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A Study of Safety and Efficacy of HPN-100 in Subjects With Cirrhosis and Episodic Hepatic Encephalopathy (HALT-HE)

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ClinicalTrials.gov Identifier: NCT00999167
Recruitment Status : Completed
First Posted : October 21, 2009
Results First Posted : September 30, 2015
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: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Cirrhosis
Hepatic Encephalopathy
Interventions Drug: HPN-100
Drug: Placebo
Enrollment 189
Recruitment Details Part A enrollment: 01 December 2009 to 24 February 2010 Part B enrollment: 01 June 2010 to 31 October 2011
Pre-assignment Details The study consisted of Part A, an open-label, dose-escalation lead-in to assess HPN-100 safety and PK, followed by Part B, a randomized, placebo controlled study to assess safety and efficacy of HPN-100.
Arm/Group Title HPN-100 6 mL and 9 mL HPN-100 6 mL Placebo
Hide Arm/Group Description Subjects will undergo a one step dose escalation over 4 weeks. Subjects will initially receive 6 mL HPN-100 BID for 1 week. On Day 7 and following a satisfactory safety assessment of the subject, the dose will be escalated to 9 mL BID for an additional 3 weeks. Subjects will receive 6 mL BID HPN-100 for 16 weeks (Part B) Subjects will receive 6 mL BID placebo for 16 weeks (Part B)
Period Title: Part A: Open Label Safety run-in
Started 15 0 0
Received 9 mL BID 15 0 0
Completed 8 0 0
Not Completed 7 0 0
Reason Not Completed
Met protocol defined stopping rule             4             0             0
Adverse Event             3             0             0
Period Title: Part B: Randomized, Placebo Controlled
Started 0 90 [1] 88
Completed 0 55 67
Not Completed 0 35 21
Reason Not Completed
Met protocol defined stopping rule             0             19             16
Withdrawal by Subject             0             7             4
Adverse Event             0             6             1
Noncompliance             0             1             0
Physician Decision             0             1             0
Physician stopped drug             0             1             0
[1]
4 subjects who participated in Part A enrolled in Part B and remainder were newly enrolled
Arm/Group Title HPN-100 Placebo Total
Hide Arm/Group Description 6 mL BID 6 mL BID Total of all reporting groups
Overall Number of Baseline Participants 90 88 178
Hide Baseline Analysis Population Description
Only the baseline characteristics of the subjects enrolled in Part B are presented.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 88 participants 178 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
85
  94.4%
78
  88.6%
163
  91.6%
>=65 years
5
   5.6%
10
  11.4%
15
   8.4%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 90 participants 88 participants 178 participants
53.8  (8.94) 55.4  (8.85) 54.6  (8.85)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 88 participants 178 participants
Female
45
  50.0%
29
  33.0%
74
  41.6%
Male
45
  50.0%
59
  67.0%
104
  58.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants 88 participants 178 participants
United States 44 44 88
Russian Federation 26 24 50
Ukraine 20 20 40
1.Primary Outcome
Title Part A: The Rate of AEs and Tolerability of HPN-100
Hide Description Part A: The rate of AEs and tolerability of 6 mL and 9 mL doses of HPN-100 were considered the primary safety endpoints for Part A. Safety assessments included adverse events, laboratory tests (including ammonia, hematology, coagulation, liver function and serum chemistry parameters), vital signs, physical and neurological examinations, and electrocardiograms.
Time Frame Part A: 28 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title HPN-100 BID
Hide Arm/Group Description:
6 mL or 9 mL BID HPN-100 (Part A)
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Subjects
Any AE 11
Gastrointestinal disorders 9
Metabolism and nutrition disorders 7
Infection and infestations 4
Nervous system disorders 4
Blood and lymphatic system disorders 2
Injury, poisoning and procedural complications 2
Musculoskeletal and connective tissue disorders 2
Psychiatric disorders 2
Any SAE 5
Death 2
2.Primary Outcome
Title Part B: Proportion of Subjects Who Exhibit an HE Episode, Defined as Either of the Following During the Treatment Phase: WH ≥2; WH Grade and Asterixis Grade Increase of 1 Each, if Baseline WH = 0
Hide Description

An HE event was defined as occurrences of either a West Haven (WH) Grade ≥2 or a WH Grade 1 and asterixis grade increase of 1 (if baseline WH = 0).

