Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 2, Fixed-Sequence, Open-Label, Switch-Over Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children 6-17 Years of Age With Urea Cycle Disorders, With a Long-Term Safety Extension|
- Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events) [ Time Frame: 1 week on each treatment for a total of 2 week. ]To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders (UCDs)
- Number and Causes of Hyperammonemic Events (Safety Extension) [ Time Frame: 1 year ]
Number of Subjects with at Least One Hyperammonemic Crisis.
Hyperammonemic crisis is defined as follows:
• Clinical symptoms associated with ammonia of ≥ 100 µmol/L
- Blood Ammonia Control [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]To evaluate control of blood ammonia by HPN-100 compared with NaPBA in pediatric patients with UCDs.
- NH3 Cmax on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
- Average Ammonia Values on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug (Switch Over) [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
- Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA vs. HPN-100 [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
- Urinary PAGN 24-hour Excretion Values on NaPBA vs. HPN-100 (Switch Over) [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]Urinary PAGN (phenylacetylglutamine) 24-hour excretion. Urine was collect during 0-12 hrs and 12-24 hrs.
- Plasma PAA (Phenylacetate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]
- Plasma PBA (Phenylbutyrate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]
- Plasma PAGN AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug [ Time Frame: Day 7 (NaPBA) and Day 14 (HPN-100) ]
- Quality of Life Assessed by the SF-15 Questionnaire [ Time Frame: 1 year ]
change from baseline to Month 12.
The SF 15 questionnaire consists of 15 questions that assess the following:
- Physical functioning (5 questions)
- Emotional functioning (4 questions)
- Social functioning (3 questions)
- School functioning (3 questions) Items were scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or a 3-point scale (0 [not at all], 2 [sometimes], or 4 [a lot] for the young child self-report). Items were reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. Total score was 0-100 scale (averaged from each functional areas). In the 0-100 scale, 0 is the worst score and 100 is best score.
Improved quality of life was shown by increased total score from baseline to Month 12.
|Study Start Date:||March 2010|
|Study Completion Date:||August 2011|
|Primary Completion Date:||August 2011 (Final data collection date for primary outcome measure)|
Experimental: HPN-100 and NaPBA
1 week of NaPBA treatment followed by 1 week of HPN-100 treatment.
HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA that 40 tablets of NapBA do.
Other Name: GT4P, Glyceryl tri-(4-phenylbutyrate)Drug: NaPBA
NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys.
Other Name: GT4P, Glyceryl tri-(4-phenylbutyrate)
This was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension part designed to assess the safety of HPN-100 in pediatric subjects and to prospectively assess the ability of HPN-100 to control blood ammonia compared with NaPBA.
For those subjects who participated in the switch over, NaPBA was dosed three times daily (TID) with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week. If there were safety concerns regarding a single-step transition from NaPBA to HPN-100, at the investigator's discretion, the transition could occur in 2 steps such that in the second week, subjects might receive 50% of the PBA equivalent dose as NaPBA and 50% as HPN-100 before receiving 100% of the PBA equivalent dose as HPN-100 in the third week. Serial blood samples were collected for PK and blood ammonia assessments after each drug reached steady state, which was achieved approximately 4 days after initiation of 100% NaPBA or HPN-100 treatment.
The subjects who completed the switch over part of the study, and up to 20 additional subjects, were offered the opportunity to continue in the study by entering the safety extension part of the study to continue receiving open-label HPN-100 for up to 12 months.
Subjects who prematurely terminated the study during the switch-over period after enrollment had safety assessments, including safety labs and a single blood sample drawn for measurement of phenylbutyrate (PBA), the active metabolite phenylacetate (PAA), and the terminal metabolite phenylacetylglutamine (PAGN). Subjects who had enrolled in the safety extension period of the study, either directly or following the switch over, but prematurely terminated the study prior to completing the extension period had Month 12 procedures performed, or at a minimum, had safety assessments including safety labs and ammonia had drawn. The time of day at which the blood sample was drawn was recorded as well as the time since the last dose of medication was taken.
Subjects followed a stable diet throughout the study, as prescribed by the investigator, and dietary compliance was recorded at each study visit for both the switch over and safety extension parts of the study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00947544
|United States, California|
|Los Angeles, California, United States, 90095|
|United States, District of Columbia|
|The George Washington DC Children's National Medical Center|
|Washington, District of Columbia, United States, 20010|
|United States, New York|
|Mount Sinai School of Medicine|
|New York, New York, United States, 10029|
|United States, Pennsylvania|
|University of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15201|
|United States, Texas|
|Baylor College of Medicine|
|Houston, Texas, United States, 77030|
|United States, Washington|
|Seattle Children's Hospital|
|Seattle, Washington, United States, 98105|
|United States, Wisconsin|
|Medical College of Wisconsin|
|Milwaukee, Wisconsin, United States, 53226|
|The Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G1X8|
|Principal Investigator:||Uta Lichter, MD||The George Washington MC Childrens Natonal Medical Center|