Clinical trial NCT00551200: Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders
Official title: A Phase 2, Open-Label, Switch-Over, Dose-Escalation Study of the Safety and Tolerability of HPN-100 Compared to Buphenyl® (Sodium Phenylbutyrate) in Patients With Urea Cycle Disorders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urea Cycle Disorders
Keywords: Buphenyl
Sodium Phenylbutyrate
Urea Cycle Disorder
UCD
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2007-10-30
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.

Detailed description: When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium.

Study acquired from Horizon in 2024.

Eligibility criteria: Inclusion Criteria:

* Male and female patients at least 18 years old
* Signed written informed consent by patient or patient's representative
* Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing
* Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1
* Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers)
* Negative pregnancy test for all females of childbearing potential. All females of childbearing potential must agree to use an acceptable method of contraception throughout the study

Exclusion Criteria:

* Use of any investigational drug within 30 days of Buphenyl® Visit 1
* Active infection (viral or bacterial) or any other condition that may increase ammonia levels
* Laboratory values outside the normal range that are determined to be clinically significant by the investigator
* Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient
* Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1
* Preexisting QTc interval prolongation (\> 450 msec for males or \> 460 msec for females)
* Other severe chronic medical conditions
* Known hypersensitivity to PAA, PBA, or benzoate
* Creatinine levels equal to or greater than 1.5 × ULN
* Liver transplant

Primary outcomes:
measure: Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)
timeFrame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation
measure: Number of Subjects Experienced Adverse Events
timeFrame: during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
measure: Number of Subjects Experienced Serious Adverse Events
timeFrame: during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Secondary outcomes:
measure: Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)
timeFrame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)
measure: Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)
timeFrame: End of Study
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007 May 31;356(22):2321-2. doi: 10.1056/NEJMe078075. No abstract available.
citation: Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596.
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.