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Pathogenesis of Adverse Drug Reactions

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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 Type Observational
Study Design Observational Model: Case-Only;   Time Perspective: Prospective
Condition Seizures
Intervention Other: No intervention; Urine Collection
Enrollment 274
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Hide Arm/Group Description No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Period Title: Overall Study
Started 53 87 134
Completed 53 87 134
Not Completed 0 0 0
Arm/Group Title Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2 Total
Hide Arm/Group Description No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management Total of all reporting groups
Overall Number of Baseline Participants 53 87 134 274
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 53 participants 87 participants 134 participants 274 participants
9.8  (4.6) 11.0  (4.0) 10.2  (4.1) 10.38  (4.16)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 87 participants 134 participants 274 participants
Female
18
  34.0%
43
  49.4%
56
  41.8%
117
  42.7%
Male
35
  66.0%
44
  50.6%
78
  58.2%
157
  57.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 87 participants 134 participants 274 participants
Hispanic or Latino
1
   1.9%
6
   6.9%
7
   5.2%
14
   5.1%
Not Hispanic or Latino
52
  98.1%
81
  93.1%
127
  94.8%
260
  94.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 87 participants 134 participants 274 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
2
   2.3%
2
   1.5%
4
   1.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   7.5%
0
   0.0%
14
  10.4%
18
   6.6%
White
47
  88.7%
80
  92.0%
111
  82.8%
238
  86.9%
More than one race
2
   3.8%
5
   5.7%
4
   3.0%
11
   4.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
3
   2.2%
3
   1.1%
1.Primary Outcome
Title Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine
Hide Description 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).
Time Frame urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Carbamazepine Phase 1 Carbamazepine Phase 2 Valproic Acid Phase 2
Hide Arm/Group Description:
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Overall Number of Participants Analyzed 53 87 134
Mean (Standard Deviation)
Unit of Measure: nmol per mg creatinine
4-Methylthio-2-hydroxyiminostilbene Number Analyzed 53 participants 87 participants 0 participants
15.2  (28.1) 13.1  (11.5)
5-N-acetylcysteine-3-ene VPA isomers Number Analyzed 0 participants 0 participants 134 participants
1.15  (1.20)
5-N-acetylcysteine-2-ene VPA Number Analyzed 0 participants 0 participants 134 participants
2.13  (1.68)
Total N-acetylcysteine conjugates Number Analyzed 0 participants 0 participants 134 participants
5.88  (5.17)
2.Secondary Outcome
Title Age-related Changes in Bioactivation
Hide Description 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.
Time Frame urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Hide Arm/Group Description:
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management
No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Overall Number of Participants Analyzed 0 87 134
Measure Type: Number
Unit of Measure: years^(-1)
4-Methylthio-2-hydroxyiminostilbene Number Analyzed 0 participants 87 participants 0 participants
-0.8876
Log (4-Methylthio-2-hydroxyiminostilbene) Number Analyzed 0 participants 87 participants 0 participants
-0.0244
Fractional Recovery MTHIS Number Analyzed 0 participants 87 participants 0 participants
-0.00033
Log (Fractional Recovery MTHIS) Number Analyzed 0 participants 87 participants 0 participants
-00122
Log (5-N-acetylcysteine-3-ene VPA isomers) Number Analyzed 0 participants 0 participants 134 participants
-0.0295
Log (5-N-acetylcysteine-2-ene VPA) Number Analyzed 0 participants 0 participants 134 participants
-0.0250
Total N-acetylcysteine conjugates Number Analyzed 0 participants 0 participants 134 participants
-0.0296
Log (Fractional Recovery NAC-3-ene VPA isomers) Number Analyzed 0 participants 0 participants 134 participants
-0.005155
Log (Fractional Recovery NAC-2-ene VPA) Number Analyzed 0 participants 0 participants 134 participants
-0.000698
Log (Fractional Recovery Total NAC conjugates) Number Analyzed 0 participants 0 participants 134 participants
-0.005272
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Carbamazepine Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (4-Methylthio-2-hydroxyiminostilbene) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Carbamazepine Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (4-Methylthio-2-hydroxyiminostilbene) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Carbamazepine Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Fractional Recovery (MTHIS)) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.018
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Carbamazepine Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery MTHIS)) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.033
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-3-ene VPA isomers)) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-2-ene VPA) ) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Total N-acetylcysteine conjugates) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-3-ene VPA isomers)) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.522
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-2-ene VPA) ) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.925
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Valporic Acid Phase 2
Comments Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery Total NAC conjugates) as a function of age
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.469
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description This was an observational study with no interventions. The study posed no significant risks to participants thus explaining 0 participants at risk.
 
Arm/Group Title Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Hide Arm/Group Description No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
All-Cause Mortality
Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/0   0/0   0/0 
Show Serious Adverse Events Hide Serious Adverse Events
Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/0   0/0   0/0 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Carbamazepine Phase 1 Carbamazepine Phase 2 Valporic Acid Phase 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/0   0/0   0/0 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: J. Steven Leeder Pharm D, PhD
Organization: The Children's Mercy Hospital
Phone: 816-234-3059
EMail: sleeder@cmh.edu
Layout table for additonal information
Responsible Party: Steve Leeder, Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier: NCT00224952     History of Changes
Other Study ID Numbers: PPRU 10606
NIH Grant HD044239
First Submitted: September 21, 2005
First Posted: September 23, 2005
Results First Submitted: April 18, 2017
Results First Posted: August 14, 2017
Last Update Posted: August 14, 2017