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

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ClinicalTrials.gov Identifier: NCT00992459
Recruitment Status : Completed
First Posted : October 9, 2009
Results First Posted : August 12, 2013
Last Update Posted : January 16, 2017
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Urea Cycle Disorders
Interventions Drug: HPN-100
Drug: Buphenyl (NaPBA)
Enrollment 46
Recruitment Details Forty six subjects were screened and randomized at the participating sites between October 2009 to August 2010.
Pre-assignment Details There were no screen failures.
Arm/Group Title Arm A Arm B
Hide Arm/Group Description Subjects in Arm A were assigned to receive NaPBA + HPN 100 placebo for 2 weeks All patients in Arm A received HPN100 placebo (+ concomitant active NaPBA) Subjects in Arm B were assigned to receive HPN-100 + NaPBA placebo for 2 weeks All patients in Arm B received NaPBA placebo (+ concomitant active HPN 100)
Period Title: Overall Study
Started 22 [1] 24 [2]
Completed 21 [3] 23 [4]
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             0             1
Adverse Event             1             0
[1]
All patients received HPN 100 placebo in Arm A (+ concomitant active NaPBA)
[2]
All patients received NaPBA placebo in Arm B (+ concomitant active HPN 100)
[3]
Totals enrolled and completed in Arm A NaPBA treatment + HPN 100 Placebo are not mutually exclusive.
[4]
Totals enrolled and completed in Arm B HPN 100 treatment + NaPBA Placebo are not mutually exclusive.
Arm/Group Title Treatment Arm A Treatment Arm B Total
Hide Arm/Group Description Patients randomized to receive NaPBA + HPN 100 placebo for 2 weeks (Treatment Period 1) followed by HPN-100 + NaPBA placebo for 2 weeks (Treatment Period 2) Patients randomized to receive HPN-100 + NaPBA placebo for 2 weeks (Treatment Period 1) followed by NaPBA + HPN-100 placebo for 2 weeks (Treatment Period 2) Total of all reporting groups
Overall Number of Baseline Participants 22 24 46
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 24 participants 46 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
22
 100.0%
24
 100.0%
46
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 24 participants 46 participants
Female
15
  68.2%
17
  70.8%
32
  69.6%
Male
7
  31.8%
7
  29.2%
14
  30.4%
1.Primary Outcome
Title The Primary Endpoint Was the 24-hour Area Under the Curve for Blood Ammonia (NH324-hour AUC) on Days 14 and 28.
Hide Description 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.
Time Frame pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: μmol∙h/L
976.6  (865.9) 865.35  (660.53)
2.Secondary Outcome
Title 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)
Hide Description 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.
Time Frame 28 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Measure Type: Number
Unit of Measure: correlation coefficient
0.437 0.219
3.Secondary Outcome
Title Maximum Ammonia Values Observed on NaPBA Versus HPN-100
Hide Description Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.
Time Frame pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: µmol/L
70.83  (66.705) 60.94  (46.213)
4.Secondary Outcome
Title Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA Versus HPN-100
Hide Description NaPBA treated arm: total 345 blood samples were collected. HPN-100 treated arm: 343 blood samples were collected.
Time Frame on Day 14 and Day 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Overall Number of Units Analyzed
Type of Units Analyzed: Blood samples
345 343
Measure Type: Number
Unit of Measure: samples
125 122
5.Secondary Outcome
Title Number and Severity of Symptomatic Hyperammonemic Crises
Hide Description Severity of symptomatic hyperammonemic crises was measured by peak ammonia level (µmol/L) when it is >= 100 µmol/L.
Time Frame 29 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: (N=45 for NaPBA; N = 44 for HPN): Patients receiving any amount of NaPBA or HPN-100 comprise the Safety population. Safety population was to be used for safety analysis performed.
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 45 44
Measure Type: Number
Unit of Measure: events
1 0
6.Secondary Outcome
Title Rate of Adverse Events in Each Treatment Group
Hide Description [Not Specified]
Time Frame 29 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population: (N=45 for NaPBA; N = 44 for HPN): Patients receiving any amount of NaPBA or HPN-100 comprise the Safety population. Safety population was to be used for safety analysis performed.
