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Phenylbutyrate Therapy for Maple Syrup Urine Disease (MSUD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01529060
Recruitment Status : Completed
First Posted : February 8, 2012
Results First Posted : March 6, 2019
Last Update Posted : March 19, 2019
Information provided by (Responsible Party):
Brendan Lee, Baylor College of Medicine

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Maple Syrup Urine Disease Drug: Phenylbutyrate Drug: Placebo powder Phase 2 Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial of Phenylbutyrate in the Treatment of Maple Syrup Urine Disease
Study Start Date : February 2013
Actual Primary Completion Date : September 2, 2017
Actual Study Completion Date : December 2017

Arm Intervention/treatment
Active Comparator: Phenylbutyrate
Study Drug
Drug: 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
Placebo 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.

Primary Outcome Measures :
  1. 0-24 Hour AUC Leucine (Samples Collected at 0, 2, 4, 8, 12, 16, 20, and 24 Hours) [ Time Frame: 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

  2. Leucine CMax 0-24 Hours [ Time Frame: 24 hours ]
    Maximal leucine concentration in 0-24 hours

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01529060

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United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Brendan Lee
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Principal Investigator: Brendan Lee, M.D., Ph.D. Baylor College of Medicine
  Study Documents (Full-Text)

Documents provided by Brendan Lee, Baylor College of Medicine:
Study Protocol  [PDF] October 16, 2017
Statistical Analysis Plan  [PDF] October 16, 2017

Additional Information:
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Responsible Party: Brendan Lee, Professor, Molecular and Human Genetics, Baylor College of Medicine Identifier: NCT01529060    
Other Study ID Numbers: H-28463
First Posted: February 8, 2012    Key Record Dates
Results First Posted: March 6, 2019
Last Update Posted: March 19, 2019
Last Verified: March 2019
Keywords provided by Brendan Lee, Baylor College of Medicine:
Additional relevant MeSH terms:
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Maple Syrup Urine Disease
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
4-phenylbutyric acid
Antineoplastic Agents