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Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder

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ClinicalTrials.gov Identifier: NCT00345605
Recruitment Status : Completed
First Posted : June 28, 2006
Results First Posted : November 5, 2014
Last Update Posted : January 31, 2018
Sponsor:
Collaborators:
Office of Rare Diseases (ORD)
Rare Diseases Clinical Research Network
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Brendan Lee, Baylor College of Medicine

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Argininosuccinic Aciduria
Amino Acid Metabolism, Inborn Errors
Urea Cycle Disorders
Interventions Drug: Sodium Phenylbutyrate
Drug: Arginine
Enrollment 12
Recruitment Details 12 subjects with argininosuccinic aciduria were recruited at Baylor College of Medicine from May 2008 to December 2010.
Pre-assignment Details patients were randomly assigned to one of the two arms HDA or LDA after treatment and an interval the same patients returned and received the crossover treatment LD or HDA depending.
Arm/Group Title High Dose First Low Dose First
Hide Arm/Group Description High dose arm 3 day wash-out followed by 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA interval then: Arg 100 mg/kg/d or 2 g/m2 BSA NaPBA 500 mg/kg/d or 10 g/m2 BSA low dose arm 3 day wash-out followed by 7 days of: Arg 100 mg/kg/d or 2 g/m2 BSA NaPBA 500 mg/kg/d or 10 g/m2 BSA interval then: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA
Period Title: Initial Washout
Started 6 6
Completed 6 6
Not Completed 0 0
Period Title: Arm 1
Started 6 6
Completed 6 5
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
Period Title: Interval
Started 6 6
Completed 6 6
Not Completed 0 0
Period Title: Crossover Wash-out
Started 6 6
Completed 6 6
Not Completed 0 0
Period Title: Arm 2, Opposite Treatment
Started 6 6
Completed 5 6
Not Completed 1 0
Reason Not Completed
Adverse Event             1             0
Arm/Group Title High-dose Arginine vs Low-dose Arginine Plus Buphenyl
Hide Arm/Group Description [Not Specified]
Overall Number of Baseline Participants 12
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
<=18 years
8
  66.7%
Between 18 and 65 years
4
  33.3%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants
15.4  (7.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
Female
7
  58.3%
Male
5
  41.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants
12
1.Primary Outcome
Title Measures of Liver Function: AST and ALT
Hide Description Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Arginine Plus Buphenyl High Dose Arginine Alone
Hide Arm/Group Description:
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine; a 3-day washout period; a 1-week treatment period of arginine alone.
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of arginine alone; a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine
Overall Number of Participants Analyzed 11 11
Mean (Standard Error)
Unit of Measure: IU/L
Plasma AST 36.2  (10.9) 52  (15.7)
ALT 31.7  (9.55) 57.86  (17.44)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Arginine Plus Buphenyl, High Dose Arginine Alone
Comments For sample size calculation, we used the means and standard deviation for PT, PTT. Assuming r=0.5 between two measurements from the same subject, 12 subjects would provide a power of 0.8 to detect a 10% reduction in primary endpoints at an alpha value of 0.05.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value 0.5
Estimation Comments Assuming r=0.5 between two measurements from the same subject, 12 subjects would provide a power of 0.8 to detect a 10% reduction in primary endpoints at an alpha value of 0.05.
2.Primary Outcome
Title Measures of Liver Function: PT and PTT
Hide Description Prothrombin time (PT) and partial thromboplastin time (PTT) were measured PT measures factors I (fibrinogen), II (prothrombin), V, VII, and X, while PTT is a performance indicator of the efficacy of the common coagulation pathways.
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Arginine Plus Buphenyl High Dose Arginine Alone
Hide Arm/Group Description:
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine; a 3-day washout period; a 1-week treatment period of arginine alone.
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of arginine alone; a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine
Overall Number of Participants Analyzed 11 11
Mean (Inter-Quartile Range)
Unit of Measure: seconds
PT
14.25
(13.7 to 14.6)
13.8
(13.6 to 14.37)
PTT
30.91
(29.55 to 32.54)
30.98
(29.16 to 31.74)
3.Primary Outcome
Title Measures of Liver Function: Coagulation Factors
Hide Description Plasma levels of coagulation factors I and IX were used as measures of hepatic synthetic function since the treatment duration was short.
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Arginine Plus Buphenyl High Dose Arginine Alone
Hide Arm/Group Description:
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine; a 3-day washout period; a 1-week treatment period of arginine alone.
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of arginine alone; a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine
Overall Number of Participants Analyzed 11 11
Mean (Standard Deviation)
Unit of Measure: mg/dL
I 222.22  (47.26) 229.77  (62.96)
IX 105.33  (33.2) 98.36  (21.03)
4.Primary Outcome
Title Measures of Liver Function: INR
Hide Description The result (in seconds) for a prothrombin time performed on a normal individual will vary according to the type of analytical system employed. This is due to the variations between different batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results. Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor. The ISI is usually between 1.0 and 2.0. The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system being used.
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Arginine Plus Buphenyl High Dose Arginine Alone
Hide Arm/Group Description:
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine; a 3-day washout period; a 1-week treatment period of arginine alone.
Participants will undergo treatments in the following order: a 3-day washout period; a 1-week treatment period of arginine alone; a 3-day washout period; a 1-week treatment period of sodium phenylbutyrate (Buphenyl-TM) plus arginine
Overall Number of Participants Analyzed 11 11
Mean (Inter-Quartile Range)
Unit of Measure: seconds
14.2
(13.7 to 14.6)
13.8
(13.6 to 14.3)
5.Secondary Outcome
Title Argininosuccinic Acid Levels
Hide Description [Not Specified]
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 11 11
Median (Inter-Quartile Range)
Unit of Measure: micromole/l
69
(44 to 165)
53
(29 to 118)
6.Secondary Outcome
Title Arginine Levels
Hide Description [Not Specified]
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 11 11
Median (Inter-Quartile Range)
Unit of Measure: micromoles/L
129
(83 to 197)
53
(41 to 61)
7.Secondary Outcome
Title Urea Production Rate
Hide Description [Not Specified]
Time Frame Measured after each 1-week treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 11 11
Mean (Standard Deviation)
Unit of Measure: micromoles/kg/hr
215  (56) 97  (35)
Time Frame during both of the 7 day treatment phases
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/12 (0.00%)      0/12 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
High-dose Arginine Alone Low-dose Arginine Plus Buphenyl
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/12 (8.33%)      1/12 (8.33%)    
Gastrointestinal disorders     
Vomiting *  1/12 (8.33%)  1 1/12 (8.33%)  1
Metabolism and nutrition disorders     
Hyperammonemia *  1/12 (8.33%)  1 1/12 (8.33%)  1
*
Indicates events were collected by non-systematic assessment
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. Sandesh Nagamani
Organization: Baylor College of Medicine
Responsible Party: Brendan Lee, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00345605     History of Changes
Other Study ID Numbers: RDCRN 5102
U54HD061221 ( U.S. NIH Grant/Contract )
First Submitted: June 26, 2006
First Posted: June 28, 2006
Results First Submitted: May 15, 2014
Results First Posted: November 5, 2014
Last Update Posted: January 31, 2018