The WH criteria are widely used for rating the severity of HE and are summarized below:

Grade 1: trivial lack of awareness, euphoria or anxiety, shortened attention span, impaired performance of addition Grade 2: lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behavior, impaired performance of subtraction Grade 3: somnolence to semi-stupor but responsive to verbal stimuli, confusion, gross disorientation Grade 4: coma (unresponsive to verbal or noxious stimuli)

Asterixis was assessed after arm and forearm extension along with wrist dorsiflexion for 30 seconds and assigned a grade according to the following criteria:

Grade 1: rare flaps Grade 2: occasional irregular flaps Grade 3: frequent flaps Grade 4: continuous flaps

Time Frame Part B: 112 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT)
Arm/Group Title HPN-100 Placebo
Hide Arm/Group Description:
HPN-100 6 mL BID (Part B)
Placebo 6 mL BID (Part B)
Overall Number of Participants Analyzed 90 88
Measure Type: Number
Unit of Measure: participants
19 32
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPN-100, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0214
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
3.Secondary Outcome
Title Total Number of HE Events
Hide Description Secondary efficacy endpoint. The total number of HE events during the treatment phase for subjects in the placebo and active arms.
Time Frame 112 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat (ITT)
Arm/Group Title HPN-100 Placebo
Hide Arm/Group Description:
6 mL BID
6 mL BID
Overall Number of Participants Analyzed 90 88
Measure Type: Number
Unit of Measure: HE event
35 57
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPN-100, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0354
Comments [Not Specified]
Method Poisson regression adjusting for country
Comments [Not Specified]
4.Secondary Outcome
Title Time to Meeting the Primary Endpoint
Hide Description Secondary efficacy endpoint. The time to the first HE episode during the treatment period was calculated using the Kaplan-Meier method. Subjects who did not experience an HE episode were censored at the time of their last asterixis assessment. Subjects who had no post-randomization data for the primary endpoint were considered to have an HE episode at Day 1.
Time Frame 112 Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat (ITT)
Arm/Group Title HPN-100 Placebo
Hide Arm/Group Description:
HPN-100 6 mL BID (Part B)
Placebo 6 mL BID (Part B)
Overall Number of Participants Analyzed 90 88
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
Data are based on Kaplan-Meier point estimates. Because of low event rate (21.1%) it is not possible to estimate the median.
[2]
Data are based on Kaplan-Meier point estimates. Because of low event rate (36.4%) it is not possible to estimate the median
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPN-100, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.047
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.56
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score
Hide Description Changes from Baseline to Day 56 and the Final Visit were compared between treatment groups using an ANCOVA model for the total index RBANS score ). The index score is a sum of the scores for each of the 5 individual domains (immediate memory, visuospatial/constructional, language, attention). The minimum and maximum total index scores are 40 and 160, respectively; a higher score is better.
Time Frame Day 56, Final Visit (D112)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat (ITT)
Arm/Group Title HPN-100 Placebo
Hide Arm/Group Description:
HPN-100 6 mL BID (Part B)
Placebo 6 mL BID (Part B)
Overall Number of Participants Analyzed 90 88
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change from Baseline to D56 (Total Score) -0.5  (1.54) 3.2  (1.37)
Change from Baseline to Final Visit (Total Score) -10.7  (2.85) -9.7  (3.33)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPN-100, Placebo
Comments Changes in the Total Index Score from Baseline and Day 56.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0713
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection HPN-100, Placebo
Comments Changes in the Total Index Score from Baseline and the Final Visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2520
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Time Frame Part A: 28 days Part B: 112 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part A: HPN-100 Part B: HPN-100 Part B: Placebo
Hide Arm/Group Description 6 mL BID for 7 days followed by 9 mL BID for 21 days, equivalent to approximately 13.2 and 19.8 grams of HPN-100/day, respectively 6 mL BID, equivalent to approximately 13.2 grams of HPN-100/day Matching HPN-100 placebo, 6 mL BID
All-Cause Mortality
Part A: HPN-100 Part B: HPN-100 Part B: Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Part A: HPN-100 Part B: HPN-100 Part B: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/15 (33.33%)      20/90 (22.22%)      12/88 (13.64%)    
