Study of the Safety, Pharmacokinetics and Efficacy of HPN-100, in Pediatric Subjects With Urea Cycle Disorders (UCDs)

Urea Cycle Disorders Clinical Trial

Official title:

A Switch-Over, Open-Label Study of the Safety, Pharmacokinetics, and Efficacy of HPN-100, Followed by Long-Term Treatment With HPN-100, in Pediatric Subjects Under 6 Years of Age With Urea Cycle Disorders (UCDs)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01347073
• Other study ID #: HPN-100-012
• Status: Completed
• Phase: Phase 3
• First received: April 29, 2011
• Last updated: January 13, 2017
• Start date: July 2011
• Est. completion date: March 2013

Study information

• Verified date: June 2015
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This non-randomized, open-label study was approximately one year in duration and consisted of a short term NaPBA to HPN-100 switchover part involving two overnight stays followed by a 12-month long term treatment period involving monthly visits.

Description:

This was an open-label study consisting of a 10-day switch-over period during which subjects were switched from their prescribed dose of sodium phenylbutyrate (BUPHENYLTM or NaPBA) to a dose of HPN-100 that delivered the same amount of the active ingredient, PBA, followed by long-term treatment with HPN-100 for up to 12 months. The study was designed to capture information important for evaluating safety, Pharmacokinetics, and efficacy while recognizing sampling limitations in young children and current standard of care. Patients eligible for this study included pediatric patients from 29 days to < 6 years of age with either a diagnosed or clinically suspected Urea Cycle Disorders (UCD) who are receiving a stable dose of the powder formulation of NaPBA. Subjects were clinically stable and had been receiving a stable dose NaPBA powder for at least 5 days at the time of enrollment.

During the switch-over part of the study, subjects switched from NaPBA to HPN-100 in one step and had two overnight stays with 24 hour blood sampling, the first of which was on Day 1, while still taking NaPBA, and the second of which was on approximately Day 10 while taking HPN-100. Subjects then continued in the long-term treatment phase which was 12 months in duration.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: March 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Years

Eligibility

Inclusion Criteria:

• Male and female subjects 29 days to < 6 years old. If the subject is born prematurely, calculation of the lower age limit begins at the corrected gestational age of 40 weeks.

• Signed informed consent by the subject's legally acceptable representative

• Suspected or confirmed UCD diagnosis of any subtype, except NAGS deficiency

• On stable dose of NaPBA powder for at least 5 days before Day 1

• Not receiving sodium benzoate for at least 5 days before Day 1

• No concomitant illness which would preclude safe participation as judged by the investigator

• Able to receive medication orally

• Has not undergone liver transplantation, including hepatocellular transplantation

• Judged sufficiently stable and compliant with diet and treatment to be suitable for enrollment

Exclusion Criteria:

• Screening ammonia level > 100 µmol/L and signs and symptoms indicative of hyperammonemia; subjects may be rescreened after their ammonia is controlled and they are clinically stable, at the discretion of the investigator

• Use of any investigational drug within 30 days of Day 1

• Active infection (viral or bacterial) or any other condition that may increase ammonia levels

• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, except Grade 3 elevations in ammonia and liver enzymes, defined as levels 5-20 times ULN (upper limit of normal)in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma glutamyl transpeptidase (GGT) in a clinically stable subject

• Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at increased risk by participating in this study

• Known hypersensitivity to PAA or PBA

• Liver transplant, including hepatocellular transplant

• Currently treated with Carbaglu® (carglumic acid)

Related Conditions & MeSH terms

• Disease
• Urea Cycle Disorders
• Urea Cycle Disorders, Inborn

Intervention

Drug:
• HPN-100
HPN-100 is a pro-drug of PAA that combines with glutamine to provide an alternative vehicle for waste nitrogen elimination. It is a liquid with minimal taste and odor. Approximately three teaspoons of HPN-100 (~17.4 mL) delivers an equivalent amount as PBA that 40 tablets of NaPBA.

Locations

Country	Name	City	State
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Baylor College of Medicine	Houston	Texas
United States	UCLA Pediatrics/Genetics	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Mount Sinai School of Medicine	New York	New York
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Pharma Ireland, Ltd., Dublin Ireland

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events	Rate of adverse events during the Switch-Over portion of the Protocol	2 weeks
Primary	Adverse Events	Rate of adverse events during the Safety Extension portion of the protocol ( please note: HPN-100 treatment only during Safety Extension )	12 months
Secondary	Blood Ammonia	24-hour ammonia AUC of blood ammonia levels on Days 1 (NaPBA) and 10 (HPN-100) were compared. Ammonia was assessed at Hour 0 (pre-first dose, fasted), Hour 8 (~2-4 hours after lunch or the second main meal and dose of NaPBA), Hour 12 (~4 hours after the last main meal) and 24 hours post-first dose (pre-first dose on following day, fasted).	2 weeks
Secondary	Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA	Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis	2 weeks
Secondary	Hyperammonemic Crisis	Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment	1 year