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

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Carbamazepine Phase 1	Carbamazepine Phase 2	Valporic Acid Phase 2
Arm/Group Description	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...
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

Baseline Characteristics

Arm/Group Title		Carbamazepine Phase 1	Carbamazepine Phase 2	Valporic Acid Phase 2	Total
Arm/Group Description		No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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%

Outcome Measures

1.Primary Outcome


Title	Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine
Description	1. To examine the individual metabolic profiles of pediatric patients ...
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

Outcome Measure Data

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
Arm/Group Description:		No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...
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
4-Methylthio-2-hydroxyiminostilbene		15.2 (28.1)	13.1 (11.5)
5-N-acetylcysteine-3-ene VPA isomers	Number Analyzed	0 participants	0 participants	134 participants
5-N-acetylcysteine-3-ene VPA isomers				1.15 (1.20)
5-N-acetylcysteine-2-ene VPA	Number Analyzed	0 participants	0 participants	134 participants
5-N-acetylcysteine-2-ene VPA				2.13 (1.68)
Total N-acetylcysteine conjugates	Number Analyzed	0 participants	0 participants	134 participants
Total N-acetylcysteine conjugates				5.88 (5.17)

2.Secondary Outcome


Title	Age-related Changes in Bioactivation
Description	2. To determine if age-related differences exist regarding the ability...
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

Outcome Measure Data

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
Arm/Group Description:		No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...
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
4-Methylthio-2-hydroxyiminostilbene			-0.8876
Log (4-Methylthio-2-hydroxyiminostilbene)	Number Analyzed	0 participants	87 participants	0 participants
Log (4-Methylthio-2-hydroxyiminostilbene)			-0.0244
Fractional Recovery MTHIS	Number Analyzed	0 participants	87 participants	0 participants
Fractional Recovery MTHIS			-0.00033
Log (Fractional Recovery MTHIS)	Number Analyzed	0 participants	87 participants	0 participants
Log (Fractional Recovery MTHIS)			-00122
Log (5-N-acetylcysteine-3-ene VPA isomers)	Number Analyzed	0 participants	0 participants	134 participants
Log (5-N-acetylcysteine-3-ene VPA isomers)				-0.0295
Log (5-N-acetylcysteine-2-ene VPA)	Number Analyzed	0 participants	0 participants	134 participants
Log (5-N-acetylcysteine-2-ene VPA)				-0.0250
Total N-acetylcysteine conjugates	Number Analyzed	0 participants	0 participants	134 participants
Total N-acetylcysteine conjugates				-0.0296
Log (Fractional Recovery NAC-3-ene VPA isomers)	Number Analyzed	0 participants	0 participants	134 participants
Log (Fractional Recovery NAC-3-ene VPA isomers)				-0.005155
Log (Fractional Recovery NAC-2-ene VPA)	Number Analyzed	0 participants	0 participants	134 participants
Log (Fractional Recovery NAC-2-ene VPA)				-0.000698
Log (Fractional Recovery Total NAC conjugates)	Number Analyzed	0 participants	0 participants	134 participants
Log (Fractional Recovery Total NAC conjugates)				-0.005272

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Adverse Events

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
Arm/Group Description	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...	No intervention; Urine Collection: ...
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
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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
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

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