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

This study has been completed.
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier:
First received: October 8, 2009
Last updated: August 27, 2015
Last verified: August 2015
This is a phase 2 study of HPN-100 in subjects with hepatic encephalopathy (HE) consisting of an open label safety lead-in (Part A), followed by randomized, double-blind, placebo-controlled treatment (Part B).

Condition Intervention Phase
Hepatic Encephalopathy
Drug: HPN-100
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of HPN-100 for Maintaining Remission in Subjects With Cirrhosis and Episodic Hepatic Encephalopathy

Resource links provided by NLM:

Further study details as provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:

Primary Outcome Measures:
  • Part A: The Rate of AEs and Tolerability of HPN-100 [ Time Frame: Part A: 28 days ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Part B: 112 Days ] [ Designated as safety issue: Yes ]

    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

Secondary Outcome Measures:
  • Total Number of HE Events [ Time Frame: 112 Days ] [ Designated as safety issue: No ]
    Secondary efficacy endpoint. The total number of HE events during the treatment phase for subjects in the placebo and active arms.

  • Time to Meeting the Primary Endpoint [ Time Frame: 112 Days ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score [ Time Frame: Day 56, Final Visit (D112) ] [ Designated as safety issue: No ]
    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.

Enrollment: 189
Study Start Date: December 2009
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: HPN-100 Drug: HPN-100
Part B: 6 mL BID for 16 weeks.
Other Name: GT4P
Placebo Comparator: Placebo Drug: Placebo
Part B: same as experimental arm

Detailed Description:

Part A: Open-label, dose-escalation lead-in to assess HPN-100 safety and PK Approximately 10 subjects with HE and cirrhosis classified as Child Pugh B or C 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 satisfactory safety assessment of the subject, the dose will be escalated to 9 mL BID for an additional 3 weeks.

In addition to a safety assessment, subjects will undergo 12-hour PK assessments on Days 7 and 28, with sampling at the following time points (relative to the first dose): 0 (pre-first daily dose of HPN-100), 2, 4, 8 (approximately 2 hours before the second daily dose of HPN 100), and 12 hours post-first dose (approximately 2 hours after the second daily dose of HPN-100). Additional PK samples will be collected on Days 8, 15, and 21 (at pre-first dose and 4 hours post-first dose).

The DSMB will review all safety information, including laboratory values, to determine if Part B may be initiated.

Subjects enrolled in Part A may be eligible for Part B as long as they meet the eligibility criteria.

Part B: Randomized, double-blind assessment of HPN-100 in HE subjects Subjects who meet all entry criteria and are judged to be compliant with their prescribed SOC will be eligible for randomization to receive either HPN-100 or matching placebo for 16 weeks. Efficacy will be assessed by the proportion of subjects experiencing episodes of HE, as well as by other outcome measures, including daily home assessments.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subjects aged 18 and over
  • Clinical diagnosis of cirrhosis of any cause
  • Potential to benefit from HE treatment
  • History of greater than or equal to 2 documented episodes of WH Grade 2 or more HE within the past 6 months, at least one of which occurred within the preceding 3 months
  • No change in other HE-specific medications within 1 week before randomization
  • Able to give informed consent and comply with study activities
  • Availability of at least one designated family member or caregiver who is capable of and willing to assume responsibility for facilitating subject compliance with study procedures
  • All females of childbearing age and all sexually active males must agree to use an acceptable method of contraception throughout the study.

Exclusion Criteria:

  • Use of any investigational drug within 30 days
  • Use of prohibited medications
  • Uncontrolled infection
  • Active GI bleeding or a history of GI bleeding requiring blood transfusion (> 2 units) within 3 months
  • Transjugular intrahepatic portosystemic shunt (TIPS) placement or revision within the past 90 days
  • Recreational drug use or alcohol consumption for subjects with a history of alcohol or drug abuse within 6 months
  • Lactating and/or pregnant females
  • Active malignancy
  • Clinically significant bowel disease, including obstruction, inflammatory bowel disease, or malabsorption
  • Expected to undergo transplantation within 6 months
  • Model for end-stage liver disease (MELD) score of > 25
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00999167

  Hide Study Locations
United States, California
Stanford University Medical Center, Division of Gastroenterology and Hepatology
Palo Alto, California, United States, 94304
United States, District of Columbia
Georgetown University Hospital
Washington, District of Columbia, United States, 20007
United States, Florida
University of Miami / Center for Liver Diseases
Miami, Florida, United States, 33136
Tampa General Hospital
Tampa, Florida, United States, 33606
United States, Illinois
The University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Louisiana
Tulane University Health Science Center
New Orleans, Louisiana, United States, 70112
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, Michigan
Henry Ford Hospital / Department of Gastroenterology
Detroit, Michigan, United States, 48202
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New York
Concorde Medical Group PLLC
New York, New York, United States, 10016
Mount Sinai Medical Center
New York, New York, United States, 10029
NYU Medical Center
New York, New York, United States, 10016
Columbia University Medical Center / Center for Liver Disease and Transplantation
New York, New York, United States, 10032
University of Rochester Medical Center
Rochester, New York, United States, 14642
New York Medical College / Westchester Medical Center
Valhalla, New York, United States, 10595
United States, Ohio
University of Cincinnati / Division of Digestive Diseases
Cincinnati, Ohio, United States, 45267
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
The Digestive Disease Center at Vanderbilt
Nashville, Tennessee, United States, 37232
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390
Methodist Dallas Medical Center
Dallas, Texas, United States, 75203
Baylor College of Medicine-St. Luke's Episcopal Hospital
Houston, Texas, United States, 77030
United States, Virginia
University of Virginia Health System
Charlottesville, Virginia, United States, 22908
United States, Wisconsin
University of Wisconsin Hospital & Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Horizon Pharma Ireland, Ltd., Dublin Ireland
  More Information

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT00999167     History of Changes
Other Study ID Numbers: HPN-100-008
Study First Received: October 8, 2009
Results First Received: July 1, 2015
Last Updated: August 27, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland:
Episodic Hepatic Encephalopathy
glycerol phenylbutyrate

Additional relevant MeSH terms:
Brain Diseases
Hepatic Encephalopathy
Liver Cirrhosis
Brain Diseases, Metabolic
Central Nervous System Diseases
Digestive System Diseases
Hepatic Insufficiency
Liver Diseases
Liver Failure
Metabolic Diseases
Nervous System Diseases

ClinicalTrials.gov processed this record on November 27, 2015