Phase 4
N=26
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
Bottom Line
View on ClinicalTrials.gov: NCT02246218 ↗Enrolled (actual)
26
Serious AEs
65.4%
Results posted
Mar 2019
Primary outcome: 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 — 100 percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 4
- Interventions
- RAVICTI (Drug)
- Age
- Pediatric · 0+ yrs
- Sex
- All
- Sponsor
- Amgen
- Primary completion
- Oct 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| 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 |
100 | — |
| 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 |
100 | — |
| SECONDARY Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Participants |
0.005 | — |
| 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 |
10; 4; 6; 0; 1; 1 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Participants |
122.43; -54.50; 7.80; -16.33; -13.00; 0.25 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Participants |
750.43; -184.33; -174.60; -374.00; -252.75; -370.25 | — |
| 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 |
872.86; -238.83; -166.80; -390.33; -265.75; -370.00 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Participants |
54.86; 2.67; 4.20; -25.67; -20.25; -20.00 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Participants |
90.86; -0.83; 9.80; -33.00; -31.25; -39.50 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Participants |
171.43; 4.00; 40.60; -27.33; -31.50; -56.00 | — |
| 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 |
0.8107; -0.2385; -0.0249; 0.1815; 0.4434; 0.1484 | — |
| 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 |
0.7143; -0.2105; -0.0704; 0.1065; 0.3365; 0.1043 | — |
| 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 |
42.44 | — |
| SECONDARY Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
1.697 | — |
| 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 |
280.936 | — |
| SECONDARY Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
8.383 | — |
| SECONDARY Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
36.52 | — |
| SECONDARY Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
4.197 | — |
| SECONDARY Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
246.126 | — |
| SECONDARY Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
7.422 | — |
| SECONDARY Plasma Phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
62.45 | — |
| SECONDARY Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
20.62 | — |
| SECONDARY Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
583.835 | — |
| SECONDARY Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
6.573 | — |
| SECONDARY Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
3273; 4140; 3145; 5202; 3950; 7561 | — |
| SECONDARY Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants |
8859; 6274; 7386; 11456; 21416; 6129 | — |
| SECONDARY Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Participants |
18.78; 6.50; 7.29; 2.60; 4.48; 4.31 | — |
| SECONDARY Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Participants |
5.82; 4.44; 3.69; 4.65; 7.14; 3.27 | — |
| SECONDARY Rate of HACs: Cohort of 0 Months to <2 Months Participants |
0.003 | — |
| SECONDARY Number of Participants With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Participants |
16; 10; 11; 0; 0; 1 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Participants |
84.97; 26.81; 25.16; 50.05; 18.77; 57.43 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Participants |
508.83; 21.04; -27.62; -15.09; -113.98; -99.82 | — |
| 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 |
593.80; 47.85; -2.46; 34.96; -95.21; -42.39 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Months Participants |
142.68; -49.09; -1.62; -20.46; -67.32; -75.45 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Participants |
133.67; -81.91; -60.80; -51.66; -82.82; -118.55 | — |
| SECONDARY Amino Acid Assessment: Baseline and Change From Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Participants |
181.49; -63.96; -39.04; -23.86; -74.41; -98.67 | — |
| 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 |
-0.0544; -0.2158; -0.2598; -0.1617; -0.0264; 0.0828 | — |
| 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 |
-0.1980; 0.2336; 0.2006; 0.2684; 0.2372; 0.1810 | — |
| SECONDARY Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
46.2 | — |
| SECONDARY Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
4.8 | — |
| SECONDARY Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
374.53 | — |
| SECONDARY Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
9.39 | — |
| SECONDARY Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
115.3 | — |
| SECONDARY Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
98.98 | — |
| SECONDARY Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
1321.18 | — |
| SECONDARY Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
9.85 | — |
| SECONDARY Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
102.1 | — |
| SECONDARY Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
69.39 | — |
| SECONDARY Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
1384.12 | — |
| SECONDARY Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
11.72 | — |
| SECONDARY Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
3530.43; 1828; 1746; 2260; 3530.43; 4404 | — |
| SECONDARY Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants |
4643; 4517; 4116; 7037; 2826; 6973 | — |
| SECONDARY Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Participants |
11.1; 46.2; 62.5; 34.6; 22.8; 35.2 | — |
| SECONDARY Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Participants |
23.7; 14.6; 12.3; 14.4; 6.4; 13.2 | — |
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.
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)
Data sourced from ClinicalTrials.gov (NCT02246218). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.