Comparative Efficacy of Phenylbutyrate (PBA) vs. Benzoate in Urea Cycle Disorders

Overview

The investigators will study and compare how effectively sodium phenylbutyrate, sodium benzoate, and a combination of the two, help excrete nitrogen in healthy volunteers. Subject participation will require three, separate, four-day study periods at least one week apart. During one study period (also called a treatment arm), subjects will take sodium phenylbutyrate; during another they will take sodium benzoate; during another they will take a combination of the two medications. We expect to find that phenylbutyrate is more effective at removing nitrogen than benzoate or a combination of the two.

Full Title of Study: “Comparative Efficacy of Phenylbutyrate vs. Benzoate in Urea Cycle Disorders”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Other
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 2015

Interventions

  • Drug: Sodium Benzoate
    • Subjects will be instructed to take the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.
  • Drug: Sodium Phenylbutyrate
    • Subjects will be instructed to take the study medication with meals (08:00 breakfast; 13:00 lunch; 19:00 dinner) for 3 days.

Arms, Groups and Cohorts

  • Active Comparator: Sodium Benzoate arm
    • Sodium benzoate 5.5 g/m2/day divided into three equal doses per day (maximum dose 12 g/day) for 3 days
  • Active Comparator: Sodium Phenylbutyrate arm
    • Sodium phenylbutyrate 7.15 g/m2/day divided into three equal doses per day (maximum dose of 20 g/day) for 3 days
  • Active Comparator: Mix Arm
    • Sodium Phenylbutyrate 3.575 g/m2/day and Sodium Benzoate 2.75 g/m2/day will be given in three equal doses per day for 3 days

Clinical Trial Outcome Measures

Primary Measures

  • Urinary Hippuric Acid
    • Time Frame: 4 days per arm
    • The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean hippuric acid levels in the phenylbutyrate arm would thus be 0.
  • Urinary PAGN Excretion
    • Time Frame: 4 days per arm
    • The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm. The mean phenylacetylglutamine levels in the benzoate arm would thus be 0.
  • Total Nitrogen as a Conjugate of the Drug
    • Time Frame: 4 days per arm
    • The objective of this protocol is to directly compare the efficacy of benzoate, phenylbutyrate and a combination of the two, to conjugate nitrogenous compounds in healthy volunteers. The nitrogenous compound of interest in each arm would be based on the medication used. This would be hippuric acid in the benzoate arm, phenylacetylglutamine in the phenylbutyrate arm, and hippuric acid AND phenylacetylglutamine in the MIX arm.

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy volunteers Exclusion Criteria:

  • Subjects with (a) a history of frequent dietary protein intolerance, (b) a history of chronic or acute liver diseases which may result in altered hepatic synthetic capacity (e.g., hepatitis), (c) acute or chronic disease or on medications that in the opinion of the clinical investigators will interfere with the measurements (e.g., drugs which may have hepatotoxicity as potential side effects), (d) a physical disability that will interfere with their ability to either conform to the dietary regimes or undergo the isotopic infusions, (e) pregnancy or recent (<6 months)/current lactation, (f) intercurrent evidence of significant hyperammonemia (more than 100 µmol/L), (g) any clinical abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v.4.0 (CTCAE), (h) any condition(s) not covered by the CTCAE, or (i) a severe or life-threatening toxicity at screening, will be excluded from the study. Subjects taking ammonia scavenger medications will not be enrolled.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 64 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Baylor College of Medicine
  • Provider of Information About this Clinical Study
    • Principal Investigator: Juan Marini, Principal Investigator – Baylor College of Medicine
  • Overall Official(s)
    • Juan C Marini, DVM., PhD, Principal Investigator, Baylor College of Medicine
    • Sandesh CS Nagamani, MD, FACMG, Principal Investigator, Baylor College of Medicine

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