Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders
Condition: Urea Cycle Disorders
MeSH terms: Urea Cycle Disorders, Inborn
Intervention: HPN-100; NaPBA
Intervention description: HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA that 40 tablets of NapBA do.; NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys.
Intervention MeSH terms: 4-phenylbutyric acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Urea Cycle Disorder; UCD; GT4P; Buphenyl; hyperammonemia; sodium phenylbutyrate

Summary:

      Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle
      disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a
      long-term (12 month) safety extension designed to assess the safety of HPN-100 and to
      prospectively assess its ability to control blood ammonia as compared with Sodium
      Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch
      over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled
      into the safety extension part of the study. HPN-100 is a triglyceride that has a similar
      mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of
      HPN-100 (~17.4mL) delivers an equivalent amount of PBA to 40 tablets of NaPBA.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female subjects 6-17 years old.

          -  Signed informed consent by subject's legally acceptable representative and assent by
             subject, as applicable.

          -  Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via
             enzymatic, biochemical, or genetic testing.

          -  On a stable dose of NaPBA for a diagnosis of UCD for at least 1 week prior to the Day
             1 visit.

             *Subjects who are not on a stable dose of NaPBA at the initial screening visit may be
             converted to a stable dose of NaPBA during the screening period and enrolled as long
             as they are on a stable dose of NaPBA at least 1 week prior to Day 1

          -  Able to perform and comply with study activities, including blood draws and urine
             collections.

          -  Negative pregnancy test for all females of childbearing potential.

          -  All females of childbearing age and all sexually active males must agree to use an
             acceptable method of contraception throughout the study.

        Exclusion Criteria:

          -  Screening ammonia level of ≥100 μmol/L or signs and symptoms indicative of
             hyperammonemia; subjects may be re-screened after their ammonia is controlled, at the
             discretion of the investigator.

          -  History of 4 or more hyperammonemic events as defined in Section 3.5.1 in the
             preceding 12 months.

          -  Use of any investigational drug within 30 days of Day 1.

          -  Active infection (viral or bacterial) or any other condition that may increase ammonia
             levels.

          -  Any clinical or laboratory abnormality of Grade 3 or greater severity according to the
             CTCAE v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times
             ULN in ALT/SGPT, aspartate aminotransferase (AST/SGOT), or gamma glutamyl
             transpeptidase (GGT) in a clinically stable subject.

          -  Any clinical or laboratory abnormality or medical condition that, at the discretion of
             the investigator, may put the subject at increased risk by participating in this
             study.

          -  Use of any medication known to significantly affect renal clearance (e.g., probenecid)
             or to increase protein catabolism (e.g., corticosteroids), or other medication known
             to increase ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and
             throughout the study.

          -  History of QTc interval prolongation or QTc interval > 450 msec at screening or
             baseline.

          -  Known hypersensitivity to PAA or PBA.

          -  Liver transplant, including hepatocellular transplant.

          -  Currently treated with sodium benzoate or Carbaglu® (carglumic acid). At the
             discretion of the investigator, subjects on sodium benzoate who are otherwise eligible
             to participate may be switched to 100% NaPBA during the 30 day screening period as
             part of the study, and at least 7 days prior to Day 1 (Visit 2).

          -  Breastfeeding or lactating females.