Efficacy and Safety of HPN-100 for the Treatment of Adults With Urea Cycle Disorders
Condition: Urea Cycle Disorders
MeSH terms: Urea Cycle Disorders, Inborn
Intervention: HPN-100; Buphenyl (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 in 40 tablets of NaPBA.; Buphenyl (NaPBA) will be the comparator drug to HPN-100 in this study.
Intervention MeSH terms: 4-phenylbutyric acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 46.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Urea Cycle Disorder (UCD); UCD; hyperammonemia; Buphenyl (NaPBA); glycerol phenylbutyrate (GPB); Sodium Phenylbutyrate (NaPBA)

Summary:

      This was a randomized, active-controlled, double-blind, cross-over study designed to enroll
      subjects with UCDs who are being treated with NaPBA.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of UCD (Urea Cycle Disorder) involving deficiencies of Carbamyl phosphate
             synthetase (CPS), Ornithine transcarbamylase (OTC), or Arginosuccinate (ASS),
             confirmed via enzymatic, biochemical, or genetic testing

          -  Adult UCD subjects 18 years of age or older who are being treated with Buphenyl/Sodium
             phenylbuterate (NaPBA) for their UCD; subjects must be on a stable dose of NaPBA for
             at least 1 week prior to the Day 1 visit. Subjects who are not receiving NaPBA at the
             initial screening visit, but who have the potential to benefit from treatment, may
             start receiving NaPBA during the screening period and be enrolled as long as they are
             on a stable dose of NaPBA for at least 1 week prior to Day 1.

          -  No clinical evidence of hyperammonemia associated with an ammonia level of ≥ 100
             μmol/L during the 2 weeks preceding screening

          -  Signed informed consent by subject

          -  Able to perform and comply with study activities, including blood draws and 24-hour
             urine samples

          -  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. 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:

          -  Screening or baseline ammonia level of ≥ 100 μmol/L or signs and symptoms indicative
             of hyperammonemia during the 2-week period preceding screening or enrollment; subjects
             may be re-screened after their ammonia is controlled and are stable for at least 14
             days, at the discretion of the investigator

          -  Use of any investigational drug within 30 days of Day 1

          -  Active infection (viral or bacterial) or any other intercurrent condition (apart from
             UCD) that may increase ammonia levels

          -  Any clinical or laboratory abnormality of Grade 3 or greater severity according to the
             Common Terminology Criteria for Adverse Events (CTCAE) v3.0, except Grade 3 elevations
             in liver enzymes, defined as levels 5-20 times upper limit of normal (ULN) in alanine
             aminotransferase (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

          -  Use of sodium benzoate within one week of Day 1

          -  History of corrected QT interval (QTc) prolongation or QTc interval > 450 msec at
             screening or baseline

          -  Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA)

          -  Liver transplant, including hepatocellular transplant

          -  Breastfeeding or lactating females