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Pharmacotoxicology of Trichloroethylene Metabolites

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ClinicalTrials.gov Identifier: NCT00874276
Recruitment Status : Completed
First Posted : April 2, 2009
Results First Posted : June 20, 2013
Last Update Posted : June 4, 2015
Sponsor:
Information provided by (Responsible Party):
University of Florida

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label)
Condition Congenital Lactic Acidosis
Interventions Drug: Dichloroacetate (DCA)
Genetic: Genetic Marker on Chromosome 14q24.3
Enrollment 21
Recruitment Details Subjects were recruited from a list of individuals who had already been genotyped. Subjects were called on the telephone to see if they wanted to participate in this study.
Pre-assignment Details 21 subjects were consented to the study; however, 7 were excluded before being assigned to a group for the following reasons: works at night, on contraindicated medication, history of mitral valve prolapse, obesity, started smoking, and elevated liver enzymes.
Arm/Group Title Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Hide Arm/Group Description

Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization)

Dichloroacetate 2.5ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged.

Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization)

Dichloroacetate 2.5ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged.

Period Title: Overall Study
Started 6 8
Completed 5 7
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             1
Arm/Group Title Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 Total
Hide Arm/Group Description This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. Total of all reporting groups
Overall Number of Baseline Participants 6 8 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 8 participants 14 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
6
 100.0%
8
 100.0%
14
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 8 participants 14 participants
26.0  (4.6) 28.2  (10.4) 26.9  (7.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 8 participants 14 participants
Female
3
  50.0%
5
  62.5%
8
  57.1%
Male
3
  50.0%
3
  37.5%
6
  42.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 6 participants 8 participants 14 participants
6 8 14
1.Primary Outcome
Title Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized.
Hide Description Terminal half-life (the amount of time needed to clear one-half of dose of the drug).
Time Frame 24 hours for analysis on Day 5, Clinical dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All completing subjects (2 withdrawals have no pharmacokinetic data on this parameter) The intent was to accrue 12 per group but the grant ended before that could be achieved. Subjects were recruited from a large pool but the two genetically defined subgroups are rare.
Arm/Group Title Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Hide Arm/Group Description:

Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization)

Dichloroacetate 2.5.ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, and 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged.

Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization)

Dichloroacetate 2.5.ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, and 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged.

Overall Number of Participants Analyzed 5 7
Median (Inter-Quartile Range)
Unit of Measure: Minutes
1592
(727 to 1774)
232
(126 to 310)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3, 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Comments We used a Wilcoxon test (and accompanying Kendal's Tau B) because these outcomes are outlier prone.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.023
Comments This is the primary outcome, and there is no adjustment.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Kendall's Tau-B
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.35 to 0.85
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.127
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Terminal Half-life (the Amount of Time Needed to Clear One-half of the Dose of Drug)for Environmental Dose 2.5 ug/kg/Day.
Hide Description Terminal half-life (the amount of time needed to clear one-half of the dose of drug)for the environmental dose 2.5 ug/kg/day.
Time Frame 24 hours for analysis on Day 5, Environmental dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
same as Primary
Arm/Group Title No EGT Allele At Least One EGT Allele
Hide Arm/Group Description:
No EGT allele
At least one EGT allele
Overall Number of Participants Analyzed 5 7
Median (Inter-Quartile Range)
Unit of Measure: minutes
65.4
(56.3 to 66.4)
74.3
(58.9 to 90.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection No EGT Allele, At Least One EGT Allele
Comments This is the same analysis as the previous, except we use the day 5 pharmacogenetics on the amount of time needed to clear one-half of dose of the drug. This is for the environmental dose. A positive (negative) Kendall's Tau is associated with the EGT allele being faster (slower) than lacking EGT in terms of metabolization of DCA.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Kendall's Tau B
Estimated Value -0.23
Confidence Interval (2-Sided) 95%
-0.23 to 0.69
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.23
Estimation Comments [Not Specified]
Time Frame Adverse events were collected from 5/2008 to 2/2009
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Hide Arm/Group Description This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3.
All-Cause Mortality
Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/6 (16.67%)      0/8 (0.00%)    
Skin and subcutaneous tissue disorders     
Rash  [1]  1/6 (16.67%)  1 0/8 (0.00%)  0
Indicates events were collected by systematic assessment
[1]
Subject had developed a rash on his right arm where the Tegraderm from his IV was applied. It was determined he had an allergic reaction to the Tegraderm.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/6 (83.33%)      5/8 (62.50%)    
Gastrointestinal disorders     
abdominal cramping and diarrhea * [1]  0/6 (0.00%)  0 1/8 (12.50%)  1
Constipation * [2]  1/6 (16.67%)  1 0/8 (0.00%)  0
General disorders     
sleepiness * [3]  5/6 (83.33%)  7 5/8 (62.50%)  5
Immune system disorders     
Hives  [4]  0/6 (0.00%)  0 1/8 (12.50%)  1
Metabolism and nutrition disorders     
slow clearance of DCA * [5]  1/6 (16.67%)  1 0/8 (0.00%)  0
Musculoskeletal and connective tissue disorders     
headache * [6]  1/6 (16.67%)  1 0/8 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Wheezing  [7]  0/6 (0.00%)  0 1/8 (12.50%)  1
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
Subject complained of abdominal cramping and diarrhea which lasted for 2 days
[2]
Complained of constipation but subject was not dehydrated. A stool softener was order which resolved the problem
[3]
Eleven subjects on 25mg/kg of DCA complained of sleepiness following taking the drug
[4]
Subject complained of having hives. When examined by the principal investigator one hive was found on her right arm and was fading
[5]
Following completion of the study when the results were being analyzed it showed that subject did not clear DCA as rapidly as other subject. It was attributed to his genotype.
[6]
Subject complained of a headache. It was resolved after she took a nap
[7]
Subject had wheezes in his lower lobes of his lungs and stated he was spitting up yellow sputum. He had been having a cold when he entered the study
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Peter Stacpoole/Principal Investigator
Organization: University of Florida
Phone: 1-352-273-9023
EMail: pws@ufl.edu
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00874276     History of Changes
Obsolete Identifiers: NCT00874705
Other Study ID Numbers: 14617-CP-004
First Submitted: April 1, 2009
First Posted: April 2, 2009
Results First Submitted: March 11, 2013
Results First Posted: June 20, 2013
Last Update Posted: June 4, 2015