hospital | 816-234-3059 | sleeder@cmh.edu |
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| ID | Term |
|---|---|
| D012640 | Seizures |
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D059349 | Urine Specimen Collection |
| D002220 | Carbamazepine |
| ID | Term |
|---|---|
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
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Urine DNA (source: blood or saliva)
|
| Kansas City |
| Missouri |
| 64108 |
| United States |
| Primary Children's Hospital, Pediatric Neurology | Salt Lake City | Utah | 84113 | United States |
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
| BG002 | Valporic Acid Phase 2 | No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management |
| BG003 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
| OG001 | Carbamazepine Phase 2 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management |
| OG002 | Valproic Acid Phase 2 | No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management |
|
|
| Secondary | Age-related Changes in Bioactivation | 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. | Change in Carbamazepine detoxification as a function of age is determined only in patients in the Carbamazepine Phase 2 arm. Changes in Valproic Acid detoxification as a function of age are determined only in patients in the Valproic Acid Phase 2 arm. | Posted | Number | years^(-1) | urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years |
|
|
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Carbamazepine Phase 2 | No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management | 0 | 0 | 0 | 0 | 0 | 0 |
| EG002 | Valporic Acid Phase 2 | No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management | 0 | 0 | 0 | 0 | 0 | 0 |
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| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D008919 | Investigative Techniques |
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| Log (4-Methylthio-2-hydroxyiminostilbene) |
|
|
| Fractional Recovery MTHIS |
|
|
| Log (Fractional Recovery MTHIS) |
|
|
| Log (5-N-acetylcysteine-3-ene VPA isomers) |
|
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| Log (5-N-acetylcysteine-2-ene VPA) |
|
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| Total N-acetylcysteine conjugates |
|
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| Log (Fractional Recovery NAC-3-ene VPA isomers) |
|
|
| Log (Fractional Recovery NAC-2-ene VPA) |
|
|
| Log (Fractional Recovery Total NAC conjugates) |
|
|
| Regression, Linear |
| 0.032 |
| Other |
| Least squares linear regression evaluating fractional analyte recovery (Fractional Recovery (MTHIS)) as a function of age | Regression, Linear | 0.018 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery MTHIS)) as a function of age | Regression, Linear | 0.033 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-3-ene VPA isomers)) as a function of age | Regression, Linear | 0.0004 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-2-ene VPA) ) as a function of age | Regression, Linear | 0.0003 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Total N-acetylcysteine conjugates) as a function of age | Regression, Linear | <0.0001 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-3-ene VPA isomers)) as a function of age | Regression, Linear | 0.522 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-2-ene VPA) ) as a function of age | Regression, Linear | 0.925 | Other |
| Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery Total NAC conjugates) as a function of age | Regression, Linear | 0.469 | Other |