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

• ClinicalTrials.gov Identifier: NCT00551200
• Recruitment Status: Completed
• First Posted: October 30, 2007
• Results First Posted: May 12, 2015
• Last Update Posted: January 16, 2017
• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Information provided by (Responsible Party): Horizon Pharma Ireland, Ltd., Dublin Ireland

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Urea Cycle Disorders	Drug: HPN-100; Drug: BUPHENYL®	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: October 2007
• Actual Primary Completion Date: July 2008
• Actual Study Completion Date: December 2008

Arms and Interventions

Arm

Intervention/treatment

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.

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

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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.
2. 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) ]
3. 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) ]

Secondary Outcome Measures :

1. 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) ]
   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.
2. Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) [ Time Frame: End of Study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Locations

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

Horizon Pharma Ireland, Ltd., Dublin Ireland

Investigators

• Study Director: Bruce Scharschmidt, MD; Horizon Pharma Ireland, Ltd., Dublin Ireland

More Information

Publications:

Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007 May 31;356(22):2321-2. doi: 10.1056/NEJMe078075. No abstract available.

Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. Epub 2013 Jan 3.

• Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
• ClinicalTrials.gov Identifier: NCT00551200
• Other Study ID Numbers: UP1204-003 (HPN-100-003)
• First Posted: October 30, 2007
• Results First Posted: May 12, 2015
• Last Update Posted: January 16, 2017
• Last Verified: June 2015

Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:

Buphenyl; Sodium Phenylbutyrate; Urea Cycle Disorder; UCD

Additional relevant MeSH terms:

Urea Cycle Disorders, Inborn; Disease; Pathologic Processes; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; 4-phenylbutyric acid; Antineoplastic Agents