Urea Cycle Disorder
Conditions
Keywords
Urea, Hyperammonemic crisis (HAC)
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.
Detailed description
Study acquired from Horizon in 2024.
Interventions
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, Controlled, Open-Label Parallel Arm study
Eligibility
Sex/Gender
ALL
Age
No minimum to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | 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 |
Countries
Italy, Spain, Switzerland, United States
Participant flow
Pre-assignment details
In the Initial Treatment Period (approximately 28 days), eligible participants were randomized to one of two treatment arms: RAVICTI or NaPBA. For all Initial Treatment Period NaPBA participants and RAVICTI participants who were treatment failures, a Transition Period (7 days ± 2 days) with RAVICTI followed. All participants received RAVICTI in the Maintenance Period (8 Weeks) and the Safety Extension Period (12 Weeks).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 11 |
| NaPBA -> RAVICTI Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study:
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.
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. | 5 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Period | Withdrawal by Parent/Guardian | 1 | 0 |
| Safety Extension Period | Adverse Event | 1 | 0 |
| Safety Extension Period | Did Not Return to Study Visit | 1 | 0 |
Baseline characteristics
| Characteristic | Total | NaPBA -> RAVICTI | RAVICTI -> RAVICTI |
|---|---|---|---|
| Age, Customized > 12 - 16 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >= 17 years | 7 Participants | 2 Participants | 5 Participants |
| Age, Customized < 2 months | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized 2 months - < 2 years | 4 Participants | 0 Participants | 4 Participants |
| Age, Customized 2 years - 12 years | 4 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 5 | 0 / 5 | 0 / 16 |
| other Total, other adverse events | 6 / 11 | 2 / 5 | 1 / 5 | 8 / 16 |
| serious Total, serious adverse events | 2 / 11 | 0 / 5 | 1 / 5 | 3 / 16 |
Outcome results
Primary
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.
Time frame: Week 4
Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAVICTI | Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period | 81.8 percentage of participants |
| NaPBA | Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period | 80.0 percentage of participants |
p-value: 195% CI: [0, 28.1]Fisher Exact
Secondary
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period
Time frame: Baseline, Initial Treatment Period Week 1, Week 2, Week 3, Week 4 (0, 4, 8 hours post dose)
Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 1 | 6.5 µmol/L | Standard Deviation 21.16 |
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 2 | 25.5 µmol/L | Standard Deviation 59.88 |
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 3 | 7.4 µmol/L | Standard Deviation 35.91 |
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 0 hour | 2.1 µmol/L | Standard Deviation 15.52 |
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 4 hours postdose | 2.6 µmol/L | Standard Deviation 23.49 |
| RAVICTI | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 8 hours postdose | 23.4 µmol/L | Standard Deviation 62.09 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 4 hours postdose | -1.1 µmol/L | Standard Deviation 8.68 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 1 | 0.0 µmol/L | Standard Deviation 10.12 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 0 hour | -0.3 µmol/L | Standard Deviation 8.49 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 2 | -10.4 µmol/L | Standard Deviation 10.17 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 4: 8 hours postdose | -0.7 µmol/L | Standard Deviation 7.37 |
| NaPBA | Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period | Week 3 | -10.9 µmol/L | Standard Deviation 6.4 |
Comparison: Initial Treatment Period Week 1p-value: 0.8464Wilcoxon rank sum test
Comparison: Initial Treatment Period Week 2p-value: 0.104Wilcoxon rank sum test
Comparison: Initial Treatment Period Week 3p-value: 0.0979Wilcoxon rank sum test
Comparison: End of Initial Treatment Period Week 4 - 0 Hrp-value: 0.9808Wilcoxon rank sum test
Comparison: End of Initial Treatment Period Week 4 - 4 Hrp-value: 0.8329Wilcoxon rank sum test
Comparison: End of Initial Treatment Period Week 4 - 8 Hrp-value: 0.2544Wilcoxon rank sum test
Secondary
Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period
Time frame: Week 4: hour 0 (predose), and hours 4 and 8 postdose
Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization. Participants with an assessment at given time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RAVICTI | Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period | 60.2 µmol/L | Standard Deviation 78.47 |
| NaPBA | Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period | 38.1 µmol/L | Standard Deviation 18.91 |
p-value: 0.7155t-test
Secondary
Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period
Time frame: Week 4: hour 0 (predose), and hours 4 and 8 postdose
Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization. Participants with an assessment at given time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RAVICTI | Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period | 331.8 µmol*h /L | Standard Deviation 342.79 |
| NaPBA | Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period | 258.9 µmol*h /L | Standard Deviation 153.35 |
p-value: 0.8579t-test
Secondary
Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period
Time frame: Baseline through Week 4
Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAVICTI | Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period | 0 percentage of participants |
| NaPBA | Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period | 0 percentage of participants |