Clinical trial NCT00947297: Study of the Safety of HPN (Hyperion)-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)
Official title: A Phase 3, Open-Label Study of the Safety of HPN-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urea Cycle Disorders
Keywords: Urea Cycle Disorder
UCD
hyperammonemia
Buphenyl
Sodium Phenylbutyrate
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2009-07-28
Enrollment: 60
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This was a long-term safety study HPN-100 in urea cycle disorder (UCD) subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Detailed description: This was a one year long-term safety study of HPN-100 in UCD subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Forty subjects with a diagnosis of UCD who completed Study HPN-100-006 were enrolled.

Twenty additional UCD subjects ≥ 6 years of age were enrolled. These subjects included those who did not qualify for HPN-100-006 \[e.g., subjects between the ages of 6-17; subjects with other UCD subtypes or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.\]. For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. See the inclusion criteria for examples of clinical evidence of potential benefit.

Monthly assessments included safety laboratory tests, amino acid panel, vital signs, electrocardiogram (ECG) monitoring, venous ammonia, and blood and urine metabolites. Adverse events (AEs) and concomitant medications were recorded on an ongoing basis.

Study acquired from Horizon in 2024.

Eligibility criteria: Inclusion Criteria:

* Male and female subjects who completed HPN-100-006:

  \*Additionally, approximately 20 UCD subjects ≥ 6 years of age may be enrolled who have not participated in HPN-100-006. These subjects may include those who did not qualify HPN-100-006 (e.g., subjects between the ages of 6-17 years, subjects with other UCD subtypes, or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.). For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. Clinical evidence of potential benefit from introduction of an ammonia-scavenging agent might include a recent history (in the past year) of clinically overt hyperammonemia accompanied by a venous ammonia ≥ 100 μmol/L, a recent history (within the past year) of protein intolerance, or a history of abnormally high venous ammonia levels accompanied by symptoms (e.g., headache) that might reasonably be attributed to hyperammonemia.
* Signed informed consent by subject and/or subject's legally acceptable representative.
* Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.
* Able to perform and comply with study activities, including blood draws.
* Negative pregnancy test for all females of childbearing potential.
* All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study.

Exclusion Criteria:

* Screening venous ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their venous ammonia is controlled, at the discretion of the investigator.
* History of 4 or more hyperammonemic events as defined in Section 3.5.1 in the preceding 12 months.
* Active infection (viral or bacterial) or any other condition that may increase venous ammonia levels.
* 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.
* Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication known to increase venous ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study.
* History of QTc (QT interval corrected) prolongation, or a QTc interval ≥ 450 msec or an increase of ≥ 60 msec during the previous HPN-100 study if applicable.
* Known hypersensitivity to PAA or PBA.
* Liver transplant, including hepatocellular transplant.
* Breastfeeding or lactating females.

Primary outcomes:
measure: Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug)
timeFrame: 1 year
Secondary outcomes:
measure: Number and Causes of Hyperammonemic Events
timeFrame: 1 year
measure: Blood Ammonia Levels
timeFrame: 1 Year
measure: Patient Satisfaction With HPN-100
timeFrame: Month 1 post dose
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Long Beach Memorial
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Iowa City
country: United States
facility: Univeristy of Iowa
state: Iowa
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: SNBL-Clinical Pharmacology Center
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Amgen
name: 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: Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. Epub 2013 Jan 3.