To Evaluate the Safety of Long-term Use of HPN-100 in the Management of Urea Cycle Disorders (UCDs)
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ClinicalTrials.gov Identifier: NCT01257737 |
Recruitment Status :
Completed
First Posted : December 10, 2010
Results First Posted : May 4, 2018
Last Update Posted : May 4, 2018
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Condition or disease | Intervention/treatment | Phase |
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Urea Cycle Disorders | Drug: HPN-100 | Phase 4 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 88 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Long Term Use of HPN-100 in Urea Cycle Disorders |
Actual Study Start Date : | October 4, 2010 |
Actual Primary Completion Date : | February 16, 2017 |
Actual Study Completion Date : | February 16, 2017 |

Arm | Intervention/treatment |
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Experimental: HPN-100
Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE.
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Drug: HPN-100
Participants received individualized doses of HPN-100 orally, three times daily (TID) with meals. The initial dose was the same dose administered at the end of the HPN-100-005SE, HPN-100-007, or HPN-100-012SE studies. Dose adjustments (including frequency adjustments) were permitted as judged clinically appropriate by the investigator based on assessment of ammonia-scavenging needs (e.g., severity of the UCD defect, dietary protein intake, and urinary phenylacetylglutamine [PAGN] excretion). The maximum recommended dose of HPN-100 in participants weighing less than 20 kg was 0.53 mL/kg/day (equivalent to 600 mg/kg/day of NaPBA), and was 11.48 mL/m²/day in heavier subjects (equivalent to 13g/m²/day of NaPBA). The maximum HPN-100 dose recommended per protocol was 17.4 mL/day, which is equivalent to 20 g/day of NaPBA.
Other Name: GT4P, Glyceryl tri-(4-phenylbutyrate), RAVICTI |
- Number of Participants With at Least One Adverse Event [ Time Frame: From the time of informed consent until 7 days after the last dose of study drug, up to 66 months ]Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs). An AE/adverse experience was any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. For additional information regarding adverse events, please see the safety section of the record.
- Mean Normalized Blood Ammonia Levels [ Time Frame: From baseline through the end of the study, up to 66 months ]Blood samples were collected for the assessment of plasma ammonia concentrations at baseline, at least every 6 months, at all unscheduled visits, and at the end of study participation. Ammonia level data were obtained from different local laboratories and each laboratory may have used a slightly different normal reference range. Therefore, the ammonia level data were normalized to a standard laboratory reference range before performing any analysis of ammonia data.
- Number of Hyperammonemic Crises [ Time Frame: From the time of informed consent until 7 days after the last dose of study drug, up to 66 months ]An hyperammonemic crisis (HAC) was defined as clinical symptoms associated with a venous ammonia concentration of ≥100 μmol/L.
- Causes of Hyperammonemic Crises [ Time Frame: From the time of informed consent until 7 days after the last dose of study drug, up to 66 months ]An hyperammonemic crisis (HAC) was defined as clinical symptoms associated with a venous ammonia concentration of ≥100 μmol/L. Peak observed ammonia concentrations during an HAC, precipitating factors, and symptoms recorded as suggestive to hyperammonemia were documented. There can be multiple contributing factors to an hyperammonemic crisis; in some cases several causes were identified.
- Mean Wechsler Abbreviated Scale of Intelligence (WASI) Scores [ Time Frame: Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) ]The Wechsler Abbreviated Scale of Intelligence (WASI) was administered to adults and pediatric participants who were at least 6 years of age. It was used to estimate general intellectual ability (IQ) based on the vocabulary and matrix reasoning subtests. The vocabulary subtest included 4 images and 38 verbal items. In the matrix reasoning subtest, the participant viewed 35 incomplete grid patterns and was asked to complete the pattern using responses from 5 possible choices. The number of correct responses for each of the subtests was converted to a T-score using the WASI assessment manual; T-scores are standard scores with a mean of 50 and a standard deviation (SD) of 10. Raw scores for the 2 subtests were summed, and converted to a standard score (mean of 100 with SD of 15) for the general IQ score for adults and to a T-score for children in accordance with the WASI manual. Higher scores indicate a higher level of intelligence.
- Mean Child Behavior Checklist (CBCL) Problems Scores [ Time Frame: Baseline, Month 12, Month 24, and study exit visit (up to 66 months) ]The Child Behavior Checklist (CBCL) is a widely-used method of identifying problem behavior. Two versions of the CBCL were used in this study; the assessment for children 6-18 years of age was used for participants ≥6 years of age, and the assessment for children 1.5-5 years of age was used for those who were at least 5 years old but <6 years of age. Parents/caregivers answered questions (120 and 100 questions, respectively, for the older and younger populations) using a 3-point Likert scale (0= not true; 1= somewhat or sometimes true; 2 =very true or often true). Using a computer program, responses to similar questions were grouped together into 20 domains (e.g., activities, social, school, etc.), and domain response scores were converted to T-scores and percentiles. A mean score of 50 is average, with a standard deviation of 10 points. Higher scores indicate greater problems. The total problems score is the sum of all of the problem items.
- Mean Behavior Rating Inventory of Executive Function (BRIEF) Scores [ Time Frame: Baseline, Month 12, Month 24, and study exit visit (up to 66 months) ]The Behavior Rating Inventory of Executive Function (BRIEF) is designed to assess executive functioning in children and adolescents ages 5 to 18 years of age. Parents/caregivers answered 86 questions on a 3-point scale (never, sometimes, often). Similar questions were grouped together into 8 scales; these scales were summed to produce 2 index measures and a global executive composite score. Raw scores for the indices/scales and composite score were converted to T-scores with corresponding 90% confidence intervals using computer software. Higher T-scores indicate a higher level of dysfunction.
- Mean California Verbal Learning Test Scores: List A Total 1-5 T-Scores [ Time Frame: Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) ]The California Verbal Learning Test - Second Edition (CVLT-II) assesses recall and recognition of word lists over several immediate- and delayed-memory trials. In the learning phase, adult participants were presented a list of 16 words (List A; 4 words each in 4 categories [e.g., fruit, toys, etc.]) for 5 trials, but words from the same category were never presented consecutively. An interference list (List B) of 16 different words was then presented for 1 trial. Short-and long-delay recalls for List A, yes/no recognition trials of List A, and a forced-choice recognition trial of List A was also administered. The total score for the 5 immediate-recall trials was converted to a T-score. Lower T-scores reflect worse performance.
- Mean California Verbal Learning Test Scores: Short and Long Delay Free Recall, Short and Long Delay Cued Recall, CVLT-II-Learning Slope, and Total Word Recognition Discrimination [ Time Frame: Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) ]The California Verbal Learning Test - Second Edition (CVLT-II) assesses recall and recognition of word lists over several immediate- and delayed-memory trials. In the learning phase, adult participants were presented a list of 16 words (List A; 4 words each in 4 categories [e.g., fruit, toys, etc.]) for 5 trials, but words from the same category were never presented consecutively. An interference list (List B) of 16 different words was then presented for 1 trial. Short-and long-delay recalls for List A, yes/no recognition trials of List A, and a forced-choice recognition trial of List A was also administered. The scores for the learning slope, the short- and long-delay scores and total word recognition discrimination scores were converted to Z-scores by computer software. The CVLT-II Z-score has a mean of 0 and a standard deviation of 1. Negative scores indicate below-average performance.

