Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders

Study Overview
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Brief Summary
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The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.

Detailed Description
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When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium.

Official Title
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A Phase 2, Open-Label, Switch-Over, Dose-Escalation Study of the Safety and Tolerability of HPN-100 Compared to Buphenyl® (Sodium Phenylbutyrate) in Patients With Urea Cycle Disorders

Conditions
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Urea Cycle Disorders

Intervention / Treatment
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* Drug: HPN-100
* Drug: BUPHENYL®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients at least 18 years old Signed written informed consent by patient or patient's representative Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1 Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers) Negative pregnancy test for all females of childbearing potential. All females of childbearing potential must agree to use an acceptable method of contraception throughout the study Exclusion Criteria: Use of any investigational drug within 30 days of Buphenyl® Visit 1 Active infection (viral or bacterial) or any other condition that may increase ammonia levels Laboratory values outside the normal range that are determined to be clinically significant by the investigator Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1 Preexisting QTc interval prolongation (> 450 msec for males or > 460 msec for females) Other severe chronic medical conditions Known hypersensitivity to PAA, PBA, or benzoate Creatinine levels equal to or greater than 1.5 × ULN Liver transplant

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BUPHENYL® to HPN-100 vs. HPN-100<br>Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment. | Drug: HPN-100<br>* Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study.<br>Drug: BUPHENYL®<br>* BUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS.<br>* Other names: NaPBA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose. | At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation | 
| Number of Subjects Experienced Adverse Events |  | during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) | 
| Number of Subjects Experienced Serious Adverse Events |  | during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | measured AUC0-24 (Area under the curve from time 0 (pre-dose) to 24 hours) for each metabolite in plasma. Data were collected at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post-first dose. | At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone) | 
| Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) |  | End of Study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD