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

NCT ID: NCT00992459

Last Updated: 2024-07-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-31
• Study Completion Date: 2010-09-30

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.

Detailed Description

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA. Subjects were randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. Venous ammonia was the primary outcome measure. Subjects were admitted to the clinical research unit for 24 hours of pharmacokinetic (PK) blood and urine sampling (including an overnight stay) at the end of each treatment period, by which time the study drug had reached steady state.

Subjects followed a stable diet throughout the study as prescribed by the investigator and dietician. Throughout the study, diet diaries were completed by the subject and dietary protein intake were assessed by a dietician based on completed dietary diaries and consultation with the subject.

Subjects who completed this study and met the study entry criteria, were offered the opportunity to enroll in the HPN-100 open-label safety protocol (HPN-100-007).

Study acquired from Horizon in 2024.

Conditions

Urea Cycle Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Buphenyl (NaPBA) /HPN 100 Placebo

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.

Group Type: EXPERIMENTAL

Buphenyl (NaPBA)

Intervention Type: DRUG

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

HPN-100/NaPBA Placebo

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.

Group Type: EXPERIMENTAL

HPN-100

Intervention Type: 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.

Interventions

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 (\~17.4mL) delivers equivalent amount of PBA in 40 tablets of NaPBA.

Intervention Type: DRUG

Buphenyl (NaPBA)

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

Intervention Type: DRUG

Other Intervention Names

GT4P, glyceryl tri-(4-phenylbutyrate); sodium phenylbutyrate

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Long Beach Memorial

Long Beach, California, United States

UCLA

Los Angeles, California, United States

Stanford University

Stanford, California, United States

Denver Children's Hospital

Aurora, Colorado, United States

Yale School of Medicine

New Haven, Connecticut, United States

Children's National Medical Center

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

University of Florida

Gainesville, Florida, United States

University of Iowa

Iowa City, Iowa, United States

Maine Medical Center

Portland, Maine, United States

SNBL-Clinical Pharmacology Center

Baltimore, Maryland, United States

Tufts-New England Medical Center

Boston, Massachusetts, United States

University of Minnesota Medical Center

Minneapolis, Minnesota, United States

Mount Sinai School of Medicine

New York, New York, United States

Westchester Medical Center

Valhalla, New York, United States

University Hospitals Case Medical Center

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Baylor College of Medicine

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 22961727 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24144944 (View on PubMed)

Other Identifiers

HPN-100-006

Identifier Type: -

Identifier Source: org_study_id