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

Primary Purpose

Argininosuccinic Aciduria, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sodium Phenylbutyrate
Arginine
Sponsored by
Brendan Lee
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Argininosuccinic Aciduria focused on measuring Argininosuccinic Acid Lyase Deficiency, ASA

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

HDA

LDA

Arm Description

High Dose Arm Wash-out then 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA

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

Outcomes

Primary Outcome Measures

Measures of Liver Function: AST and ALT
Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.
Measures of Liver Function: PT and PTT
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.
Measures of Liver Function: Coagulation Factors
Plasma levels of coagulation factors I and IX were used as measures of hepatic synthetic function since the treatment duration was short.
Measures of Liver Function: INR
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

Argininosuccinic Acid Levels
Arginine Levels
Urea Production Rate

Full Information

First Posted
June 26, 2006
Last Updated
January 26, 2018
Sponsor
Brendan Lee
Collaborators
Office of Rare Diseases (ORD), Rare Diseases Clinical Research Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT00345605
Brief Title
Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder
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 Type
Interventional

2. Study Status

Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
February 2008 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Brendan Lee
Collaborators
Office of Rare Diseases (ORD), Rare Diseases Clinical Research Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Argininosuccinic Aciduria, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders
Keywords
Argininosuccinic Acid Lyase Deficiency, ASA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HDA
Arm Type
Experimental
Arm Description
High Dose Arm Wash-out then 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA
Arm Title
LDA
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Sodium Phenylbutyrate
Other Intervention Name(s)
Buphenyl-TM
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Arginine
Intervention Description
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
Primary Outcome Measure Information:
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
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
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
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
Secondary Outcome Measure Information:
Title
Argininosuccinic Acid Levels
Time Frame
Measured after each 1-week treatment period
Title
Arginine Levels
Time Frame
Measured after each 1-week treatment period
Title
Urea Production Rate
Time Frame
Measured after each 1-week treatment period

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brendan Lee, MD, PhD
Organizational Affiliation
Baylor College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
12970464
Citation
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. doi: 10.1148/radiol.2292021128. Epub 2003 Sep 11.
Results Reference
background
PubMed Identifier
14606100
Citation
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. doi: 10.3748/wjg.v9.i11.2574.
Results Reference
background
PubMed Identifier
14522733
Citation
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. doi: 10.1093/ajcn/78.4.749.
Results Reference
background
PubMed Identifier
10869432
Citation
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. doi: 10.1073/pnas.140082197.
Results Reference
background
PubMed Identifier
8794176
Citation
Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-70. No abstract available.
Results Reference
background

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

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