To Evaluate the Safety of Long-term Use of HPN-100 in the Management of Urea Cycle Disorders (UCDs)
- Registration Number
- NCT01257737
- Lead Sponsor
- Amgen
- Brief Summary
This was an open-label, long-term safety study of HPN-100 (RAVICTI; glycerol phenylbutyrate) in participants with a urea cycle disorder (UCD) who completed the safety extensions of HPN-100-005 (NCT00947544; HPN-100-005SE), HPN-100-006 (NCT00947297; HPN-100-007), or HPN-100-012 (NCT01347073; HPN-100-012SE). The initial studies were 1- to 2-week crossover studies, and their associated safety extensions were 12-month, open-label studies. All participants who completed the initial studies were eligible to enroll in the associated safety extension studies, and new participants were also permitted to enroll directly into the safety extension studies.
- Detailed Description
The duration of treatment in this study was open-ended. Participants were to return for clinic visits as prescribed by the investigator, and were to be seen at a minimum of every 6 months. At each clinic visit, participants were queried about any adverse events (AEs) or hyperammonemic crises (HACs) that occurred since the last visit. Physical and neurological examinations were performed, and blood samples were collected for the analysis of ammonia, amino acid panels, and routine clinical laboratory safety tests. Participants underwent neuropsychological testing at baseline, every 12 months thereafter, and at the final study visit.
Study acquired from Horizon in 2024.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 88
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description HPN-100 HPN-100 Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE.
- Primary Outcome Measures
Name Time Method Number of Participants With at Least One Adverse Event 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.
- Secondary Outcome Measures
Name Time Method Mean Wechsler Abbreviated Scale of Intelligence (WASI) Scores 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 Behavior Rating Inventory of Executive Function (BRIEF) Scores 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 Normalized Blood Ammonia Levels 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 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 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 Child Behavior Checklist (CBCL) Problems Scores 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 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 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.
Mean California Verbal Learning Test Scores: List A Total 1-5 T-Scores 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.
Trial Locations
- Locations (16)
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital of Pittsburg of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
UCLA Pediatrics/Genetics
🇺🇸Los Angeles, California, United States
University of Minnesota Medical Center
🇺🇸Minneapolis, Minnesota, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Denver Children's Hospital
🇺🇸Aurora, Colorado, United States
Stanford University School of Medicine
🇺🇸Palo Alto, California, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Maine Medical Center
🇺🇸Portland, Maine, United States
Mount Sinai School of Medicine
🇺🇸New York, New York, United States