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

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

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).

Study Overview

• Status: Completed
• Conditions: Hepatic Encephalopathy; Cirrhosis
• Intervention / Treatment: Drug: HPN-100; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Part B: same as experimental arm
Experimental: HPN-100	Drug: HPN-100; Part B: 6 mL BID for 16 weeks.; Other Names: GT4P

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 A: 28 days
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	Part B: 112 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	112 Days
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.	112 Days
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.	Day 56, Final Visit (D112)

Collaborators and Investigators

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: October 8, 2009
• First Submitted That Met QC Criteria: October 20, 2009
• First Posted (Estimate): October 21, 2009

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Cirrhosis; HE; glycerol phenylbutyrate; GT4P; HPN-100; Episodic Hepatic Encephalopathy
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Brain Diseases, Metabolic; Fibrosis; Liver Cirrhosis; Hepatic Encephalopathy; Brain Diseases
• Other Study ID Numbers: HPN-100-008