Phenylbutyrate Therapy for Maple Syrup Urine Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease

Conditions
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Maple Syrup Urine Disease

Intervention / Treatment
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* Drug: Phenylbutyrate
* Drug: Placebo powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: May not have used sodium phenylbutyrate within 30 days of Visit 1. 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 1. 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.

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phenylbutyrate<br>Study Drug | Drug: Phenylbutyrate<br>* Dosage of phenylbutyrate powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day, the standard UCD dose studied in our preliminary studies, for 14 days.<br>* Other names: Buphenyl-TM;|
| Placebo Comparator: Inactive Powder<br>Placebo powder | Drug: Placebo powder<br>* Dosage of inactive placebo powder will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients in four divided doses per day for 14 days. Subjects will receive the same amount of powder for each arm of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 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 | 24 Hours | 
| Leucine CMax 0-24 Hours | Maximal leucine concentration in 0-24 hours | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phenylbutyrate, MSUD, Buphenyl-TM