Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier:
NCT00551200
First received: October 26, 2007
Last updated: June 8, 2015
Last verified: June 2015

October 26, 2007
June 8, 2015
October 2007
July 2008   (final data collection date for primary outcome measure)
  • Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) [ 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 ]
    Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose.
  • Number of Subjects Experienced Adverse Events [ Time Frame: during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) ] [ Designated as safety issue: Yes ]
  • Number of Subjects Experienced Serious Adverse Events [ Time Frame: during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) ] [ Designated as safety issue: Yes ]
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, GT4P alone), and at steady state (1 week) after each dose escalation ]
Complete list of historical versions of study NCT00551200 on ClinicalTrials.gov Archive Site
  • 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) ] [ Designated as safety issue: No ]
    measured AUC0-24 (Area under the curve from time 0 (pre-dose) to 24 hours) for each metabolite in plasma. Data were collected at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post-first dose.
  • Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) [ Time Frame: End of Study ] [ Designated as safety issue: No ]
  • Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, GT4P alone), and at steady state (1 week) after each dose escalation ]
  • Pharmacodynamics (venous ammonia levels and their correlation with PK parameters) [ Time Frame: At steady state (1 week) on each medication (Buphenyl® alone, GT4P alone), and at steady state (1 week) after each dose escalation ]
  • 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, GT4P alone), and at steady state (1 week) after each dose escalation ]
  • Drug preference for GT4P or Buphenyl® (as assessed by global preference question) [ Time Frame: End of Study ]
  • Convenience and comfort associated with drug treatment (as assessed by UCD Drug Evaluation Questionnaire) [ Time Frame: Questionnaire administered at each visit ]
  • Study drug compliance and diet (as assessed by diary data/interview) [ Time Frame: Assessed at each visit, except follow-up visit ]
Not Provided
Not Provided
 
Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders
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
The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.
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.
Interventional
Phase 2
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Urea Cycle Disorders
  • 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 phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate 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.
  • Drug: BUPHENYL®
    BUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS.
    Other Names:
    • Sodium Phenylbutyrate
    • NaPBA
Active Comparator: BUPHENYL® to HPN-100 vs. HPN-100
Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment.
Interventions:
  • Drug: HPN-100
  • Drug: BUPHENYL®

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
14
December 2008
July 2008   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00551200
UP1204-003 (HPN-100-003)
Yes
Not Provided
Not Provided
Horizon Pharma Ireland, Ltd., Dublin Ireland
Horizon Pharma Ireland, Ltd., Dublin Ireland
Not Provided
Study Director: Bruce Scharschmidt, MD Horizon Pharma Ireland, Ltd., Dublin Ireland
Horizon Pharma Ireland, Ltd., Dublin Ireland
June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP