A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- 0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours)
研究概览
简要总结
The investigators have learned in past research that the drug phenylbutyrate can decrease the amounts of branched chain amino acids and their byproducts in the bloodstreams of healthy volunteer patients and also patients with certain disorders of protein breakdown including maple syrup urine disease. Through this study, the investigators will try to find out how well phenylbutyrate (NaPBA), also known by name brand "Buphenyl-TM", decreases BCAA and branched chain keto chain acids in the blood of patients with MSUD. The investigators hope is that through this research the investigators will be better able to treat these patients.
Subjects with MSUD will take phenylbutyrate (NaPBA) in powder form for a two-week treatment period and powder placebo, a substance with no effect on the body, for a two-week treatment period. They will be given the same amount of powder and undergo the same laboratory testing during both of the two-week treatment periods. The results will be compared once the study is over.
详细描述
Maple syrup urine disease is a severe inborn error of amino acid metabolism caused by deficiency of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) resulting in the accumulation of branched-chain amino acids (BCAA) (isoleucine, leucine, and valine) and their corresponding branched-chain alpha-ketoacids (BCKA) [alpha-keto-beta-methylvalerate (KMV), alpha-ketoisocaproate (KIC), and alpha-ketoisovalerate(KIV)] in tissues and plasma. The disorder typically manifests with potentially lethal episodes of intoxication presenting with acute neurological deterioration, feeding problems, weight loss, and a maple syrup odor to the urine. Current treatment is based on dietary manipulations with protein restriction and a synthetic formula with reduced BCAA content. However, mental and social impairment are still present in the majority of these patients in spite of dietary management.
Our study seeks to investigate the potential small molecule inhibition of the kinase that regulates BCKDC by applying a novel activity of sodium phenylbutyrate (NaPBA), in MSUD. Sodium phenylbutyrate is has been used to treat patients with urea cycle disorders (UCDs). In our extensive studies with UCDs, we noted that patients on therapy with NaPBA had decreased plasma levels of BCAA. This led us to hypothesize that NaPBA has effects on BCAA metabolism.
This will be a single-site, randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with MSUD. Subjects will be randomly assigned to receive either sodium phenylbutyrate (PB) or placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks.
If study findings show sodium phenylbutyrate lowers BCAA and BCKA levels in these patients, it may prove to be an effective adjunct treatment for these patients. A treatment option that could prevent or decrease the accumulation of BCAA and BCKA during states of catabolism induced by fasting or intercurrent illnesses, and thereby minimize or prevent the neurologic sequelae and loss of human potential that result, would greatly benefit society.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 3 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be 3 years or older at enrollment.
- •Must have a diagnosis of maple syrup urine disease (MSUD) confirmed by the presence of plasma alloisoleucine (>5 micromol/L) and/or genetic testing showing mutations in both alleles of any subunit of BCKDHA (E1alpha subunit gene, MSUD type 1A), BCKDHB (E1beta subunit gene, MSUD type 1B), or DBT (E2 subunit gene, MSUD type 2).
- •Participants must have a history of compliance to diet and treatment.
- •Signed informed consent by subject and/or subject's legally acceptable representative.
- •Must be capable of completing study procedures, including taking oral or G- tube medication.
- •Negative pregnancy test for all females of childbearing potential.
- •All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.
排除标准
- •May not have used sodium phenylbutyrate within 30 days of Visit
- •May not have an active infection (viral or bacterial) or any condition which may exacerbate their MSUD causing metabolic decompensation.
- •Cannot have any clinical or laboratory abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity).
- •May not have taken any medications known to significantly affect renal clearance or to increase protein catabolism within the 24 hours prior to Visit
- •May not participate if they have a known hypersensitivity to phenylacetate or phenylbutyrate or creatinine levels 1.5 times or more ULN.
- •Since a total of 53 mL will be drawn over Days 14 and 15 of both treatment periods, only subjects weighing more than 30 pounds can be enrolled.
研究组 & 干预措施
Phenylbutyrate
Study Drug
干预措施: Phenylbutyrate (Drug)
Inactive Powder
Placebo powder
干预措施: Placebo powder (Drug)
结局指标
主要结局
0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours)
时间窗: 24 Hours
Total Leucine exposure over 24 hours was calculated by serial blood draws at times 0, 2, 4, 8, 12, 16, 20, and 24 hours
Leucine CMax 0-24 Hours
时间窗: 24 hours
Maximal leucine concentration in 0-24 hours
次要结局
未报告次要终点
研究者
Brendan Lee
Professor, Molecular and Human Genetics
Baylor College of Medicine