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

• Sponsor: Brendan Lee (Other)
• Overall Status: Completed
• CT.gov ID: NCT00345605
• Collaborator: Office of Rare Diseases (ORD) (NIH), Rare Diseases Clinical Research Network (Other), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 12
• Location: 1
• Arms: 2
• Duration (Months): 57
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Urea cycle disorders are inherited illnesses in which the body does not produce enough of the chemicals that remove ammonia, a byproduct of protein metabolism, from the blood stream. Elevated ammonia levels can lead to brain damage and death. Argininosuccinic aciduria (ASA) is a type of urea cycle disorder that is characterized specifically by high levels of argininosuccinic acid, a chemical involved in the urea cycle. People with ASA are at risk for serious liver damage, which may be due to the elevated levels of argininosuccinic acid. Sodium phenylbutyrate (Buphenyl-TM) is a drug that has been used to treat other types of urea cycle disorders. This study will evaluate whether Buphenyl-TM in conjunction with decreased arginine dose (in addition to a normal regimen of protein) will improve short-term liver function and decrease plasma citrulline and ASA levels in people with ASA.

Condition or Disease	Intervention/Treatment	Phase
Argininosuccinic Aciduria; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders	Drug: Sodium Phenylbutyrate; Drug: Arginine	Phase 2

Detailed Description

The cause of liver damage in people with ASA is unknown. However, because ASA is the only urea cycle disorder that is characterized by both liver damage and elevated levels of argininosuccinic acid, researchers believe that the elevated acid levels cause the liver damage. Common treatments for urea cycle disorders include a low-protein diet and arginine supplementation, which, when combined, help to decrease ammonia levels in the blood. Buphenyl-TM may aid in lowering ammonia and argininosuccinic acid levels. Although Buphenyl-TM has been FDA-approved for use in people with some types of urea cycle disorders, there is little information on the effectiveness of the drug in children with ASA. This study will evaluate whether treatment of ASA patients with Buphenyl-TM in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production.

Initially, participants in this double-blind, placebo-controlled, crossover study will undergo a 3-day washout period during which no Buphenyl-TM will be given. They will then be randomly assigned to one of two groups: either Buphenyl-TM (500 mg/kg/day or 10 grams/m2) and arginine (100 mg/kg/day or 2 grams/m2)), or arginine alone (500 mg/kg/day or 10 grams/m2). Participants will remain on this initial treatment arm for 1 week, at the conclusion of which an assessment of hepatic synthetic function, ureagenesis, and nitric oxide production will be performed. After this assessment, participants will undergo a second 3-day washout and then crossover to the other treatment arm for 1 week. At the end of the 1-week treatment period, a second assessment will be performed. During the washout period before each treatment period, no Buphenyl-TM will be administered, and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients With Argininosuccinic Aciduria
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HDA High Dose Arm Wash-out then 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA	Drug: Sodium Phenylbutyrate; None will be administered during the washout period; 500 mg/kg/day or 10 grams/m2 will be administered during the first one week treatment period in addition to arginine; Other Names: Buphenyl-TM ; Drug: Arginine; Standard therapeutic dose of 500 mg/kg/day or 10 grams/2 will be administered during the washout periods, during the first one week treatment period when receiving arginine plus Buphenyl, 100 mg/kg/day or 2 grams/m2 will be administered, during the second treatment week, when receiving arginine alone, 500 mg/kg/day or 10 grams/m2 will be administered
Experimental: LDA Low Dose Arm 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	Drug: Sodium Phenylbutyrate; None will be administered during the washout period; 500 mg/kg/day or 10 grams/m2 will be administered during the first one week treatment period in addition to arginine; Other Names: Buphenyl-TM ; Drug: Arginine; Standard therapeutic dose of 500 mg/kg/day or 10 grams/2 will be administered during the washout periods, during the first one week treatment period when receiving arginine plus Buphenyl, 100 mg/kg/day or 2 grams/m2 will be administered, during the second treatment week, when receiving arginine alone, 500 mg/kg/day or 10 grams/m2 will be administered

Outcome Measures

Primary Outcome Measures

1. Measures of Liver Function: AST and ALT [Measured after each 1-week treatment period]

   Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.

2. Measures of Liver Function: PT and PTT [Measured after each 1-week treatment period]

   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.

3. Measures of Liver Function: Coagulation Factors [Measured after each 1-week treatment period]

   Plasma levels of coagulation factors I and IX were used as measures of hepatic synthetic function since the treatment duration was short.

4. Measures of Liver Function: INR [Measured after each 1-week treatment period]

   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.

Secondary Outcome Measures

1. Argininosuccinic Acid Levels [Measured after each 1-week treatment period]

2. Arginine Levels [Measured after each 1-week treatment period]

3. Urea Production Rate [Measured after each 1-week treatment period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has confirmed diagnosis of ASA by amino acid or enzyme assay

• Has a history of adequate compliance to the diet and treatment

• Able to take oral or G-tube medication

• Able to perform 24 hour urine collection

• Agrees to travel to Baylor College of Medicine

• If female, of child bearing potential, and sexually active, agrees to use an acceptable method of birth control

• Greater than 5 years of age

Exclusion Criteria:

• Has a history of congestive heart failure, severe renal insufficiency, or any condition that causes sodium retention or edema

