Trial Outcomes & Findings for Pathogenesis of Adverse Drug Reactions (NCT NCT00224952)

Last Updated: 2017-08-14

Results Overview

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).

Recruitment status

COMPLETED

Target enrollment

274 participants

Primary outcome timeframe

urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years

Results posted on

2017-08-14

Participant Flow

Participant milestones

Participant milestones
Measure	Carbamazepine Phase 1 No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Carbamazepine Phase 2 No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Valporic Acid Phase 2 No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Overall Study STARTED	53	87	134
Overall Study COMPLETED	53	87	134
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pathogenesis of Adverse Drug Reactions

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Carbamazepine Phase 1 n=53 Participants No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Carbamazepine Phase 2 n=87 Participants No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Valporic Acid Phase 2 n=134 Participants No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management	Total n=274 Participants Total of all reporting groups
Age, Continuous	9.8 Years STANDARD_DEVIATION 4.6 • n=5 Participants	11.0 Years STANDARD_DEVIATION 4.0 • n=7 Participants	10.2 Years STANDARD_DEVIATION 4.1 • n=5 Participants	10.38 Years STANDARD_DEVIATION 4.16 • n=4 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	43 Participants n=7 Participants	56 Participants n=5 Participants	117 Participants n=4 Participants
Sex: Female, Male Male	35 Participants n=5 Participants	44 Participants n=7 Participants	78 Participants n=5 Participants	157 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants	14 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	52 Participants n=5 Participants	81 Participants n=7 Participants	127 Participants n=5 Participants	260 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	0 Participants n=7 Participants	14 Participants n=5 Participants	18 Participants n=4 Participants
Race (NIH/OMB) White	47 Participants n=5 Participants	80 Participants n=7 Participants	111 Participants n=5 Participants	238 Participants n=4 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

Timeframe: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years

Population: 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.

Outcome measures

Outcome measures
Measure	Carbamazepine Phase 1 n=53 Participants No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Carbamazepine Phase 2 n=87 Participants No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Valproic Acid Phase 2 n=134 Participants No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine 4-Methylthio-2-hydroxyiminostilbene	15.2 nmol per mg creatinine Standard Deviation 28.1	13.1 nmol per mg creatinine Standard Deviation 11.5	—
Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine 5-N-acetylcysteine-3-ene VPA isomers	—	—	1.15 nmol per mg creatinine Standard Deviation 1.20
Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine 5-N-acetylcysteine-2-ene VPA	—	—	2.13 nmol per mg creatinine Standard Deviation 1.68
Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine Total N-acetylcysteine conjugates	—	—	5.88 nmol per mg creatinine Standard Deviation 5.17

SECONDARY outcome

Timeframe: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Carbamazepine Phase 1 No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Carbamazepine Phase 2 n=87 Participants No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management	Valproic Acid Phase 2 n=134 Participants No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management
Age-related Changes in Bioactivation Log (Fractional Recovery NAC-3-ene VPA isomers)	—	—	-0.005155 years^(-1)
Age-related Changes in Bioactivation Log (Fractional Recovery NAC-2-ene VPA)	—	—	-0.000698 years^(-1)
Age-related Changes in Bioactivation 4-Methylthio-2-hydroxyiminostilbene	—	-0.8876 years^(-1)	—
Age-related Changes in Bioactivation Log (4-Methylthio-2-hydroxyiminostilbene)	—	-0.0244 years^(-1)	—
Age-related Changes in Bioactivation Fractional Recovery MTHIS	—	-0.00033 years^(-1)	—
Age-related Changes in Bioactivation Log (Fractional Recovery MTHIS)	—	-00122 years^(-1)	—
Age-related Changes in Bioactivation Log (5-N-acetylcysteine-3-ene VPA isomers)	—	—	-0.0295 years^(-1)
Age-related Changes in Bioactivation Log (5-N-acetylcysteine-2-ene VPA)	—	—	-0.0250 years^(-1)
Age-related Changes in Bioactivation Total N-acetylcysteine conjugates	—	—	-0.0296 years^(-1)
Age-related Changes in Bioactivation Log (Fractional Recovery Total NAC conjugates)	—	—	-0.005272 years^(-1)

Adverse Events

Carbamazepine Phase 1

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Carbamazepine Phase 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Valporic Acid Phase 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

J. Steven Leeder Pharm D, PhD

The Children's Mercy Hospital

Phone: 816-234-3059

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place