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

Urea Cycle Disorder Clinical Trial

Official title:

An Open Label Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate (GPB; RAVICTI®) in Pediatric Subjects Under Two Years of Age With Urea Cycle Disorders (UCDs)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02246218
• Other study ID #: HPN-100-009
• Secondary ID: 2016-003460-38
• Status: Completed
• Phase: Phase 4
• Start date: December 31, 2014
• Est. completion date: July 17, 2017

Study information

• Verified date: February 2019
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: July 17, 2017
• Est. primary completion date: October 17, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 2 Years

Eligibility

Inclusion Criteria:

• 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 If genetic testing is inconsistent with or excludes a UCD diagnosis, the subject will be withdrawn from the study.

Exclusion Criteria:

• 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)

Related Conditions & MeSH terms

• Disease
• Urea Cycle Disorder
• Urea Cycle Disorders, Inborn

Intervention

Drug:
• RAVICTI

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Emory University	Decatur	Georgia
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Shands at University of Florida	Gainesville	Florida
United States	Indiana University	Indianapolis	Indiana
United States	Kaiser Permanente Regional Metabolic Center	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Mount Sinai School of Medicine	New York	New York
United States	Stanford Center for Clinical & Translational Research & Education	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Utah	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Therapeutics, LLC

Countries where clinical trial is conducted

United States,  Canada, 

References & 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 — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Participants	HAC is defined having signs and symptoms consistent with hyperammonemia (such as but not limited to frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high blood ammonia and requiring medical intervention. Rate of HACs per 6 months during the safety extension is calculated as sum of (number of HAC) / sum of (days during first 6 months starting on Day 8 or number days on RAVICTI, whichever is less) across all participants in the corresponding group.	Day 8 through up to Month 6
Secondary	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	An adverse event (AE) is any untoward medical occurrence, whether or not the event is considered related to the study drug. A serious AE is any AE that: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. TEAEs are defined as AEs with an onset date on or after the first dose of study medication until study discontinuation. The Investigator assessed the causal relationship of each TEAE to the study drug as not related, possibly related, or probably related.	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).
Secondary	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
Secondary	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
Secondary	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
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine 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
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Leucine 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
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Valine 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
Secondary	Assessment of Growth and Development: Baseline and Change From Baseline in Body Mass Index (BMI) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Participants	To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BMI. The Z-scores are based on the World Health Organization's Child Growth Standards charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender.	Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Assessment of Growth and Development: Baseline and Change From Baseline in Body Surface Area (BSA) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Participants	To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BSA. The Z-scores are based on weight-for-length charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender.	Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Plasma Phenylbutyrate/Phenylbutyric Acid (PBA) Maximum Plasma Concentration (Cmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma Phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 0.5 and 1 hour, 1.5 and 2.5 hours, 4 and 6 hours, 7.5 and 8.5 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants		Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, End of Trial (up to Month 18)
Secondary	Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants		Hour 0 and between 0.5 and 1.5 hours, 1.5 and 2.5 hours, 4 and 6 hours, 7.5 and 8.5 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants		Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 15, Month 18, End of Trial (up to Month 18)
Secondary	Rate of HACs: Cohort of 0 Months to <2 Months Participants	HAC is defined as having signs and symptoms consistent with hyperammonemia (such as but not limited to frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high blood ammonia and requiring medical intervention. Rate of HACs per 6 months during the safety extension was calculated as sum of (number of HAC) / sum of (days during first 6 months starting on Day 8 or number days on RAVICTI, whichever is less) across all participants in the corresponding group.	Day 8 through up to Month 6
Secondary	Number of Participants With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Participants	An AE is any untoward medical occurrence, whether or not the event is considered related to the study drug. A serious AE is any AE that: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. TEAEs are defined as AEs with an onset date on or after the first dose of study medication until study discontinuation. The Investigator assessed the causal relationship of each TEAE to the study drug as not related, possibly related, or probably related.	From the first dose of study treatment through 30 days after the final dose (mean [SD] duration of treatment was 10.67 [6.142] months).
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Participants		Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Assessment of Growth and Development: Baseline and Change From Baseline in BMI Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Participants	To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BMI. The Z-scores are based on the World Health Organization's Child Growth Standards charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender.	Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Assessment of Growth and Development: Baseline and Change From Baseline in BSA Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Participants	To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BSA. The Z-scores are based on weight-for-length charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender.	Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Secondary	Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 0.5 and 1 hour, 1.5 and 2.5 hours, 4 and 6 hours, 7.5 and 8.5 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants		Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, End of Trial (up to Month 15)
Secondary	Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants		Hour 0 and between 0.5 and 1.5 hours, 1.5 and 2.5 hours, 4 and 6 hours, 7.5 and 8.5 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable participants and on Day 2 for participants in HAC
Secondary	Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants		Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 15, End of Trial (up to Month 15)

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