A Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate in Pediatric Subjects Under 2 Years of Age With Urea Cycle Disorders

NCT02246218 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: HPN-100-0092016-003460-38
• Study Type: interventional
• Target: 27
• Locations: 2 countries
• Sites: 17

Brief Summary

This is an open-label study consisting of a transition period to RAVICTI, followed by a safety extension period for at least 6 months and up to 24 months of treatment with RAVICTI, depending on age at enrollment. It is designed to capture information important for evaluating safety, pharmacokinetics and efficacy in young children. Subjects who are followed by or referred to the Investigator for management of their UCD. Subjects eligible for this study will include patients ranging from newborn to \< 2 years of age with either a diagnosed or clinically suspected UCD.

Conditions

Urea Cycle Disorder

Keywords

Urea Cycle Disorder; UCD; Buphenyl; Glycerol Phenylbutyrate; Ravicti; Hyperammonemia; Sodium Phenylbutyrate; GPB; HPN-100

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 2 Months to <2 Years Participants

  The percentage of participants with successful transition is based on Investigator response to the question, "Has transition to 100% RAVICTI been successful with controlled ammonia?" For participants 2 months of age and older, after a minimum of 24 hours of ammonia monitoring following the first full dose of RAVICTI alone, the participant was effectively transitioned when following conditions were met: no signs and symptoms of hyperammonemia; ammonia level less than 100 μmol/L (without normalization of ammonia, ie, without conversion of values from local laboratories with varying normal ranges to standardized values); and eligible for discharge per Investigator judgment.

  Up to Day 4

• Percentage of Participants With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 0 Months to <2 Months Participants

  The percentage of participants with successful transition is based on Investigator response to the question, "Has transition to 100% RAVICTI been successful with controlled ammonia?" For participants \< 2 months of age, after a minimum of 24 hours of ammonia monitoring following the first full dose of RAVICTI alone, the participant was effectively transitioned when following conditions were met: no signs and symptoms of hyperammonemia; ammonia level less than 100 μmol/L (without normalization of ammonia, ie, without conversion of values from local laboratories with varying normal ranges to standardized values); and eligible for discharge per Investigator judgment.

  Up to Day 4

Secondary Outcomes (52)

• Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Participants

  Day 8 through up to Month 6

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 2 Months to <2 Years Participants

  From the first dose of study treatment through 30 days after the final dose (mean [SD] duration of treatment was 9.13 [6.838] months).

• Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Participants

  Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

• Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Participants

  Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

• Amino Acid Assessment: Baseline and Change From Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Participants

  Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Study Arms (1)

RAVICTI

EXPERIMENTAL

RAVICTI Oral Liquid should be administered just prior to breastfeeding or intake of formula or food. The recommended dosing regimen is 3-6 times per day depending on feeding schedule and at the discretion of the Investigator.

Drug: RAVICTI

Interventions

RAVICTI DRUG

Also known as: HPN-100, Glycerol Phenylbutyrate, GPB

RAVICTI

Eligibility Criteria

• Age: 1 Day - 2 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female subjects up to 2 years of age
• Signed informed consent by subject's parent/legal guardian
• UCD diagnosis or suspected diagnosis of any subtype, except N-acetyl glutamate synthetase deficiency. If UCD has not been previously confirmed by genetic testing, consent must be obtained from parent/legal guardian prior to perform genetic testing. If genetic testing is inconsistent with or excludes a UCD diagnosis, the subject will be withdrawn from the study.

You may not qualify if:

• Use of any investigational drug within 30 days of Day 1
• Uncontrolled infection (viral or bacterial) or any other condition known to precipitate hyperammonemic crises. Once these precipitating factors are medically controlled, patients presenting in crisis are eligible.
• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, except Grade 3 elevations in ammonia and liver enzymes, defined as levels 5-20 times the upper limit of normal in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 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
• Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA)
• Liver transplantation, including hepatocellular transplant
• Subjects on hemodialysis at time of initiating RAVICTI
• Subjects on RAVICTI for UCD management
• Currently treated with Carbaglu® (carglumic acid)

Sponsors & Collaborators

• Amgen: lead

Study Sites (17)

Kaiser Permanente Regional Metabolic Center

Los Angeles, California, 90027, United States

Location

Stanford Center for Clinical & Translational Research & Education

Palo Alto, California, 94034, United States

Location

Children's National Medical Center

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

Location

Shands at University of Florida

Gainesville, Florida, 32610, United States

Location

Emory University

Decatur, Georgia, 30033, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

The Hospital for Sick Children

Toronto, M5G 1Hs, Canada

Location

Related Publications (2)

• Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J. Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years. Mol Genet Metab. 2017 Nov;122(3):46-53. doi: 10.1016/j.ymgme.2017.09.002. Epub 2017 Sep 8.

  PMID: 28916119 RESULT

• Berry SA, Vockley J, Vinks AA, Dong M, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Perdok R, Robinson B, Holt RJ, Longo N. Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders. Mol Genet Metab. 2018 Nov;125(3):251-257. doi: 10.1016/j.ymgme.2018.09.001. Epub 2018 Sep 4.

  PMID: 30217721 RESULT

Related Links

• Related Info

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: Colleen Canavan, Director
• Organization: Horizon Therapeutics, LLC

clinicaltrials@horizonpharma.com

866-479-6742

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2014
• First Posted: September 22, 2014
• Study Start: December 31, 2014
• Primary Completion: October 17, 2016
• Study Completion: July 17, 2017
• Last Updated: July 1, 2024
• Results First Posted: March 5, 2019

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 (16)