To Evaluate the Safety of Long-term Use of HPN-100 in the Management of Urea Cycle Disorders (UCDs)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Long Term Use of HPN-100 in Urea Cycle Disorders

Conditions
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Urea Cycle Disorders

Intervention / Treatment
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* Drug: HPN-100


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HPN-100<br>Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE. | Drug: HPN-100<br>* 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.<br>* Other names: GT4P, Glyceryl tri-(4-phenylbutyrate), RAVICTI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Adverse Event | 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. | From the time of informed consent until 7 days after the last dose of study drug, up to 66 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Normalized Blood Ammonia Levels | 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. | From baseline through the end of the study, up to 66 months | 
| Number of Hyperammonemic Crises | An hyperammonemic crisis (HAC) was defined as clinical symptoms associated with a venous ammonia concentration of ≥100 μmol/L. | From the time of informed consent until 7 days after the last dose of study drug, up to 66 months | 
| Causes of Hyperammonemic Crises | 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. | From the time of informed consent until 7 days after the last dose of study drug, up to 66 months | 
| Mean Wechsler Abbreviated Scale of Intelligence (WASI) Scores | 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. | Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) | 
| Mean Child Behavior Checklist (CBCL) Problems Scores | 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. | Baseline, Month 12, Month 24, and study exit visit (up to 66 months) | 
| Mean Behavior Rating Inventory of Executive Function (BRIEF) Scores | 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. | Baseline, Month 12, Month 24, and study exit visit (up to 66 months) | 
| Mean California Verbal Learning Test Scores: List A Total 1-5 T-Scores | 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. | Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) | 
| 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 | 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. | Baseline, Month 12, Month 24, Month 36, Month 48, and study exit visit (up to 66 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BUPHENYL, Urea Cycle Disorders, GT4P, HPN-100, Sodium Phenylbutyrate (NaPBA), Glyceryl tri-(4-phenylbutyrate), Phenylbutyrate, Hyperion, hyperammonemia