Back to results

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

Primary Purpose

Urea Cycle Disorders

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

HPN-100

BUPHENYL®

About this trial

This is an interventional treatment trial for Urea Cycle Disorders focused on measuring Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Minnesota
Baylor College of Medicine

Arms of the Study

Arm 1

Arm Type

Active Comparator

Arm Label

BUPHENYL® to HPN-100 vs. HPN-100

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Number of Subjects Experienced Adverse Events

Number of Subjects Experienced Serious Adverse Events

Secondary Outcome Measures

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.

Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)

Full Information

NCT ID

NCT00551200

First Posted

October 26, 2007

Last Updated

January 13, 2017

Sponsor

Horizon Pharma Ireland, Ltd., Dublin Ireland

1. Study Identification

Unique Protocol Identification Number

NCT00551200

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2015

Overall Recruitment Status

Completed

Study Start Date

October 2007 (undefined)

Primary Completion Date

July 2008 (Actual)

Study Completion Date

December 2008 (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

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

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Urea Cycle Disorders

Keywords

Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

BUPHENYL® to HPN-100 vs. HPN-100

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

HPN-100

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

BUPHENYL®

Other Intervention Name(s)

Sodium Phenylbutyrate, NaPBA

Intervention Description

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.

Primary Outcome Measure Information:

Title

Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)

Description

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.

Time Frame

At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation

Title

Number of Subjects Experienced Adverse Events

Time Frame

during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)

Title

Number of Subjects Experienced Serious Adverse Events

Time Frame

during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)

Secondary Outcome Measure Information:

Title

Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)

Description

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.

Time Frame

At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)

Title

Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)

Time Frame

End of Study

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bruce Scharschmidt, MD

Organizational Affiliation

Horizon Pharma Ireland, Ltd., Dublin Ireland

Official's Role

Study Director

Facility Information:

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

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

17538092

Citation

Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007 May 31;356(22):2321-2. doi: 10.1056/NEJMe078075. No abstract available.

Results Reference

background

PubMed Identifier

17538087

Citation

Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596.

Results Reference

background

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

22961727

Citation

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. Epub 2013 Jan 3.

Results Reference

derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs