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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Measures of Liver Function: AST and ALT
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
HDA
High Dose Arm
Wash-out then 7 days of:
Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA
干预措施: Sodium Phenylbutyrate (Drug)
HDA
High Dose Arm
Wash-out then 7 days of:
Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA
干预措施: Arginine (Drug)
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
干预措施: Sodium Phenylbutyrate (Drug)
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
干预措施: Arginine (Drug)
结局指标
主要结局
Measures of Liver Function: AST and ALT
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
研究者
Brendan Lee
MD, PhD
Baylor College of Medicine