To Evaluate the Safety of Long-term Use of HPN-100 in the Management of Urea Cycle Disorders (UCDs)
|ClinicalTrials.gov Identifier: NCT01257737|
Recruitment Status : Completed
First Posted : December 10, 2010
Results First Posted : May 4, 2018
Last Update Posted : May 4, 2018
|Condition or disease||Intervention/treatment||Phase|
|Urea Cycle Disorders||Drug: HPN-100||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||88 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE.
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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01257737
|United States, California|
|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|
|The Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G 1X8|
|Study Director:||Colleen Canavan, BS||Horizon Therapeutics, LLC|