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

Primary Purpose

Urea Cycle Disorders

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
HPN-100
Sponsored by
Horizon Pharma Ireland, Ltd., Dublin Ireland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urea Cycle Disorders focused on measuring Urea Cycle Disorder, UCD, GT4P, Buphenyl, hyperammonemia, sodium phenylbutyrate

Eligibility Criteria

29 Days - 6 Years (Child)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • UCLA Pediatrics/Genetics
  • Children's National Medical Center
  • Maine Medical Center
  • University of Minnesota
  • Mount Sinai School of Medicine
  • University Hospitals Case Medical Center
  • Oregon Health & Science University
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HPN-100

Arm Description

Switch over from sodium phenylbutyrate to open label HPN-100 oral liquid over 10 days then open label, long term treatment for 12 months

Outcomes

Primary Outcome Measures

Adverse Events
Rate of adverse events during the Switch-Over portion of the Protocol
Adverse Events
Rate of adverse events during the Safety Extension portion of the protocol ( please note: HPN-100 treatment only during Safety Extension )

Secondary Outcome Measures

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).
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
Hyperammonemic Crisis
Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment

Full Information

First Posted
April 29, 2011
Last Updated
January 13, 2017
Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland
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1. Study Identification

Unique Protocol Identification Number
NCT01347073
Brief Title
Study of the Safety, Pharmacokinetics and Efficacy of HPN-100, in Pediatric Subjects With Urea Cycle Disorders (UCDs)
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)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
July 2011 (undefined)
Primary Completion Date
February 2013 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urea Cycle Disorders
Keywords
Urea Cycle Disorder, UCD, GT4P, Buphenyl, hyperammonemia, sodium phenylbutyrate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HPN-100
Arm Type
Experimental
Arm Description
Switch over from sodium phenylbutyrate to open label HPN-100 oral liquid over 10 days then open label, long term treatment for 12 months
Intervention Type
Drug
Intervention Name(s)
HPN-100
Other Intervention Name(s)
RAVICTI, Glycerol phenylbuterate
Intervention Description
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.
Primary Outcome Measure Information:
Title
Adverse Events
Description
Rate of adverse events during the Switch-Over portion of the Protocol
Time Frame
2 weeks
Title
Adverse Events
Description
Rate of adverse events during the Safety Extension portion of the protocol ( please note: HPN-100 treatment only during Safety Extension )
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Blood Ammonia
Description
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).
Time Frame
2 weeks
Title
Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA
Description
Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis
Time Frame
2 weeks
Title
Hyperammonemic Crisis
Description
Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
29 Days
Maximum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce F Scharschmidt, M.D.
Organizational Affiliation
Hyperion Therapeutics
Official's Role
Study Chair
Facility Information:
Facility Name
UCLA Pediatrics/Genetics
City
Los Angeles
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Maine Medical Center
City
Portland
State/Province
Maine
ZIP/Postal Code
04101
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mount Sinai School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24144944
Citation
Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.
Results Reference
derived
PubMed Identifier
23324524
Citation
Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, LeMons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B. Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr. 2013 Jun;162(6):1228-34, 1234.e1. doi: 10.1016/j.jpeds.2012.11.084. Epub 2013 Jan 13.
Results Reference
derived

Learn more about this trial

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

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