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

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ClinicalTrials.gov Identifier: NCT01347073
Recruitment Status : Completed
First Posted : May 4, 2011
Results First Posted : May 28, 2015
Last Update Posted : January 16, 2017
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland

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.

Condition or disease Intervention/treatment Phase
Urea Cycle Disorders Drug: HPN-100 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : July 2011
Actual Primary Completion Date : February 2013
Actual Study Completion Date : March 2013

Arm Intervention/treatment
Experimental: HPN-100
Switch over from sodium phenylbutyrate to open label HPN-100 oral liquid over 10 days then open label, long term treatment for 12 months
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.
Other Names:
  • Glycerol phenylbuterate

Primary Outcome Measures :
  1. Adverse Events [ Time Frame: 2 weeks ]
    Rate of adverse events during the Switch-Over portion of the Protocol

  2. Adverse Events [ Time Frame: 12 months ]
    Rate of adverse events during the Safety Extension portion of the protocol ( please note: HPN-100 treatment only during Safety Extension )

Secondary Outcome Measures :
  1. Blood Ammonia [ Time Frame: 2 weeks ]
    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. Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) on HPN-100 Compared With NaPBA [ Time Frame: 2 weeks ]
    Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis

  3. Hyperammonemic Crisis [ Time Frame: 1 year ]
    Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment

Information from the National Library of Medicine

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Ages Eligible for Study:   29 Days to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01347073

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United States, California
UCLA Pediatrics/Genetics
Los Angeles, California, United States, 90404
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, 04101
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
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
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Horizon Pharma Ireland, Ltd., Dublin Ireland
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Study Chair: Bruce F Scharschmidt, M.D. Hyperion Therapeutics
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT01347073    
Other Study ID Numbers: HPN-100-012
First Posted: May 4, 2011    Key Record Dates
Results First Posted: May 28, 2015
Last Update Posted: January 16, 2017
Last Verified: June 2015
Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:
Urea Cycle Disorder
sodium phenylbutyrate
Additional relevant MeSH terms:
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Urea Cycle Disorders, Inborn
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
Cryoprotective Agents
Protective Agents
Physiological Effects of Drugs