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

Primary Purpose

Cirrhosis, Hepatic Encephalopathy

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
HPN-100
Placebo
Sponsored by
Horizon Pharma Ireland, Ltd., Dublin Ireland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cirrhosis focused on measuring Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford University Medical Center, Division of Gastroenterology and Hepatology
  • Georgetown University Hospital
  • University of Miami / Center for Liver Diseases
  • Tampa General Hospital
  • The University of Chicago Medical Center
  • Indiana University
  • University of Iowa Hospitals and Clinics
  • University of Kansas Medical Center
  • Tulane University Health Science Center
  • University of Maryland
  • Henry Ford Hospital / Department of Gastroenterology
  • University of Nebraska Medical Center
  • Dartmouth Hitchcock Medical Center
  • Concorde Medical Group PLLC
  • NYU Medical Center
  • Mount Sinai Medical Center
  • Columbia University Medical Center / Center for Liver Disease and Transplantation
  • University of Rochester Medical Center
  • New York Medical College / Westchester Medical Center
  • University of Cincinnati / Division of Digestive Diseases
  • Cleveland Clinic
  • University of Pennsylvania
  • The Digestive Disease Center at Vanderbilt
  • Methodist Dallas Medical Center
  • UT Southwestern Medical Center
  • Baylor College of Medicine-St. Luke's Episcopal Hospital
  • University of Virginia Health System
  • University of Wisconsin Hospital & Clinics

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

HPN-100

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Part A: The Rate of AEs and Tolerability of HPN-100
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
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
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
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
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.

Full Information

First Posted
October 8, 2009
Last Updated
January 13, 2017
Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland
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1. Study Identification

Unique Protocol Identification Number
NCT00999167
Brief Title
A Study of Safety and Efficacy of HPN-100 in Subjects With Cirrhosis and Episodic Hepatic Encephalopathy
Acronym
HALT-HE
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
December 2009 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
April 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Hepatic Encephalopathy
Keywords
Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
189 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HPN-100
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
HPN-100
Other Intervention Name(s)
GT4P
Intervention Description
Part B: 6 mL BID for 16 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Part B: same as experimental arm
Primary Outcome Measure Information:
Title
Part A: The Rate of AEs and Tolerability of HPN-100
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
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
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
Secondary Outcome Measure Information:
Title
Total Number of HE Events
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
Title
Time to Meeting the Primary Endpoint
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
Title
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Stanford University Medical Center, Division of Gastroenterology and Hepatology
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
University of Miami / Center for Liver Diseases
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Tampa General Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Iowa Hospitals and Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Tulane University Health Science Center
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
University of Maryland
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Henry Ford Hospital / Department of Gastroenterology
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Dartmouth Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Concorde Medical Group PLLC
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
NYU Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Columbia University Medical Center / Center for Liver Disease and Transplantation
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
New York Medical College / Westchester Medical Center
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
University of Cincinnati / Division of Digestive Diseases
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
The Digestive Disease Center at Vanderbilt
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Methodist Dallas Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75203
Country
United States
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Baylor College of Medicine-St. Luke's Episcopal Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Virginia Health System
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
University of Wisconsin Hospital & Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23847109
Citation
Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Alexeeva O, Zupanets IA, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klaryts'ka I, Morozov V, Grewal P, McCashland T, Reddy KG, Reddy KR, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt BF; HALT-HE Study Group. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology. 2014 Mar;59(3):1073-83. doi: 10.1002/hep.26611.
Results Reference
result
PubMed Identifier
24144944
Citation
Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.
Results Reference
derived

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

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