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

Urea Cycle Disorder Clinical Trial

Official title:

A Randomised, Controlled, Open-Label Parallel Arm Study of Safety, PK and Ammonia Control of RAVICTI® (Glycerol Phenylbutyrate) Oral Liquid and Sodium Phenylbutyrate in Phenylbutyrate Treatment Naïve Patients With Urea Cycle Disorders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03335488
• Other study ID #: HPN-100-021
• Secondary ID: 2015-000075-27
• Status: Completed
• Phase: Phase 4
• Start date: February 20, 2018
• Est. completion date: December 20, 2022

Study information

• Verified date: July 2023
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: December 20, 2022
• Est. primary completion date: July 5, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 99 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Urea Cycle Disorder
• Urea Cycle Disorders, Inborn

Intervention

Drug:
• RAVICTI
RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose
• NaPBA
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

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino	Padua	Veneto
Italy	Bambino Gesù Children's Research Hospital	Rome
Spain	Hospital Universitario de Cruces	Barakaldo	Vizcaya
Spain	Hospital Materno-Infantil (HRU Carlos Haya)	Málaga	Andalucia
Switzerland	Universitätsspital, Inselspital Bern	Bern
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	University of Texas, Southwestern Medical Centre	Dallas	Texas
United States	University of Florida (UF) - Shands Hospital	Gainesville	Florida
United States	Mount Sinai School of Medicine	New York	New York
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Therapeutics, LLC

Countries where clinical trial is conducted

United States,  Italy,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period		Baseline through Week 4
Secondary	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)
Secondary	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
Secondary	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