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

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ClinicalTrials.gov Identifier: NCT00551200
Recruitment Status : Completed
First Posted : October 30, 2007
Results First Posted : May 12, 2015
Last Update Posted : January 16, 2017
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Urea Cycle Disorders
Interventions Drug: HPN-100
Drug: BUPHENYL®
Enrollment 14
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Buphenyl to HPN-100
Hide Arm/Group Description HPN-100 : Subjects took prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects took prescribed dose of Buphenyl® TID for first week of study, and then switched over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 was increased and the dose of Buphenyl® was decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate was HPN-100. Target HPN-100 dose contained the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject took HPN-100 alone for one week and then switched back to previous dose of Buphenyl for the last week of the study.
Period Title: Overall Study
Started 14
Completed 10
Not Completed 4
Arm/Group Title Buphenyl to HPN-100
Hide Arm/Group Description HPN-100 : 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.
Overall Number of Baseline Participants 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
<=18 years
0
   0.0%
Between 18 and 65 years
13
  92.9%
>=65 years
1
   7.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 14 participants
35.7  (16.3)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Female
9
  64.3%
Male
5
  35.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 14 participants
14
1.Primary Outcome
Title Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title NaPBA Steady State HPN-100 Steady State
Hide Arm/Group Description:
Subjects were on NaPBA TID treatment for at least 2 weeks prior to enrollment, and were thus expected to be at steady-state levels prior to enrollment. After enrollment, subjects received 1 week of NaPBA treatment before switching over to HPN-100 dose escalation phase.
After dose escalation to full dose of HPN-100 was completed, subjects received only HPN-100 for 1 week (and achieved steady state) prior to switching back to their original NaPBA treatment.
Overall Number of Participants Analyzed 10 10
Overall Number of Units Analyzed
Type of Units Analyzed: Concentration of ammonia
10 10
Mean (Standard Deviation)
Unit of Measure: μmol/L
in peak 79.1  (40.1) 56.3  (27.9)
in TNAUC (time-normalized area under the curve) 38.4  (19.6) 26.5  (10.7)
2.Primary Outcome
Title Number of Subjects Experienced Adverse Events
Hide Description [Not Specified]
Time Frame during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Buphenyl HPN-100
Hide Arm/Group Description:
Subjects took prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects took prescribed dose of Buphenyl® TID for first week of study before blood sample collection.
HPN-100 dose contained the same amount of phenylbutyrates as the subject's prescribed daily dose of Buphenyl®. Subject took HPN-100 alone for one week to reach steady state before blood sample collection.
Overall Number of Participants Analyzed 14 10
Measure Type: Number
Unit of Measure: participants
7 5
3.Primary Outcome
Title Number of Subjects Experienced Serious Adverse Events
Hide Description [Not Specified]
Time Frame during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Buphenyl HPN-100
Hide Arm/Group Description:
Subjects took prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects took prescribed dose of Buphenyl® TID for first week of study before blood sample collection.
HPN-100 dose contained the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject took HPN-100 alone for one week to reach steady state before blood sample collection.
Overall Number of Participants Analyzed 14 10
Measure Type: Number
Unit of Measure: participants
1 0
4.Secondary Outcome
Title Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title NaPBA Steady State HPN-100 Steady State
Hide Arm/Group Description:
Subjects were on NaPBA TID treatment for at least 2 weeks prior to enrollment, and were thus expected to be at steady-state levels prior to enrollment. After enrollment, subjects received 1 week of NaPBA treatment before switching over to HPN-100 dose escalation phase.
After dose escalation to full dose of HPN-100 was completed, subjects received only HPN-100 for 1 week (and achieved steady state) prior to switching back to their original NaPBA treatment.
Overall Number of Participants Analyzed 10 10
Overall Number of Units Analyzed
Type of Units Analyzed: Plasma
86 82
Mean (Standard Deviation)
Unit of Measure: μg*h/mL
AUC0-24 PBA (phenylbutyrate) in plasma 740  (363) 540  (325)
AUC0-24 PAA (phenylacetate) in plasma 596  (738) 575  (970)
AUC0-24 PAGN (phenylacetylglutamine) in plasma 1133  (352) 1098  (485)
5.Secondary Outcome
Title Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)
Hide Description [Not Specified]
Time Frame End of Study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Buphenyl to HPN-100
Hide Arm/Group Description:
HPN-100 : 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.
Overall Number of Participants Analyzed 10
Measure Type: Number
Unit of Measure: participants
prefer Buphenyl 1
prefer HPN-100 9
Time Frame [Not Specified]
Adverse Event Reporting Description The occurrence of adverse events was assessed by investigator assessment, clinical laboratory measurements, ECG, vitals signs measurements and symptom survey.
 
Arm/Group Title Buphenyl HPN-100
Hide Arm/Group Description HPN-100 : 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. HPN-100 : 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.
All-Cause Mortality
Buphenyl HPN-100
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Buphenyl HPN-100
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/14 (7.14%)      0/10 (0.00%)    
Metabolism and nutrition disorders     
Hyperammonaemia  1  1/14 (7.14%)  1 0/10 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Buphenyl HPN-100
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/14 (50.00%)      5/10 (50.00%)    
Gastrointestinal disorders     
Nausea  1  2/14 (14.29%)  0/10 (0.00%) 
Dyspepsia  1  1/14 (7.14%)  0/10 (0.00%) 
Abdominal Pain  1  2/14 (14.29%)  0/10 (0.00%) 
Gastrooesophageal Reflux Disease  1  1/14 (7.14%)  0/10 (0.00%) 
Metabolism and nutrition disorders     
Increased Appetite  1  1/14 (7.14%)  3/10 (30.00%) 
Hyperammonaemia  1  1/14 (7.14%)  0/10 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pharyngolaryngeal Pain  1  0/14 (0.00%)  2/10 (20.00%) 
Skin and subcutaneous tissue disorders     
Skin Odour Abnormal  1  1/14 (7.14%)  0/10 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
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: Sr. Vice President and Chief Medical Officer, Bruce F. Scharschmidt
Organization: Hyperion Therapeutics
Phone: (650) 745-7851
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT00551200     History of Changes
Other Study ID Numbers: UP1204-003 (HPN-100-003)
First Submitted: October 26, 2007
First Posted: October 30, 2007
Results First Submitted: August 28, 2013
Results First Posted: May 12, 2015
Last Update Posted: January 16, 2017