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 45 44
Measure Type: Number
Unit of Measure: participants
23 27
7.Secondary Outcome
Title Cmax for PAA of NaPBA and HPN-100 in Plasma
Hide Description Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.
Time Frame pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: μg/mL
52.2  (41.86) 38.5  (39.5)
8.Secondary Outcome
Title Cmax for PBA of NaPBA and HPN-100 in Plasma
Hide Description Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.
Time Frame pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: μg/mL
80.9  (52.5) 51.9  (34.87)
9.Secondary Outcome
Title Cmax PAGN of NaPBA and HPN-100 in Plasma
Hide Description Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.
Time Frame pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: μg/mL
78.6  (43.86) 86.8  (44.7)
10.Secondary Outcome
Title U-PAGN24-hour Excr of NaPBA and HPN-100
Hide Description [Not Specified]
Time Frame 24 hours on Day 14 of each treatments
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) (N = 45): Patients receiving any amount of NaPBA or HPN-100 comprise the ITT population. ITT population was to be used for the primary analysis of this secondary endpoint. One subject who withdrew from study after receiving one dose of NaPBA yielding N=44
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description:
Patients treated with NaPBA
Patients treated with HPN-100
Overall Number of Participants Analyzed 44 44
Mean (Standard Deviation)
Unit of Measure: μg
13627515  (7086307.8) 13502745  (7088941.1)
Time Frame 29 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title NaPBA HPN-100
Hide Arm/Group Description Patients received NaPBA Patients received HPN-100
All-Cause Mortality
NaPBA HPN-100
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
NaPBA HPN-100
Affected / at Risk (%) Affected / at Risk (%)
Total   1/45 (2.22%)   1/44 (2.27%) 
Infections and infestations     
Gastroenteritis  1  0/45 (0.00%)  1/44 (2.27%) 
Metabolism and nutrition disorders     
Hyperammonaemia  1  1/45 (2.22%)  0/44 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE v3.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4.4%
NaPBA HPN-100
Affected / at Risk (%) Affected / at Risk (%)
Total   23/45 (51.11%)   27/44 (61.36%) 
Gastrointestinal disorders     
Abdominal discomfort * 1  3/45 (6.67%)  0/44 (0.00%) 
abdominal pain  1  2/45 (4.44%)  3/44 (6.82%) 
diarrhea  1  3/45 (6.67%)  7/44 (15.91%) 
flatulence  1  1/45 (2.22%)  6/44 (13.64%) 
nausea  1  3/45 (6.67%)  1/44 (2.27%) 
vomiting  1  2/45 (4.44%)  3/44 (6.82%) 
General disorders     
Oral discomfort  1  2/45 (4.44%)  0/44 (0.00%) 
dyspepsia  1  3/45 (6.67%)  2/44 (4.55%) 
fatigue  1  1/45 (2.22%)  3/44 (6.82%) 
food aversion  1  2/45 (4.44%)  1/44 (2.27%) 
Investigations     
ammonia increased  1  1/45 (2.22%)  2/44 (4.55%) 
Metabolism and nutrition disorders     
decreased appetite  1  2/45 (4.44%)  3/44 (6.82%) 
increased appetite  1  2/45 (4.44%)  0/44 (0.00%) 
Nervous system disorders     
headache  1  4/45 (8.89%)  6/44 (13.64%) 
dizziness  1  4/45 (8.89%)  0/44 (0.00%) 
Skin and subcutaneous tissue disorders     
dermatitis contact  1  0/45 (0.00%)  2/44 (4.55%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE v3.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Bruce Scharschmidt, MD, SVP, Chief MedicaL & Development Officer
Organization: Hyperion Therapeutics
Phone: 650-745-7851
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT00992459     History of Changes
Other Study ID Numbers: HPN-100-006
First Submitted: October 8, 2009
First Posted: October 9, 2009
Results First Submitted: April 4, 2013
Results First Posted: August 12, 2013
Last Update Posted: January 16, 2017