Study of the Safety of HPN (Hyperion)-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)

A Phase 3, Open-Label Study of the Safety of HPN-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)

This was a long-term safety study HPN-100 in urea cycle disorder (UCD) subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Study Overview

• Status: Completed
• Conditions: Urea Cycle Disorders
• Intervention / Treatment: Drug: HPN-100

Detailed Description

This was a one year long-term safety study of HPN-100 in UCD subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Forty subjects with a diagnosis of UCD who completed Study HPN-100-006 were enrolled.

Twenty additional UCD subjects ≥ 6 years of age were enrolled. These subjects included those who did not qualify for HPN-100-006 [e.g., subjects between the ages of 6-17; subjects with other UCD subtypes or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.]. For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. See the inclusion criteria for examples of clinical evidence of potential benefit.

Monthly assessments included safety laboratory tests, amino acid panel, vital signs, electrocardiogram (ECG) monitoring, venous ammonia, and blood and urine metabolites. Adverse events (AEs) and concomitant medications were recorded on an ongoing basis.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • The Hospital for Sick Children
• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial
    • Los Angeles, California, United States, 90095
      • UCLA
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Univeristy of Iowa
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • SNBL-Clinical Pharmacology Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts-New England Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University Of Minnesota Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects who completed HPN-100-006:

  *Additionally, approximately 20 UCD subjects ≥ 6 years of age may be enrolled who have not participated in HPN-100-006. These subjects may include those who did not qualify HPN-100-006 (e.g., subjects between the ages of 6-17 years, subjects with other UCD subtypes, or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.). For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. Clinical evidence of potential benefit from introduction of an ammonia-scavenging agent might include a recent history (in the past year) of clinically overt hyperammonemia accompanied by a venous ammonia ≥ 100 μmol/L, a recent history (within the past year) of protein intolerance, or a history of abnormally high venous ammonia levels accompanied by symptoms (e.g., headache) that might reasonably be attributed to hyperammonemia.

• Signed informed consent by subject and/or subject's legally acceptable representative.
• Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.
• Able to perform and comply with study activities, including blood draws.
• Negative pregnancy test for all females of childbearing potential.
• All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study.

Exclusion Criteria:

• Screening venous ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their venous 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.
• Active infection (viral or bacterial) or any other condition that may increase venous ammonia levels.
• 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 venous ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study.
• History of QTc (QT interval corrected) prolongation, or a QTc interval ≥ 450 msec or an increase of ≥ 60 msec during the previous HPN-100 study if applicable.
• Known hypersensitivity to PAA or PBA.
• Liver transplant, including hepatocellular transplant.
• Breastfeeding or lactating females.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: HPN-100; Patients who were treated with HPN-100	Drug: HPN-100; 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 (~17.4 mL) delivers equivalent of PBA that 40 tablets of NaPBA do.; Other Names: GT4P, Glyceryl tri-(4-phenylbutyrate)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and Causes of Hyperammonemic Events	Number of hyperammonemic crises per patient	1 year
Blood Ammonia Levels	Venous Ammonia levels over time	1 Year
Patient Satisfaction With HPN-100	Drug preference will be noted at week 3	Month 1 post dose

Collaborators and Investigators

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (ACTUAL): September 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: July 24, 2009
• First Submitted That Met QC Criteria: July 27, 2009
• First Posted (ESTIMATE): July 28, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: UCD; hyperammonemia; Sodium Phenylbutyrate; Urea Cycle Disorder; Buphenyl
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Disease; Urea Cycle Disorders, Inborn; Antineoplastic Agents; 4-phenylbutyric acid
• Other Study ID Numbers: HPN-100-007