Efficacy and Safety of HPN-100 for the Treatment of Adults With Urea Cycle Disorders

NCT00992459 | Completed Phase 3 Results DMC

• 1 other identifier: HPN-100-006
• Study Type: interventional
• Target: 46
• Locations: 2 countries
• Sites: 22

Brief Summary

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA.

Conditions

Urea Cycle Disorders

Keywords

Urea Cycle Disorder (UCD); UCD; hyperammonemia; Buphenyl (NaPBA); glycerol phenylbutyrate (GPB); Sodium Phenylbutyrate (NaPBA)

Outcome Measures

Primary Outcomes (1)

• The Primary Endpoint Was the 24-hour Area Under the Curve for Blood Ammonia (NH324-hour AUC) on Days 14 and 28.

  Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. Arm A day 14 and Arm B day 28 data were combined as a NaPBA treatment Arm. Arm B day 14 and Arm A day 28 data were combined as a HPN-100 treatment Arm.

  pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28

Secondary Outcomes (9)

• Correlation Between Urinary Phenylacetylglutamine (PAGN) Excretion Over 24 Hours (U-PAGN24-hour Excr) and Venous Ammonia - Area Under the Concentration-time Curve From Time 0 (Predose) to 24 Hours (AUC0-24)

  28 Days

• Maximum Ammonia Values Observed on NaPBA Versus HPN-100

  pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28

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

  on Day 14 and Day 28

• Number and Severity of Symptomatic Hyperammonemic Crises

  29 Days

• Rate of Adverse Events in Each Treatment Group

  29 Days

Study Arms (2)

Buphenyl (NaPBA) /HPN 100 Placebo

EXPERIMENTAL

Subjects in Arm A were randomly assigned to receive NaPBA + HPN 100 placebo for 2 weeks and then crossed over to receive HPN 100 + NaPBA Placebo for 2 weeks.

Drug: Buphenyl (NaPBA)

HPN-100/NaPBA Placebo

EXPERIMENTAL

Subjects in Arm B were randomly assigned to receive HPN-100 + NaPBA placebo for 2 weeks and then crossed over to receive NaPBA + HPN 100 placebo for 2 weeks.

Drug: HPN-100

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 in 40 tablets of NaPBA.

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

HPN-100/NaPBA Placebo

Buphenyl (NaPBA) DRUG

Buphenyl (NaPBA) will be the comparator drug to HPN-100 in this study.

Also known as: sodium phenylbutyrate

Buphenyl (NaPBA) /HPN 100 Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of UCD (Urea Cycle Disorder) involving deficiencies of Carbamyl phosphate synthetase (CPS), Ornithine transcarbamylase (OTC), or Arginosuccinate (ASS), confirmed via enzymatic, biochemical, or genetic testing
• Adult UCD subjects 18 years of age or older who are being treated with Buphenyl/Sodium phenylbuterate (NaPBA) for their UCD; subjects must be on a stable dose of NaPBA for at least 1 week prior to the Day 1 visit. Subjects who are not receiving NaPBA at the initial screening visit, but who have the potential to benefit from treatment, may start receiving NaPBA during the screening period and be enrolled as long as they are on a stable dose of NaPBA for at least 1 week prior to Day 1.
• No clinical evidence of hyperammonemia associated with an ammonia level of ≥ 100 μmol/L during the 2 weeks preceding screening
• Signed informed consent by subject
• Able to perform and comply with study activities, including blood draws and 24-hour urine samples
• 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. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.

You may not qualify if:

• Screening or baseline ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia during the 2-week period preceding screening or enrollment; subjects may be re-screened after their ammonia is controlled and are stable for at least 14 days, at the discretion of the investigator
• Use of any investigational drug within 30 days of Day 1
• Active infection (viral or bacterial) or any other intercurrent condition (apart from UCD) that may increase ammonia levels
• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times upper limit of normal (ULN) in alanine aminotransferase (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
• Use of sodium benzoate within one week of Day 1
• History of corrected QT interval (QTc) prolongation or QTc interval \> 450 msec at screening or baseline
• Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA)
• Liver transplant, including hepatocellular transplant
• Breastfeeding or lactating females

Sponsors & Collaborators

• Amgen: lead

Study Sites (22)

Long Beach Memorial

Long Beach, California, 90806, United States

Location

UCLA

Los Angeles, California, 90095, United States

Location

Stanford University

Stanford, California, 94304, United States

Location

Denver Children's Hospital

Aurora, Colorado, 80045, United States

Location

Yale School of Medicine

New Haven, Connecticut, 06510, United States

Location

Children's National Medical Center

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

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

SNBL-Clinical Pharmacology Center

Baltimore, Maryland, 21201, United States

Location

Tufts-New England Medical Center

Boston, Massachusetts, 02111, United States

Location

University of Minnesota Medical Center

Minneapolis, Minnesota, 55454, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

Westchester Medical Center

Valhalla, New York, 10595, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (2)

• 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 BACKGROUND

• 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

MeSH Terms

Conditions

Urea Cycle Disorders, Inborn; Hyperammonemia

Interventions

glycerol phenylbutyrate; 4-phenylbutyric acid

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: Bruce Scharschmidt, MD, SVP, Chief MedicaL & Development Officer
• Organization: Hyperion Therapeutics

bruce.scharschmidt@hyperiontx.com

650-745-7851

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 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2009
• First Posted: October 9, 2009
• Study Start: October 1, 2009
• Primary Completion: September 1, 2010
• Study Completion: September 1, 2010
• Last Updated: July 9, 2024
• Results First Posted: August 12, 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

US (21); CA (1)