Study of the Safety of HPN (Hyperion)-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00947297
• Collaborator: (none)
• Enrollment: 60
• Locations: 22
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a long-term safety study HPN-100 in urea cycle disorder (UCD) subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Condition or Disease	Intervention/Treatment	Phase
Urea Cycle Disorders	Drug: HPN-100	Phase 3

Detailed Description

This was a one year long-term safety study of HPN-100 in UCD subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.

Forty subjects with a diagnosis of UCD who completed Study HPN-100-006 were enrolled.

Twenty additional UCD subjects ≥ 6 years of age were enrolled. These subjects included those who did not qualify for HPN-100-006 [e.g., subjects between the ages of 6-17; subjects with other UCD subtypes or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.]. For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. See the inclusion criteria for examples of clinical evidence of potential benefit.

Monthly assessments included safety laboratory tests, amino acid panel, vital signs, electrocardiogram (ECG) monitoring, venous ammonia, and blood and urine metabolites. Adverse events (AEs) and concomitant medications were recorded on an ongoing basis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-Label Study of the Safety of HPN-100 for the Long-Term Treatment of Urea Cycle Disorders (Treat UCD)
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HPN-100 Patients who were treated with HPN-100	Drug: HPN-100; 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 (~17.4 mL) delivers equivalent of PBA that 40 tablets of NaPBA do.; Other Names: GT4P, Glyceryl tri-(4-phenylbutyrate)

Outcome Measures

Primary Outcome Measures

1. Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug) [1 year]

Secondary Outcome Measures

1. Number and Causes of Hyperammonemic Events [1 year]

   Number of hyperammonemic crises per patient

2. Blood Ammonia Levels [1 Year]

   Venous Ammonia levels over time

3. Patient Satisfaction With HPN-100 [Month 1 post dose]

   Drug preference will be noted at week 3

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female subjects who completed HPN-100-006:

*Additionally, approximately 20 UCD subjects ≥ 6 years of age may be enrolled who have not participated in HPN-100-006. These subjects may include those who did not qualify HPN-100-006 (e.g., subjects between the ages of 6-17 years, subjects with other UCD subtypes, or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.). For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. Clinical evidence of potential benefit from introduction of an ammonia-scavenging agent might include a recent history (in the past year) of clinically overt hyperammonemia accompanied by a venous ammonia ≥ 100 μmol/L, a recent history (within the past year) of protein intolerance, or a history of abnormally high venous ammonia levels accompanied by symptoms (e.g., headache) that might reasonably be attributed to hyperammonemia.

• Signed informed consent by subject and/or subject's legally acceptable representative.

• Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.

• Able to perform and comply with study activities, including blood draws.

• Negative pregnancy test for all females of childbearing potential.

• All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study.

Exclusion Criteria:

• Screening venous ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their venous ammonia is controlled, at the discretion of the investigator.

• History of 4 or more hyperammonemic events as defined in Section 3.5.1 in the preceding 12 months.

• Active infection (viral or bacterial) or any other condition that may increase venous ammonia levels.

• 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 venous ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study.

• History of QTc (QT interval corrected) prolongation, or a QTc interval ≥ 450 msec or an increase of ≥ 60 msec during the previous HPN-100 study if applicable.

• Known hypersensitivity to PAA or PBA.

• Liver transplant, including hepatocellular transplant.

• Breastfeeding or lactating females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Long Beach Memorial	Long Beach	California	United States	90806
2	UCLA	Los Angeles	California	United States	90095
3	Stanford University	Stanford	California	United States	94305
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Yale School of Medicine	New Haven	Connecticut	United States	06510
6	Children's National Medical Center	Washington	District of Columbia	United States	20010
7	University of Florida	Gainesville	Florida	United States	32611
8	Univeristy of Iowa	Iowa City	Iowa	United States	52242
9	Maine Medical Center	Portland	Maine	United States	04102
10	SNBL-Clinical Pharmacology Center	Baltimore	Maryland	United States	21201
11	Tufts-New England Medical Center	Boston	Massachusetts	United States	02111
12	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55454
13	Mount Sinai School of Medicine	New York	New York	United States	10029
14	Westchester Medical Center	Valhalla	New York	United States	10595
15	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
16	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
17	Oregon Health & Science University	Portland	Oregon	United States	97239
18	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15260
19	Baylor College of Medicine	Houston	Texas	United States	77030
20	University of Utah	Salt Lake City	Utah	United States	84112
21	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
22	The Hospital for Sick Children	Toronto	Ontario	Canada