• Currently taking Probenecid, Haloperidol, Valproate or oral corticosteroids

• Pregnant or lactating

• Currently being treated for an acute illness

• Has co-morbid associations causing difficulties in the detection of hyperammonemic episodes, liver damage, or difficulties in the diet compliance

• Has known hypersensitivity to sodium phenylbutyrate

• Has taken any experimental medication within the last 30 days

• Has renal insufficiency with creatinine greater than 1.5 mg/dl at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baylor College of Medicine	Houston	Texas	United States	77030

Sponsors and Collaborators

• Brendan Lee
• Office of Rare Diseases (ORD)
• Rare Diseases Clinical Research Network
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Brendan Lee, MD, PhD, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Annet L, Materne R, Danse E, Jamart J, Horsmans Y, Van Beers BE. Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension. Radiology. 2003 Nov;229(2):409-14. Epub 2003 Sep 11.
• Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-70. Review.
• Lee B, Yu H, Jahoor F, O'Brien W, Beaudet AL, Reeds P. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8021-6.
• Lu LG, Zeng MD, Wan MB, Li CZ, Mao YM, Li JQ, Qiu DK, Cao AP, Ye J, Cai X, Chen CW, Wang JY, Wu SM, Zhu JS, Zhou XQ. Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. World J Gastroenterol. 2003 Nov;9(11):2574-8.
• Scaglia F, Marini J, Rosenberger J, Henry J, Garlick P, Lee B, Reeds P. Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and ornithine transcarbamylase deficiency carriers. Am J Clin Nutr. 2003 Oct;78(4):749-55.

• Responsible Party: Brendan Lee, MD, PhD, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00345605
• Other Study ID Numbers: RDCRN 5102; U54HD061221
• First Posted: Jun 28, 2006
• Last Update Posted: Jan 31, 2018
• Last Verified: Oct 1, 2015

• Keywords provided by Brendan Lee, MD, PhD, Baylor College of Medicine: Argininosuccinic Acid Lyase Deficiency; ASA
• Additional relevant MeSH terms: Urea Cycle Disorders, Inborn; Argininosuccinic Aciduria; Metabolism, Inborn Errors; Amino Acid Metabolism, Inborn Errors; 4-phenylbutyric acid

Study Results

Participant Flow

Recruitment Details	12 subjects with argininosuccinic aciduria were recruited at Baylor College of Medicine from May 2008 to December 2010.
Pre-assignment Detail	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
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: Initial Washout
STARTED	6	6
COMPLETED	6	5
NOT COMPLETED	0	1
Period Title: Initial Washout
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0
Period Title: Initial Washout
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0
Period Title: Initial Washout
STARTED	6	6
COMPLETED	5	6
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	High-dose Arginine vs Low-dose Arginine Plus Buphenyl
Arm/Group Description
Overall Participants	12
Age (Count of Participants)
<=18 years	8 66.7%
Between 18 and 65 years	4 33.3%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.4 (7.2)
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Measures of Liver Function: AST and ALT
Description	Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.
Time Frame	Measured after each 1-week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Arginine Plus Buphenyl	High Dose Arginine Alone
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
Measure Participants	11	11
Plasma AST	36.2 (10.9)	52 (15.7)
ALT	31.7 (9.55)	57.86 (17.44)

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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	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. Secondary Outcome

Title	Argininosuccinic Acid Levels
Time Frame	Measured after each 1-week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-dose Arginine Alone	Low-dose Arginine Plus Buphenyl
Arm/Group Description
Measure Participants	11	11
Median (Inter-Quartile Range) [micromole/l]	69	53

3. Secondary Outcome

Title	Arginine Levels
Time Frame	Measured after each 1-week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-dose Arginine Alone	Low-dose Arginine Plus Buphenyl
Arm/Group Description
Measure Participants	11	11
Median (Inter-Quartile Range) [micromoles/L]	129	53

4. Secondary Outcome

Title	Urea Production Rate
Time Frame	Measured after each 1-week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-dose Arginine Alone	Low-dose Arginine Plus Buphenyl
Arm/Group Description
Measure Participants	11	11
Mean (Standard Deviation) [micromoles/kg/hr]	215 (56)	97 (35)

5. Primary Outcome

Title	Measures of Liver Function: PT and PTT
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Arginine Plus Buphenyl	High Dose Arginine Alone
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
Measure Participants	11	11
PT	14.25	13.8
PTT	30.91	30.98

6. Primary Outcome

Title	Measures of Liver Function: Coagulation Factors
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Arginine Plus Buphenyl	High Dose Arginine Alone
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
Measure Participants	11	11
I	222.22 (47.26)	229.77 (62.96)
IX	105.33 (33.2)	98.36 (21.03)

7. Primary Outcome

Title	Measures of Liver Function: INR
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Arginine Plus Buphenyl	High Dose Arginine Alone
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
Measure Participants	11	11
Mean (Inter-Quartile Range) [seconds]	14.2	13.8

Adverse Events

Time Frame	during both of the 7 day treatment phases
Arm/Group Title	High-dose Arginine Alone		Low-dose Arginine Plus Buphenyl
Arm/Group Description
All Cause Mortality
	High-dose Arginine Alone		Low-dose Arginine Plus Buphenyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	High-dose Arginine Alone		Low-dose Arginine Plus Buphenyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	High-dose Arginine Alone		Low-dose Arginine Plus Buphenyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		1/12 (8.3%)
Gastrointestinal disorders
Vomiting	1/12 (8.3%)	1	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hyperammonemia	1/12 (8.3%)	1	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

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.