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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Urea Cycle Disorder

Intervention / Treatment
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* Drug: RAVICTI
* Drug: NaPBA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Controlled, Open-Label Parallel Arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAVICTI -> RAVICTI<br>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<br>* RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose<br>* Other names: HPN-100;|
| Active Comparator: NaPBA -> RAVICTI<br>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<br>* 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<br>* Other names: Sodium phenylbutyrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urea, Hyperammonemic crisis (HAC)