Phenylbutyrate Therapy for Maple Syrup Urine Disease (MSUD)
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.
|Maple Syrup Urine Disease||Drug: Phenylbutyrate Drug: Placebo powder||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
|Official Title:||A Double-Blind, Randomized, Placebo-Controlled Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease|
- Cmax and Area Under the Curve (AUC)for BCAA and BCKA [ Time Frame: Pre-dose and 2hrs, 4hrs, 8hrs, 12hrs, 16hrs, 20hrs and 24hrs post-dose ]On the last study day of each intervention period.
|Study Start Date:||February 2013|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||February 2017 (Final data collection date for primary outcome measure)|
Active Comparator: Phenylbutyrate
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.
Other Name: Buphenyl-TM
Placebo Comparator: Inactive Powder
Drug: Placebo powder
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01529060
|United States, Texas|
|Baylor College of Medicine|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Brendan Lee, M.D., Ph.D.||Baylor College of Medicine|