Blood and lymphatic system disorders       
Anaemia  0/15 (0.00%)  0 1/90 (1.11%)  1 1/88 (1.14%)  1
Cardiac disorders       
Bradycardia  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Postural orthostatic tachycardia syndrome  1/15 (6.67%)  1 0/90 (0.00%)  0 0/88 (0.00%)  0
Gastrointestinal disorders       
Gastrointestinal haemorrhage  1/15 (6.67%)  1 4/90 (4.44%)  4 0/88 (0.00%)  0
Ascites  0/15 (0.00%)  0 2/90 (2.22%)  2 0/88 (0.00%)  0
Abdominal Pain  0/15 (0.00%)  0 2/90 (2.22%)  2 0/88 (0.00%)  0
Oesophageal varices haemorrhage  1/15 (6.67%)  1 0/90 (0.00%)  0 1/88 (1.14%)  1
Hepatobiliary disorders       
Hepatic failure  1/15 (6.67%)  1 0/90 (0.00%)  0 2/88 (2.27%)  2
Cholelithiasis  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Hepatic cirrhosis  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Hepatorenal syndrome  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Liver disorder  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Infections and infestations       
Urinary tract infections  0/15 (0.00%)  0 2/90 (2.22%)  2 1/88 (1.14%)  1
Peritonitis bacterial  0/15 (0.00%)  0 1/90 (1.11%)  1 1/88 (1.14%)  1
Cellulitis  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Sepsis  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Urosepsis  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Injury, poisoning and procedural complications       
Humerus fracture  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Pelvic fracture  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Investigations       
Haemoglobin decreased  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Transaminases increased  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Metabolism and nutrition disorders       
Hyperglycaemia  0/15 (0.00%)  0 0/90 (0.00%)  0 2/88 (2.27%)  2
Hypoglycaemia  1/15 (6.67%)  1 2/90 (2.22%)  2 0/88 (0.00%)  0
Hyponatraemia  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Diabetes mellitus inadequate control  1/15 (6.67%)  1 0/90 (0.00%)  0 0/88 (0.00%)  0
Nervous system disorders       
Epilepsy  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Syncope  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Psychiatric disorders       
Acute psychosis  0/15 (0.00%)  0 1/90 (1.11%)  1 0/88 (0.00%)  0
Psychotic disorder  1/15 (6.67%)  1 0/90 (0.00%)  0 0/88 (0.00%)  0
Renal and urinary disorders       
Renal failure acute  0/15 (0.00%)  0 2/90 (2.22%)  2 0/88 (0.00%)  0
Renal failure  1/15 (6.67%)  1 0/90 (0.00%)  0 0/88 (0.00%)  0
Renal impairment  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  0/15 (0.00%)  0 2/90 (2.22%)  2 0/88 (0.00%)  0
Respiratory failure  0/15 (0.00%)  0 0/90 (0.00%)  0 1/88 (1.14%)  1
1
Term from vocabulary, MedDRA (12.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part A: HPN-100 Part B: HPN-100 Part B: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/15 (73.33%)      71/90 (78.89%)      67/88 (76.14%)    
Blood and lymphatic system disorders       
Thrombocytopenia  2/15 (13.33%)  2 0/90 (0.00%)  0 0/88 (0.00%)  0
Gastrointestinal disorders       
Nausea  2/15 (13.33%)  2 11/90 (12.22%)  11 13/88 (14.77%)  15
Diarrhoea  3/15 (20.00%)  3 8/90 (8.89%)  8 9/88 (10.23%)  9
abdominal pain  2/15 (13.33%)  2 5/90 (5.56%)  5 5/88 (5.68%)  5
Vomiting  0/15 (0.00%)  0 2/90 (2.22%)  2 8/88 (9.09%)  8
Constipation  0/15 (0.00%)  0 4/90 (4.44%)  4 5/88 (5.68%)  6
Ascites  0/15 (0.00%)  0 5/90 (5.56%)  6 0/88 (0.00%)  0
Fatigue  0/15 (0.00%)  0 6/90 (6.67%)  6 7/88 (7.95%)  8
General disorders       
Oedema peripheral  0/15 (0.00%)  0 13/90 (14.44%)  14 7/88 (7.95%)  7
Pyrexia  0/15 (0.00%)  0 5/90 (5.56%)  5 3/88 (3.41%)  3
Infections and infestations       
Urinary tract infection  2/15 (13.33%)  2 0/90 (0.00%)  0 0/88 (0.00%)  0
Investigations       
AST increased  0/15 (0.00%)  0 10/90 (11.11%)  11 5/88 (5.68%)  5
ALT increased  0/15 (0.00%)  0 8/90 (8.89%)  9 4/88 (4.55%)  4
White blood cell count (WBC) decreased  0/15 (0.00%)  0 5/90 (5.56%)  5 2/88 (2.27%)  2
Metabolism and nutrition disorders       
Hypokalaemia  3/15 (20.00%)  3 0/90 (0.00%)  0 0/88 (0.00%)  0
Hypoglycaemia  2/15 (13.33%)  2 0/90 (0.00%)  0 0/88 (0.00%)  0
Hyponatraemia  2/15 (13.33%)  2 0/90 (0.00%)  0 0/88 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  0/15 (0.00%)  0 5/90 (5.56%)  5 3/88 (3.41%)  3
Nervous system disorders       
Headache  2/15 (13.33%)  2 8/90 (8.89%)  10 5/88 (5.68%)  5
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  0/15 (0.00%)  0 5/90 (5.56%)  6 3/88 (3.41%)  3
1
Term from vocabulary, MedDRA (12.0)
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: Julia Egofske
Organization: Horizon Therapeutics, Inc.
Phone: 224-383-3078
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT00999167     History of Changes
Other Study ID Numbers: HPN-100-008
First Submitted: October 8, 2009
First Posted: October 21, 2009
Results First Submitted: July 1, 2015
Results First Posted: September 30, 2015
Last Update Posted: January 16, 2017