Efficacy and Safety of HPN-100 for the Treatment of Adults With Urea Cycle Disorders

Study Overview
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Brief Summary
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This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA.

Detailed Description
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This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA. Subjects were randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. Venous ammonia was the primary outcome measure. Subjects were admitted to the clinical research unit for 24 hours of pharmacokinetic (PK) blood and urine sampling (including an overnight stay) at the end of each treatment period, by which time the study drug had reached steady state. Subjects followed a stable diet throughout the study as prescribed by the investigator and dietician. Throughout the study, diet diaries were completed by the subject and dietary protein intake were assessed by a dietician based on completed dietary diaries and consultation with the subject. Subjects who completed this study and met the study entry criteria, were offered the opportunity to enroll in the HPN-100 open-label safety protocol (HPN-100-007).

Official Title
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A Phase 3, Randomized, Double-Blind, Cross-Over, Active-Controlled Study of the Efficacy and Safety of HPN-100, Glyceryl Tri-(4-phenylbutyrate), for the Treatment of Adults With Urea Cycle Disorders (Help UCD)

Conditions
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Urea Cycle Disorders

Intervention / Treatment
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* Drug: HPN-100
* Drug: Buphenyl (NaPBA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of UCD (Urea Cycle Disorder) involving deficiencies of Carbamyl phosphate synthetase (CPS), Ornithine transcarbamylase (OTC), or Arginosuccinate (ASS), confirmed via enzymatic, biochemical, or genetic testing Adult UCD subjects 18 years of age or older who are being treated with Buphenyl/Sodium phenylbuterate (NaPBA) for their UCD; subjects must be on a stable dose of NaPBA for at least 1 week prior to the Day 1 visit. Subjects who are not receiving NaPBA at the initial screening visit, but who have the potential to benefit from treatment, may start receiving NaPBA during the screening period and be enrolled as long as they are on a stable dose of NaPBA for at least 1 week prior to Day 1. No clinical evidence of hyperammonemia associated with an ammonia level of ≥ 100 μmol/L during the 2 weeks preceding screening Signed informed consent by subject Able to perform and comply with study activities, including blood draws and 24-hour urine samples Negative pregnancy test for all females of childbearing potential All females of childbearing age and all sexually active males must agree to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active. Exclusion Criteria: Screening or baseline ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia during the 2-week period preceding screening or enrollment; subjects may be re-screened after their ammonia is controlled and are stable for at least 14 days, 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 intercurrent condition (apart from UCD) 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) v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times upper limit of normal (ULN) in alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 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 Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication known to increase ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study Use of sodium benzoate within one week of Day 1 History of corrected QT interval (QTc) prolongation or QTc interval > 450 msec at screening or baseline Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA) Liver transplant, including hepatocellular transplant Breastfeeding or lactating females

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buphenyl (NaPBA) /HPN 100 Placebo<br>Subjects in Arm A were randomly assigned to receive NaPBA + HPN 100 placebo for 2 weeks and then crossed over to receive HPN 100 + NaPBA Placebo for 2 weeks. | Drug: Buphenyl (NaPBA)<br>* Buphenyl (NaPBA) will be the comparator drug to HPN-100 in this study.<br>* Other names: sodium phenylbutyrate;|
| Experimental: HPN-100/NaPBA Placebo<br>Subjects in Arm B were randomly assigned to receive HPN-100 + NaPBA placebo for 2 weeks and then crossed over to receive NaPBA + HPN 100 placebo for 2 weeks. | Drug: HPN-100<br>* 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 in 40 tablets of NaPBA.<br>* Other names: GT4P, glyceryl tri-(4-phenylbutyrate);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Endpoint Was the 24-hour Area Under the Curve for Blood Ammonia (NH324-hour AUC) on Days 14 and 28. | Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. Arm A day 14 and Arm B day 28 data were combined as a NaPBA treatment Arm. Arm B day 14 and Arm A day 28 data were combined as a HPN-100 treatment Arm. | pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation Between Urinary Phenylacetylglutamine (PAGN) Excretion Over 24 Hours (U-PAGN24-hour Excr) and Venous Ammonia - Area Under the Concentration-time Curve From Time 0 (Predose) to 24 Hours (AUC0-24) | The correlation between 24-hour urinary phenylacetylglutamine (PAGN) excretion (U-PAGN24-hour Excr) and venous ammonia AUC0-24 was summarized and the correlation was tested using the Spearman rank-order correlation. | 28 Days | 
| Maximum Ammonia Values Observed on NaPBA Versus HPN-100 | Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. | pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28 | 
| Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA Versus HPN-100 | NaPBA treated arm: total 345 blood samples were collected. HPN-100 treated arm: 343 blood samples were collected. | on Day 14 and Day 28 | 
| Number and Severity of Symptomatic Hyperammonemic Crises | Severity of symptomatic hyperammonemic crises was measured by peak ammonia level (µmol/L) when it is >= 100 µmol/L. | 29 Days | 
| Rate of Adverse Events in Each Treatment Group |  | 29 Days | 
| Cmax for PAA of NaPBA and HPN-100 in Plasma | Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. | pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28 | 
| Cmax for PBA of NaPBA and HPN-100 in Plasma | Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. | pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28 | 
| Cmax PAGN of NaPBA and HPN-100 in Plasma | Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. | pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28 | 
| U-PAGN24-hour Excr of NaPBA and HPN-100 |  | 24 hours on Day 14 of each treatments | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urea Cycle Disorder (UCD), UCD, hyperammonemia, Buphenyl (NaPBA), glycerol phenylbutyrate (GPB), Sodium Phenylbutyrate (NaPBA)