Study of Glycerol Phenylbutyrate & Sodium Phenylbutyrate in Phenylbutyrate Naïve Patients With Urea Cycle Disorders (UCDs)

NCT03335488 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: HPN-100-0212015-000075-27
• Study Type: interventional
• Target: 16
• Locations: 4 countries
• Sites: 11

Brief Summary

This is a randomized, controlled, open-label parallel arm study to assess the safety, tolerability, pharmacokinetics and ammonia control, of RAVICTI® as compared to Sodium phenylbutyrate (NaPBA) in urea cycle disorder subjects not currently or previously chronically treated with phenylacetic acid (phenylacetate; PAA) prodrugs. The study design will include: 1) Baseline Period; 2) Initial Treatment Period; 3) a RAVICTI only Transition Period 4) a RAVICTI only Maintenance Period; and 5) a RAVICTI only Safety Extension Period. The study will run for approximately 25 weeks.

Conditions

Urea Cycle Disorder

Keywords

Urea; Hyperammonemic crisis (HAC)

Outcome Measures

Primary Outcomes (1)

• Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period

  A participant was considered a Treatment Success for the assigned treatment arm if the participant had not experienced an unprovoked hyperammonemic crisis (HAC) (i.e., a HAC that cannot be attributed to one or more specific precipitating factors such as infection, intercurrent illness, diet noncompliance, treatment noncompliance, etc.) on the assigned treatment and had met at least 2 of the following 3 criteria: * Had absolute values at the 3 time points (pre-dose, after dose at 4 hours and 8 hours) of plasma ammonia levels which do not exceed ULN at the Week 4(End of Initial Treatment Period visit) * Had normal (≤ ULN) glutamine levels at the Week 4 (End of Initial Treatment Period visit at the time point Zero Hour. * Had normal (≤ ULN) essential amino acids including branched chain amino acid levels (threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) at the End of Initial Treatment Period visit at time point Zero Hour.

  Week 4

Secondary Outcomes (4)

• Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period

  Baseline through Week 4

• Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period

  Baseline, Initial Treatment Period Week 1, Week 2, Week 3, Week 4 (0, 4, 8 hours post dose)

• Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period

  Week 4: hour 0 (predose), and hours 4 and 8 postdose

• Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period

  Week 4: hour 0 (predose), and hours 4 and 8 postdose

Study Arms (2)

RAVICTI -> RAVICTI

EXPERIMENTAL

Initial Treatment, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.

Drug: RAVICTI

NaPBA -> RAVICTI

ACTIVE COMPARATOR

Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study. Transition, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.

Drug: NaPBA

Interventions

RAVICTI DRUG

RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose

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

RAVICTI -> RAVICTI

NaPBA DRUG

* NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose * NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose

Also known as: Sodium phenylbutyrate

NaPBA -> RAVICTI

Eligibility Criteria

• Age: Up to 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent given by the subject or the subject's parent/legal guardian for those under 18 years of age or the age of consent by local regulation.
• Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype, except n-acetylglutamate synthetase (NAGS) deficiency.
• Suspected diagnosis is defined as having experienced a hyperammonemic crisis (HAC) or a documented high ammonia of \>=100 µmol/L
• Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing.
• Requires nitrogen-binding agents according to the judgment of the Investigator
• Birth and older.
• All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception from signing the informed consent throughout the study and for 30 days after the last dose of study drug. Acceptable forms of contraception are (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:

• Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA, Pheburane, or other) longer than 14 consecutive days within one year prior to enrollment.
• Temporary use of NaPBA for acute management of a hyperammonemic crisis in the past is acceptable.
• Any concomitant illness (e.g., malabsorption or clinically significant liver or bowel disease) which would preclude the subject's safe participation, as judged by the Investigator.
• Has undergone liver transplantation, including hepatocellular transplant.
• Subjects on sodium benzoate (NaBz) at Baseline will be excluded if they are viewed by the Investigator as being unable to undergo NaBz transition to a PAA prodrug during the Initial Treatment Period.
• Known hypersensitivity to phenylbutyric acid (PBA) or any excipients of the NaPBA/PBA formulations.
• Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed at the Baseline Visit prior to the start of study drug.

Sponsors & Collaborators

• Amgen: lead

Study Sites (11)

University of Florida (UF) - Shands Hospital

Gainesville, Florida, 32610-0214, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106-6005, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

University of Texas, Southwestern Medical Centre

Dallas, Texas, 753908565, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino

Padua, Veneto, 35128, Italy

Location

Bambino Gesù Children's Research Hospital

Rome, 00165, Italy

Location

Hospital Materno-Infantil (HRU Carlos Haya)

Málaga, Andalusia, 29006, Spain

Location

Hospital Universitario de Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

Universitätsspital, Inselspital Bern

Bern, 3010, Switzerland

Location

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: Horizon Therapeutics, LLC
• Organization: Horizon Therapeutics, LLC

clinicaltrials@horizontherapeutics.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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, Controlled, Open-Label Parallel Arm study

Study Record Dates

• First Submitted: October 18, 2017
• First Posted: November 7, 2017
• Study Start: February 20, 2018
• Primary Completion: July 5, 2022
• Study Completion: December 20, 2022
• Last Updated: July 1, 2024
• Results First Posted: July 10, 2023

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

CH (1); IT (2); US (6); ES (2)