Clinical trial NCT01347073: Study of the Safety, Pharmacokinetics and Efficacy of HPN-100, in Pediatric Subjects With Urea Cycle Disorders (UCDs)
Official title: A Switch-Over, Open-Label Study of the Safety, Pharmacokinetics, and Efficacy of HPN-100, Followed by Long-Term Treatment With HPN-100, in Pediatric Subjects Under 6 Years of Age With Urea Cycle Disorders (UCDs)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urea Cycle Disorders
Keywords: Urea Cycle Disorder
UCD
GT4P
Buphenyl
hyperammonemia
sodium phenylbutyrate
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2011-05-04
Enrollment: 23
Sex: ALL
Minimum age (years): 29
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Adverse Events
timeFrame: 2 weeks
measure: Adverse Events
timeFrame: 12 months
Secondary outcomes:
measure: Blood Ammonia
timeFrame: 2 weeks
measure: Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA
timeFrame: 2 weeks
measure: Hyperammonemic Crisis
timeFrame: 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Pediatrics/Genetics
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Amgen
name: F MD
role: STUDY_DIRECTOR
References:
citation: Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.
citation: Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, LeMons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B. Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr. 2013 Jun;162(6):1228-34, 1234.e1. doi: 10.1016/j.jpeds.2012.11.084. Epub 2013 Jan 13.