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Ages Eligible for Study: | 1 Year and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male and female subjects who completed Studies HPN-100-005SE, HPN-100-007, or HPN-100-012SE
- Signed informed consent by participant and/or participant's legally authorized representative
- Negative pregnancy test for all females of childbearing potential
Exclusion Criteria:
- Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may have put the participant at increased risk when participating
- Known hypersensitivity to PAA (phenylacetate) or PBA (phenylbutyrate).
- Liver transplant, including hepatocellular transplant
- Pregnant, breastfeeding or lactating females

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01257737
United States, California | |
UCLA Pediatrics/Genetics | |
Los Angeles, California, United States, 90095 | |
Stanford University School of Medicine | |
Palo Alto, California, United States, 94305 | |
United States, Colorado | |
Denver Children's Hospital | |
Aurora, Colorado, United States, 80045 | |
United States, District of Columbia | |
Children's National Medical Center | |
Washington, District of Columbia, United States, 20010 | |
United States, Maine | |
Maine Medical Center | |
Portland, Maine, United States, 04102 | |
United States, Minnesota | |
University of Minnesota Medical Center | |
Minneapolis, Minnesota, United States, 55454 | |
United States, New York | |
Mount Sinai School of Medicine | |
New York, New York, United States, 10029 | |
United States, Ohio | |
University Hospitals Case Medical Center | |
Cleveland, Ohio, United States, 44106 | |
Nationwide Children's Hospital | |
Columbus, Ohio, United States, 43205 | |
United States, Oregon | |
Oregon Health & Science University | |
Portland, Oregon, United States, 97239 | |
United States, Pennsylvania | |
Children's Hospital of Pittsburg of UPMC | |
Pittsburgh, Pennsylvania, United States, 15224 | |
United States, Texas | |
Baylor College of Medicine | |
Houston, Texas, United States, 77030 | |
United States, Utah | |
University of Utah | |
Salt Lake City, Utah, United States, 84112 | |
United States, Washington | |
Seattle Children's Hospital | |
Seattle, Washington, United States, 98105 | |
United States, Wisconsin | |
Children's Hospital of Wisconsin | |
Milwaukee, Wisconsin, United States, 53226 | |
Canada, Ontario | |
The Hospital for Sick Children | |
Toronto, Ontario, Canada, M5G 1X8 |
Study Director: | Colleen Canavan, BS | Horizon Therapeutics, LLC |
Documents provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC ):
Responsible Party: | Horizon Therapeutics, LLC |
ClinicalTrials.gov Identifier: | NCT01257737 |
Other Study ID Numbers: |
HPN-100-011 |
First Posted: | December 10, 2010 Key Record Dates |
Results First Posted: | May 4, 2018 |
Last Update Posted: | May 4, 2018 |
Last Verified: | April 2018 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Undecided |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Urea Cycle Disorders GT4P HPN-100 Sodium Phenylbutyrate (NaPBA) Glyceryl tri-(4-phenylbutyrate) |
Phenylbutyrate Hyperion BUPHENYL hyperammonemia |
Urea Cycle Disorders, Inborn Disease Pathologic Processes Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Brain Diseases Central Nervous System Diseases |
Nervous System Diseases Amino Acid Metabolism, Inborn Errors Metabolism, Inborn Errors Genetic Diseases, Inborn Metabolic Diseases 4-phenylbutyric acid Antineoplastic Agents |