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

NCT00345605 | Completed Phase 2 Results DMC

• 2 other identifiers: RDCRN 5102U54HD061221
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Argininosuccinic Acid Lyase Deficiency; ASA

Outcome Measures

Primary Outcomes (4)

• Measures of Liver Function: AST and ALT

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

  Measured after each 1-week treatment period

• 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.

  Measured after each 1-week treatment period

• 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.

  Measured after each 1-week treatment period

• 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.

  Measured after each 1-week treatment period

Secondary Outcomes (3)

• Argininosuccinic Acid Levels

  Measured after each 1-week treatment period

• Arginine Levels

  Measured after each 1-week treatment period

• Urea Production Rate

  Measured after each 1-week treatment period

Study Arms (2)

HDA

EXPERIMENTAL

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; Drug: Arginine

LDA

EXPERIMENTAL

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; Drug: Arginine

Interventions

Sodium Phenylbutyrate DRUG

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

Also known as: Buphenyl-TM

HDA; LDA

Arginine DRUG

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

HDA; LDA

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (5)

• 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.

  PMID: 12970464 BACKGROUND

• 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.

  PMID: 14606100 BACKGROUND

• 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.

  PMID: 14522733 BACKGROUND

• 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.

  PMID: 10869432 BACKGROUND

• Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-70. No abstract available.

  PMID: 8794176 BACKGROUND

MeSH Terms

Conditions

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

Interventions

4-phenylbutyric acid; Arginine

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential

Results Point of Contact

• Title: Dr. Sandesh Nagamani
• Organization: Baylor College of Medicine

nagamani@bcm.edu

Study Officials

• Brendan Lee, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: June 26, 2006
• First Posted: June 28, 2006
• Study Start: February 1, 2008
• Primary Completion: May 1, 2011
• Study Completion: November 1, 2012
• Last Updated: January 31, 2018
• Results First Posted: November 5, 2014

Record last verified: 2015-10

Locations

US (1)