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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00345605

Enrollment

Registered

2006-06-28

Start date

2008-02-29

Completion date

2012-11-30

Last updated

2018-01-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

Argininosuccinic Acid Lyase Deficiency, ASA

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.

Interventions

DRUGSodium 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

DRUGArginine

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

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

5 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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

Measure	Time frame
Arginine Levels	Measured after each 1-week treatment period
Urea Production Rate	Measured after each 1-week treatment period
Argininosuccinic Acid Levels	Measured after each 1-week treatment period

Countries

United States

Participant flow

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.

Participants by arm

Arm	Count
High-dose Arginine vs Low-dose Arginine Plus Buphenyl	12
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001
Arm 1	Adverse Event	0	1
Arm 2, Opposite Treatment	Adverse Event	1	0

Baseline characteristics

Characteristic	High-dose Arginine vs Low-dose Arginine Plus Buphenyl
Age, Categorical <=18 years	8 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	4 Participants
Age, Continuous	15.4 years STANDARD_DEVIATION 7.2
Region of Enrollment United States	12 participants
Sex: Female, Male Female	7 Participants
Sex: Female, Male Male	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	1 / 12	1 / 12
serious Total, serious adverse events	0 / 12	0 / 12