Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders

NCT00947544 | Completed Phase 2 Results DMC

• 1 other identifier: HPN-100-005
• Study Type: interventional
• Target: 17
• Locations: 2 countries
• Sites: 8

Brief Summary

Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with Sodium Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled into the safety extension part of the study. 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 an equivalent amount of PBA to 40 tablets of NaPBA.

Conditions

Urea Cycle Disorders

Keywords

Urea Cycle Disorder; UCD; GT4P; Buphenyl; hyperammonemia; sodium phenylbutyrate

Outcome Measures

Primary Outcomes (1)

• Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events)

  To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders (UCDs)

  1 week on each treatment for a total of 2 week.

Secondary Outcomes (10)

• Number and Causes of Hyperammonemic Events (Safety Extension)

  1 year

• Blood Ammonia Control

  Day 7 (NaPBA) and Day 14 (HPN-100)

• NH3 Cmax on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug

  Day 7 (NaPBA) and Day 14 (HPN-100)

• Average Ammonia Values on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug (Switch Over)

  Day 7 (NaPBA) and Day 14 (HPN-100)

• Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA vs. HPN-100

  Day 7 (NaPBA) and Day 14 (HPN-100)

Study Arms (1)

HPN-100 and NaPBA

EXPERIMENTAL

1 week of NaPBA treatment followed by 1 week of HPN-100 treatment.

Drug: HPN-100; Drug: NaPBA

Interventions

HPN-100 DRUG

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 that 40 tablets of NapBA do.

Also known as: GT4P, Glyceryl tri-(4-phenylbutyrate)

HPN-100 and NaPBA

NaPBA DRUG

NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys.

Also known as: GT4P, Glyceryl tri-(4-phenylbutyrate)

HPN-100 and NaPBA

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female subjects 6-17 years old.
• Signed informed consent by subject's legally acceptable representative and assent by subject, as applicable.
• Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.
• On a stable dose of NaPBA for a diagnosis of UCD for at least 1 week prior to the Day 1 visit.
• \*Subjects who are not on a stable dose of NaPBA at the initial screening visit may be converted to a stable dose of NaPBA during the screening period and enrolled as long as they are on a stable dose of NaPBA at least 1 week prior to Day 1
• Able to perform and comply with study activities, including blood draws and urine collections.
• 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.

You may not qualify if:

• Screening ammonia level of ≥100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their 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.
• Use of any investigational drug within 30 days of Day 1.
• Active infection (viral or bacterial) or any other condition that may increase ammonia levels.
• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the CTCAE v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times ULN in 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.
• History of QTc interval prolongation or QTc interval \> 450 msec at screening or baseline.
• Known hypersensitivity to PAA or PBA.
• Liver transplant, including hepatocellular transplant.
• Currently treated with sodium benzoate or Carbaglu® (carglumic acid). At the discretion of the investigator, subjects on sodium benzoate who are otherwise eligible to participate may be switched to 100% NaPBA during the 30 day screening period as part of the study, and at least 7 days prior to Day 1 (Visit 2).
• Breastfeeding or lactating females.

Sponsors & Collaborators

• Amgen: lead

Study Sites (8)

UCLA

Los Angeles, California, 90095, United States

Location

The George Washington DC Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15201, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

The Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (2)

• 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.

  PMID: 24144944 DERIVED

• 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.

  PMID: 22961727 DERIVED

MeSH Terms

Conditions

Urea Cycle Disorders, Inborn; Hyperammonemia

Interventions

glycerol phenylbutyrate

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Craig James-Associate Director, Clinical Operations
• Organization: Hyperion Therapeutics

craig.james@hyperiontx.com

650-745-7840

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2009
• First Posted: July 28, 2009
• Study Start: March 1, 2010
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: July 11, 2024
• Results First Posted: December 25, 2013

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.

Locations

CA (1); US (7)