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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Urea Cycle Disorders

Intervention / Treatment
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* Drug: HPN-100


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 29 Days
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HPN-100<br>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<br>* 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.<br>* Other names: Glycerol phenylbuterate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Rate of adverse events during the Switch-Over portion of the Protocol | 2 weeks | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Hyperammonemic Crisis | Rate of HAC during pre-enrollment on NaPBA compared to HAC during HPN-100 treatment | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UCD, sodium phenylbutyrate, Urea Cycle Disorder, GT4P, Buphenyl, hyperammonemia