Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders

This study has been completed.
Information provided by (Responsible Party):
Hyperion Therapeutics, Inc. Identifier:
First received: October 26, 2007
Last updated: August 9, 2013
Last verified: August 2013

The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.

Condition Intervention Phase
Urea Cycle Disorders
Drug: HPN-100
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2, Open-Label, Switch-Over, Dose-Escalation Study of the Safety and Tolerability of HPN-100 Compared to Buphenyl® (Sodium Phenylbutyrate) in Patients With Urea Cycle Disorders

Resource links provided by NLM:

Further study details as provided by Hyperion Therapeutics, Inc.:

Primary Outcome Measures:
  • Safety, as assessed by reported adverse events, serious adverse events, symptom survey, vital signs, 12-lead ECG, clinical laboratory measurements, urinalysis, and urine orotic acid. [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetics (plasma and urine PK parameters of study drugs and their metabolites) [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation ] [ Designated as safety issue: No ]
  • Pharmacodynamics (venous ammonia levels and their correlation with PK parameters) [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation ] [ Designated as safety issue: No ]
  • Exploratory efficacy, as measured by TNUAC and peak/trough venous ammonia levels, venous ammonia, glutamine and glutamate levels at each timepoint, urinary excretion of PAGN, intrapatient variability of venous ammonia levels [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation ] [ Designated as safety issue: No ]
  • Drug preference for HPN-100 or Buphenyl® (as assessed by global preference question) [ Time Frame: End of Study ] [ Designated as safety issue: No ]
  • Convenience and comfort associated with drug treatment (as assessed by UCD Drug Evaluation Questionnaire) [ Time Frame: Questionnaire administered at each visit ] [ Designated as safety issue: No ]
  • Study drug compliance and diet (as assessed by diary data/interview) [ Time Frame: Assessed at each visit, except follow-up visit ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: October 2007
Study Completion Date: December 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: HPN-100
Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment; subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase; the dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrates is HPN-100; target HPN-100 dose will contain the same amount of phenylbutyrates as the subject's prescribed daily dose of Buphenyl®; subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study.

Detailed Description:

When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male and female patients at least 18 years old
  • Signed written informed consent by patient or patient's representative
  • Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing
  • Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1
  • Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers)
  • Negative pregnancy test for all females of childbearing potential. All females of childbearing potential must agree to use an acceptable method of contraception throughout the study

Exclusion Criteria:

  • Use of any investigational drug within 30 days of Buphenyl® Visit 1
  • Active infection (viral or bacterial) or any other condition that may increase ammonia levels
  • Laboratory values outside the normal range that are determined to be clinically significant by the investigator
  • Any clinical or laboratory abnormality of Grade 3 or greater severity 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); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient
  • Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1
  • Preexisting QTc interval prolongation (> 450 msec for males or > 460 msec for females)
  • Other severe chronic medical conditions
  • Known hypersensitivity to PAA, PBA, or benzoate
  • Creatinine levels equal to or greater than 1.5 × ULN
  • Liver transplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00551200

United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Hyperion Therapeutics, Inc.
Study Director: Bruce Scharschmidt, MD Hyperion Therapeutics, Inc.
  More Information

Additional Information:
Enns, GM; Berry SA; Berry GT; Rhead WJ; Brusilow, SW; Hamosh A.Survival after Treatment with Phenylacetate and Benzoate for Urea Cycle Disorders.New England Journal of Medicine 356(22):2282-92, 2007.

Additional publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Hyperion Therapeutics, Inc. Identifier: NCT00551200     History of Changes
Other Study ID Numbers: UP1204-003
Study First Received: October 26, 2007
Last Updated: August 9, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Hyperion Therapeutics, Inc.:
Buphenyl, Sodium Phenylbutyrate, HPN-100, Urea Cycle Disorder, UCD

Additional relevant MeSH terms:
Brain Diseases, Metabolic, Inborn
Urea Cycle Disorders, Inborn
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
4-phenylbutyric acid
Antineoplastic Agents
Pharmacologic Actions
Therapeutic Uses processed this record on April 16, 2015