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

NCT00551200 | Completed Phase 2 Results DMC

• 1 other identifier: UP1204-003 (HPN-100-003)
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Urea Cycle Disorders

Keywords

Buphenyl; Sodium Phenylbutyrate; Urea Cycle Disorder; UCD

Outcome Measures

Primary Outcomes (3)

• Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)

  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.

  At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation

• Number of Subjects Experienced Adverse Events

  during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)

• Number of Subjects Experienced Serious Adverse Events

  during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)

Secondary Outcomes (2)

• Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)

  At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)

• Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)

  End of Study

Study Arms (1)

BUPHENYL® to HPN-100 vs. HPN-100

ACTIVE COMPARATOR

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; Drug: BUPHENYL®

Interventions

HPN-100 DRUG

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.

BUPHENYL® to HPN-100 vs. HPN-100

BUPHENYL® DRUG

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.

Also known as: Sodium Phenylbutyrate, NaPBA

BUPHENYL® to HPN-100 vs. HPN-100

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Amgen: lead

Study Sites (2)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Related Publications (4)

• 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.

  PMID: 17538092 BACKGROUND

• 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.

  PMID: 17538087 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

• 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

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

Results Point of Contact

• Title: Sr. Vice President and Chief Medical Officer, Bruce F. Scharschmidt
• 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 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2007
• First Posted: October 30, 2007
• Study Start: October 1, 2007
• Primary Completion: July 1, 2008
• Study Completion: December 1, 2008
• Last Updated: July 10, 2024
• Results First Posted: May 12, 2015

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 (2)