Back to resultsA Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate in Pediatric Subjects Under 2 Years of Age With Urea Cycle Disorders
Primary Purpose
Urea Cycle Disorder
Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
RAVICTI
Sponsored by
About this trial
This is an interventional treatment trial for Urea Cycle Disorder focused on measuring Urea Cycle Disorder, UCD, Buphenyl, Glycerol Phenylbutyrate, Ravicti, Hyperammonemia, Sodium Phenylbutyrate, GPB, HPN-100
Eligibility Criteria
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 If genetic testing is inconsistent with or excludes a UCD diagnosis, the subject will be withdrawn from the study.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)
Sites / Locations
- Kaiser Permanente Regional Metabolic Center
- Stanford Center for Clinical & Translational Research & Education
- Children's National Medical Center
- Shands at University of Florida
- Emory University
- Indiana University
- Maine Medical Center
- Children's Hospital of Michigan
- University of Minnesota
- Mount Sinai School of Medicine
- University Hospitals Case Medical Center
- Oregon Health & Science University
- Children's Hospital of Philadelphia
- Children's Hospital of Pittsburgh
- University of Utah
- Seattle Children's Hospital
- The Hospital for Sick Children
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
RAVICTI
Arm Description
RAVICTI Oral Liquid should be administered just prior to breastfeeding or intake of formula or food. The recommended dosing regimen is 3-6 times per day depending on feeding schedule and at the discretion of the Investigator.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Participants
Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Participants
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
Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Participants
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.
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.
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
Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
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
Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma Phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants
Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants
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.
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.
Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Participants
Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Participants
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
Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Participants
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.
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.
Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants
Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants
Full Information
NCT ID
NCT02246218
First Posted
September 17, 2014
Last Updated
February 8, 2019
Sponsor
Horizon Therapeutics, LLC
1. Study Identification
Unique Protocol Identification Number
NCT02246218
Brief Title
A Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate in Pediatric Subjects Under 2 Years of Age With Urea Cycle Disorders
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)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
December 31, 2014 (Actual)
Primary Completion Date
October 17, 2016 (Actual)
Study Completion Date
July 17, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Therapeutics, LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urea Cycle Disorder
Keywords
Urea Cycle Disorder, UCD, Buphenyl, Glycerol Phenylbutyrate, Ravicti, Hyperammonemia, Sodium Phenylbutyrate, GPB, HPN-100
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
RAVICTI
Arm Type
Experimental
Arm Description
RAVICTI Oral Liquid should be administered just prior to breastfeeding or intake of formula or food. The recommended dosing regimen is 3-6 times per day depending on feeding schedule and at the discretion of the Investigator.
Intervention Type
Drug
Intervention Name(s)
RAVICTI
Other Intervention Name(s)
HPN-100, Glycerol Phenylbutyrate, GPB
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Up to Day 4
Title
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
Description
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.
Time Frame
Up to Day 4
Secondary Outcome Measure Information:
Title
Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Participants
Description
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.
Time Frame
Day 8 through up to Month 6
Title
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
Description
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.
Time Frame
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).
Title
Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
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
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24
Title
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
Description
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.
Time Frame
Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
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
Description
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.
Time Frame
Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
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
Time Frame
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
Title
Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
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
Time Frame
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
Title
Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma Phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants
Time Frame
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)
Title
Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants
Time Frame
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
Title
Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants
Time Frame
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)
Title
Rate of HACs: Cohort of 0 Months to <2 Months Participants
Description
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.
Time Frame
Day 8 through up to Month 6
Title
Number of Participants With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Participants
Description
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.
Time Frame
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).
Title
Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
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
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Participants
Time Frame
Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
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
Description
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.
Time Frame
Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
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
Description
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.
Time Frame
Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Title
Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants
Time Frame
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)
Title
Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants
Time Frame
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
Title
Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants
Time Frame
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Colleen Canavan, BS
Organizational Affiliation
Horizon Therapeutics, LLC
Official's Role
Study Director
Facility Information:
Facility Name
Kaiser Permanente Regional Metabolic Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Stanford Center for Clinical & Translational Research & Education
City
Palo Alto
State/Province
California
ZIP/Postal Code
94034
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Shands at University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Emory University
City
Decatur
State/Province
Georgia
ZIP/Postal Code
30033
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Maine Medical Center
City
Portland
State/Province
Maine
ZIP/Postal Code
04102
Country
United States
Facility Name
Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mount Sinai School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
The Hospital for Sick Children
City
Toronto
ZIP/Postal Code
M5G 1Hs
Country
Canada
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28916119
Citation
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 Genet Metab. 2017 Nov;122(3):46-53. doi: 10.1016/j.ymgme.2017.09.002. Epub 2017 Sep 8.
Results Reference
result
PubMed Identifier
30217721
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 age with urea cycle disorders. Mol Genet Metab. 2018 Nov;125(3):251-257. doi: 10.1016/j.ymgme.2018.09.001. Epub 2018 Sep 4.
Results Reference
result
Links:
URL
https://www.ravicti.com
Description
Related Info
Learn more about this trial
A Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate in Pediatric Subjects Under 2 Years of Age With Urea Cycle Disorders
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