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

Phase 4

Completed

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.

Recruitment & 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.

Arm && Interventions

Group	Intervention	Description
RAVICTI -> RAVICTI	RAVICTI	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.
NaPBA -> RAVICTI	NaPBA	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.

Primary Outcome Measures

Name	Time	Method
Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period	Week 4	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.

Secondary Outcome Measures

Name	Time	Method
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

Locations (11): Mount Sinai School of Medicine
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New York, New York, United States
Hospital Materno-Infantil (HRU Carlos Haya)
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Málaga, Andalucia, Spain
Bambino Gesù Children's Research Hospital
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Rome, Italy
Hospital Universitario de Cruces
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Barakaldo, Vizcaya, Spain
University Hospitals Case Medical Center
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Cleveland, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
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Pittsburgh, Pennsylvania, United States
University of Texas, Southwestern Medical Centre
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Dallas, Texas, United States
University of Utah
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Salt Lake City, Utah, United States
University of Florida (UF) - Shands Hospital
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Gainesville, Florida, United States
Universitätsspital, Inselspital Bern
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Bern, Switzerland
Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino
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Padua, Veneto, Italy