A Study of Glyceryl Tri-(4-phenylbutyrate) (GT4P)

Overview

To determine the safety and tolerability of single oral doses of HPN-100 as a formulation (GT4P-F) and GT4P as the active pharmaceutical ingredient (GT4P-API) administered to healthy male subjects.

Full Title of Study: “A Randomized, Crossover, Open-label Phase 1 Study of Glyceryl Tri-(4-phenylbutyrate) (GT4P)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)

Detailed Description

A randomized, open-label, four-treatment, four-period crossover study in which healthy male subjects received a single dose of each of the following four treatments on four separate dosing days, 7 days apart: – Oral sodium phenylbutyrate (Buphenyl®) equivalent to 3 g/m2 of 4-phenylbutyric acid (PBA) per dose – Oral GT4P-F mole equivalents to 3 g/m2 of PBA per dose – Oral GT4P-API mole equivalents to 3 g/m2 of PBA per dose – Intravenous 10% sodium phenylacetate plus 10% sodium benzoate (Ammonul®) 2.75 g/m2

Interventions

  • Drug: HPN-100
    • HPN-100 is a triglyceride that has a similar mechanism of action as Buphenyl. It is a liquid with minimal taste and odor. HPN-100 is broken down to phenylbutyric acid (PBA). PBA is converted to phenyl acetic acid (PAA) that is the active metabolite. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA that 40 tablets of NaPBA do.
  • Drug: Ammonul
  • Drug: Buphenyl

Arms, Groups and Cohorts

  • Experimental: GT4P-F
    • GT4P-F (80% GT4P) was supplied as an odorless, colorless, tasteless liquid oil in 125 ml bottles. This formulation was designed to be mixed in water and create a self-emulsifying suspension, thus administered in water for the trial. The administered dose was calculated to contain the number of moles of PBA equivalent to 3 g/m2 of PBA. GT4P-F was mixed in 50 ml of water, taken orally, and then the cup rinsed with 50 ml of water and taken orally. GT4P-F was stored at ambient temperature away from light.
  • Experimental: GT4P-API
    • GT4P-API was supplied as an odorless, colorless, tasteless oil in 125 ml bottles. The administered dose was calculated to contain the number of moles of PBA equivalent to 3 g/m2 of PBA. GT4P-API was taken orally and washed down with 100 ml of water. GT4P-API was stored at ambient temperature, away from light.
  • Active Comparator: Ammonul
    • Ammonul® was supplied as single-use glass vials of 10% sodium phenylacetate and 10% sodium benzoate for intravenous injection. Ammonul® was diluted before use with sterile dextrose injection 10% to a concentration of 9 mg/ml. Once diluted it was kept at room temperature and used within 24 hours. The dose was 2.75 g/m2 and was administered as an intravenous infusion over a 120-minute period. Ammonul® was stored at 25°C, within a range of 15-30°C.
  • Active Comparator: Buphenyl
    • Sodium phenylbutyrate or Buphenyl® was supplied as a white powder in 250 g bottles. The required amount of powder (equivalent to 3 g/m2 of PBA) was weighed out, mixed in 100 ml of water, and administered orally. Doses were calculated on a weight/volume basis and corrected for sodium content and purity. Buphenyl® was stored at ambient temperature.

Clinical Trial Outcome Measures

Primary Measures

  • The rate of adverse events
    • Time Frame: 33 Days

Participating in This Clinical Trial

Inclusion Criteria

Subjects were required to fulfill the following criteria in order to participate in the study:

  • Males aged 18 to 45 years of age – Ability to provide written, informed consent before any study-related procedures, and ability, in the opinion of the investigator, to comply with all the requirements of the study – Subjects who were in good health as determined by a medical history, physical examination, serum chemistry, hematology, urinalysis, 12 lead ECG, and vital signs – Weight within the range of 60-120 kg Exclusion Criteria:

Subjects who fulfilled any of the following criteria were excluded from the study:

  • Clinically significant history or evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, neurologic, immunologic, or psychiatric disorder(s), as determined by the investigator – Clinically significant abnormal laboratory values (as determined by the investigator) – Significant illness within 14 days prior to screening – Any disorder that might significantly interfere with the absorption, distribution, metabolism, or excretion of any drug – Use of any prescription medication within 14 days prior to screening – Use of dietary supplements, herbal medicines, vitamins, or over-the-counter medication(s) (with the exception of acetaminophen ≤ 500 mg/day) within 10 days prior to first dosing – Positive drugs of abuse urine test at screening or pre-dose day (cocaine, amphetamines, barbiturates, opiates, benzodiazepines, cannabinoids, methadone) – Positive alcohol breath test at screening or pre-dose day – Donation or loss of blood (500 ml or more) within 30 days prior to first dosing, or during the study – Donation or loss of plasma within 7 days prior to first dosing, or during the study – History of or current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (anti-HC) – History of acquired immunodeficiency syndrome (AIDS) or determined HIV positive at screening – Use of any investigational drug within 12 weeks prior to first dosing – Known hypersensitivity to sodium phenylbutyrate or similar drugs – Previous exposure to sodium phenylbutyrate

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Horizon Pharma Ireland, Ltd., Dublin Ireland
  • Collaborator
    • Ucyclyd Pharma, Inc.
  • Overall Official(s)
    • Igor Zupanets, MD, Principal Investigator, The National University of Pharmacy

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