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
• Sponsor: Horizon Therapeutics, LLC
• Information provided by (Responsible Party): Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Urea Cycle Disorders	Drug: HPN-100	Phase 4

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 Design

• 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

Arms and Interventions

Arm

Intervention/treatment

Experimental: HPN-100; Participants continued HPN-100 treatment after completion of HPN-100-005SE, HPN-100-007, or HPN-100-012SE.

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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

Horizon Therapeutics, LLC

Investigators

• Study Director: Colleen Canavan, BS; Horizon Therapeutics, LLC

  Study Documents (Full-Text)

Documents provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC ):

Study Protocol  [PDF] October 21, 2015

Statistical Analysis Plan  [PDF] November 18, 2015

More Information

• Responsible Party: Horizon Therapeutics, LLC
• ClinicalTrials.gov Identifier: NCT01257737
• Other Study ID Numbers: HPN-100-011
• First Posted: December 10, 2010
• 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

Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC ):

Urea Cycle Disorders; GT4P; HPN-100; Sodium Phenylbutyrate (NaPBA); Glyceryl tri-(4-phenylbutyrate); Phenylbutyrate; Hyperion; BUPHENYL; hyperammonemia

Additional relevant MeSH terms:

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