Urea Cycle Disorders
Conditions
Keywords
Urea Cycle Disorder, UCD, GT4P, Buphenyl, hyperammonemia, sodium phenylbutyrate
Brief summary
This non-randomized, open-label study was approximately one year in duration and consisted of a short term NaPBA to HPN-100 switchover part involving two overnight stays followed by a 12-month long term treatment period involving monthly visits.
Detailed description
This was an open-label study consisting of a 10-day switch-over period during which subjects were switched from their prescribed dose of sodium phenylbutyrate (BUPHENYLTM or NaPBA) to a dose of HPN-100 that delivered the same amount of the active ingredient, PBA, followed by long-term treatment with HPN-100 for up to 12 months. The study was designed to capture information important for evaluating safety, Pharmacokinetics, and efficacy while recognizing sampling limitations in young children and current standard of care. Patients eligible for this study included pediatric patients from 29 days to \< 6 years of age with either a diagnosed or clinically suspected Urea Cycle Disorders (UCD) who are receiving a stable dose of the powder formulation of NaPBA. Subjects were clinically stable and had been receiving a stable dose NaPBA powder for at least 5 days at the time of enrollment. During the switch-over part of the study, subjects switched from NaPBA to HPN-100 in one step and had two overnight stays with 24 hour blood sampling, the first of which was on Day 1, while still taking NaPBA, and the second of which was on approximately Day 10 while taking HPN-100. Subjects then continued in the long-term treatment phase which was 12 months in duration. Study acquired from Horizon in 2024.
Interventions
DRUGHPN-100
HPN-100 is a pro-drug of PAA that combines with glutamine to provide an alternative vehicle for waste nitrogen elimination. It is a liquid with minimal taste and odor. Approximately three teaspoons of HPN-100 (\ 17.4 mL) delivers an equivalent amount as PBA that 40 tablets of NaPBA.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
29 Days to 6 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects 29 days to \< 6 years old. If the subject is born prematurely, calculation of the lower age limit begins at the corrected gestational age of 40 weeks. * Signed informed consent by the subject's legally acceptable representative * Suspected or confirmed UCD diagnosis of any subtype, except NAGS deficiency * On stable dose of NaPBA powder for at least 5 days before Day 1 * Not receiving sodium benzoate for at least 5 days before Day 1 * No concomitant illness which would preclude safe participation as judged by the investigator * Able to receive medication orally * Has not undergone liver transplantation, including hepatocellular transplantation * Judged sufficiently stable and compliant with diet and treatment to be suitable for enrollment
Exclusion criteria
* Screening ammonia level \> 100 μmol/L and signs and symptoms indicative of hyperammonemia; subjects may be rescreened after their ammonia is controlled and they are clinically stable, at the discretion of the investigator * Use of any investigational drug within 30 days of Day 1 * Active infection (viral or bacterial) or any other condition that may increase ammonia levels * 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 ULN (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 PAA or PBA * Liver transplant, including hepatocellular transplant * Currently treated with Carbaglu® (carglumic acid)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 2 weeks | Rate of adverse events during the Switch-Over portion of the Protocol |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Ammonia | 2 weeks | 24-hour ammonia AUC of blood ammonia levels on Days 1 (NaPBA) and 10 (HPN-100) were compared. Ammonia was assessed at Hour 0 (pre-first dose, fasted), Hour 8 (\ 2-4 hours after lunch or the second main meal and dose of NaPBA), Hour 12 (\ 4 hours after the last main meal) and 24 hours post-first dose (pre-first dose on following day, fasted). |
| Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA | 2 weeks | Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis |
| Hyperammonemic Crisis | 1 year | Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment |
Countries
United States
Participant flow
Recruitment details
Study Locations: Houston, TX; Minneapolis, MN; Washington, DC; New York, NY; Cleveland, OH; Portland, ME; Portland, OR Study Initiation Date: September 9, 2011 Study Completion Date: April 4, 2013
Pre-assignment details
This is an open-label, fixed-sequence NaPBA to HPN-100 switchover study with no control group.
Participants by arm
| Arm | Count |
|---|---|
| HPN-100 The first part of this open-label study consisted of a switch-over period during which patients were switched from the current medication (NaPBA) to HPN-100. The second part of this open-label study consisted of a 12-month long-term treatment phase with HPN-100. All participants in the switch-over were enrolled into the long-term treatment phase. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Liver Transplant | 1 |
Baseline characteristics
| Characteristic | HPN-100 |
|---|---|
| Age, Categorical <=18 years | 23 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 23 |
| serious Total, serious adverse events | 11 / 23 |
Outcome results
Primary
Adverse Events
Rate of adverse events during the Switch-Over portion of the Protocol
Time frame: 2 weeks
Population: All patients who received any amount of study medication were included in this population, which is the primary population for all baseline, accountability, demographic and safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA | Adverse Events | 0 participants |
| HPN-100 | Adverse Events | 6 participants |
Primary
Adverse Events
Rate of adverse events during the Safety Extension portion of the protocol ( please note: HPN-100 treatment only during Safety Extension )
Time frame: 12 months
Population: All patients that entered the Safety Extension were included in the analysis of adverse events
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA | Adverse Events | 23 participants |
Secondary
Blood Ammonia
24-hour ammonia AUC of blood ammonia levels on Days 1 (NaPBA) and 10 (HPN-100) were compared. Ammonia was assessed at Hour 0 (pre-first dose, fasted), Hour 8 (\ 2-4 hours after lunch or the second main meal and dose of NaPBA), Hour 12 (\ 4 hours after the last main meal) and 24 hours post-first dose (pre-first dose on following day, fasted).
Time frame: 2 weeks
Population: All patients who received any amount of both study medications (NaPBA and HPN-100) were included in this population, which is the primary population for analysis of efficacy and pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaPBA | Blood Ammonia | 914.43 umol/L*hours | Standard Deviation 630.21 |
| HPN-100 | Blood Ammonia | 647.63 umol/L*hours | Standard Deviation 379.94 |
Secondary
Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA
Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis
Time frame: 2 weeks
Population: All patients who received any amount of both study medications (NaPBA and HPN-100) were included in this population, which is the primary population for analysis of efficacy and pharmacokinetic parameters.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA | Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA | 22 Ammonia Values > ULN |
| HPN-100 | Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA | 8 Ammonia Values > ULN |
Secondary
Hyperammonemic Crisis
Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA | Hyperammonemic Crisis | 29 number of crises |
| HPN-100 | Hyperammonemic Crisis | 12 number of crises |