Sponsors and Collaborators

• Horizon Pharma Ireland, Ltd., Dublin Ireland

Investigators

• Principal Investigator: Brendan Lee, MD, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
• ClinicalTrials.gov Identifier: NCT00947297
• Other Study ID Numbers: HPN-100-007
• First Posted: Jul 28, 2009
• Last Update Posted: Jan 16, 2017
• Last Verified: Jun 1, 2015

• Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland: Urea Cycle Disorder; UCD; hyperammonemia; Buphenyl; Sodium Phenylbutyrate
• Additional relevant MeSH terms: Urea Cycle Disorders, Inborn; Disease; 4-phenylbutyric acid

Study Results

Participant Flow

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100
Period Title: Overall Study
STARTED	60
COMPLETED	53
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100
Overall Participants	60
Age (Count of Participants)
<=18 years	9 15%
Between 18 and 65 years	51 85%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.83 (13.933)
Gender (Count of Participants)
Female	41 68.3%
Male	19 31.7%
Region of Enrollment (participants) [Number]
United States	54 90%
Canada	6 10%

Outcome Measures

1. Primary Outcome

Title	Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100
Measure Participants	60
Number [participants]	33 55%

2. Secondary Outcome

Title	Number and Causes of Hyperammonemic Events
Description	Number of hyperammonemic crises per patient
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100
Measure Participants	60
Mean (Standard Deviation) [hyperammonemic events]	0.20 (0.514)

3. Secondary Outcome

Title	Blood Ammonia Levels
Description	Venous Ammonia levels over time
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100 HPN-100: 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 (~17.4 mL) delivers equivalent of PBA that 40 tablets of NaPBA do.
Measure Participants	60
Baseline	27.623 (15.8875)
Month 12	24.202 (20.6124)

4. Secondary Outcome

Title	Patient Satisfaction With HPN-100
Description	Drug preference will be noted at week 3
Time Frame	Month 1 post dose

Outcome Measure Data

Analysis Population Description

all available questionnaires

Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100 HPN-100: 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 (~17.4 mL) delivers equivalent of PBA that 40 tablets of NaPBA do.
Measure Participants	50
Number [% preferred HPN-100]	90

Adverse Events

Time Frame	1 year
Arm/Group Title	HPN-100
Arm/Group Description	Patients who were treated with HPN-100
All Cause Mortality
	HPN-100
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	HPN-100
	Affected / at Risk (%)	# Events
Total	12/60 (20%)
Gastrointestinal disorders
Abdominal pain	1/60 (1.7%)
Infections and infestations
Gastroenteritis	1/60 (1.7%)
Lobar pneumonia	1/60 (1.7%)
Metabolism and nutrition disorders
Hyperammonaemia	9/60 (15%)
Nervous system disorders
Dizziness	1/60 (1.7%)
Neuropathy peripheral	1/60 (1.7%)
Psychiatric disorders
Psychotic disorder	1/60 (1.7%)
Reproductive system and breast disorders
Pelvic pain	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Lung infiltration	1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	HPN-100
	Affected / at Risk (%)	# Events
Total	59/60 (98.3%)
Gastrointestinal disorders
Abdominal discomfort	4/60 (6.7%)
Abdominal distension	3/60 (5%)
Diarrhoea	11/60 (18.3%)
Dyspepsia	4/60 (6.7%)
Nausea	13/60 (21.7%)
Vomiting	19/60 (31.7%)
General disorders
Abdominal pain	6/60 (10%)
Constipation	4/60 (6.7%)
Fatigue	7/60 (11.7%)
Pyrexia	4/60 (6.7%)
Infections and infestations
Bronchitis	4/60 (6.7%)
Gastroenteritis	4/60 (6.7%)
Gastroenteritis viral	6/60 (10%)
Nasopharyngitis	11/60 (18.3%)
Upper respiratory tract infection	19/60 (31.7%)
Investigations
Aspartate aminotransferase increased	3/60 (5%)
Vitamin D decreased	4/60 (6.7%)
Metabolism and nutrition disorders
Decreased appetite	8/60 (13.3%)
Hyperammonaemia	9/60 (15%)
Increased appetite	3/60 (5%)
Musculoskeletal and connective tissue disorders
Back pain	4/60 (6.7%)
Pain in extremity	4/60 (6.7%)
Nervous system disorders
Convulsion	3/60 (5%)
Dizziness	9/60 (15%)
Headache	10/60 (16.7%)
Tremor	3/60 (5%)
Reproductive system and breast disorders
Metrorrhagia	3/60 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	8/60 (13.3%)
Nasal congestion	4/60 (6.7%)
Oropharyngeal pain	7/60 (11.7%)
Rhinorrhoea	4/60 (6.7%)
Skin and subcutaneous tissue disorders
Acne	3/60 (5%)
Rash	6/60 (10%)
Skin odour abnormal	4/60 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.