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

Cirrhosis Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00999167
• Other study ID #: HPN-100-008
• Status: Completed
• Phase: Phase 2
• First received: October 8, 2009
• Last updated: January 13, 2017
• Start date: December 2009
• Est. completion date: April 2012

Study information

• Verified date: August 2015
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 189
• Est. completion date: April 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Cirrhosis
• Fibrosis
• Hepatic Encephalopathy
• Liver Cirrhosis

Intervention

Drug:
• HPN-100
Part B: 6 mL BID for 16 weeks.
• Placebo
Part B: same as experimental arm

Locations

Country	Name	City	State
United States	University of Maryland	Baltimore	Maryland
United States	University of Virginia Health System	Charlottesville	Virginia
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati / Division of Digestive Diseases	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Methodist Dallas Medical Center	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Hospital / Department of Gastroenterology	Detroit	Michigan
United States	Baylor College of Medicine-St. Luke's Episcopal Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Wisconsin Hospital & Clinics	Madison	Wisconsin
United States	University of Miami / Center for Liver Diseases	Miami	Florida
United States	The Digestive Disease Center at Vanderbilt	Nashville	Tennessee
United States	Tulane University Health Science Center	New Orleans	Louisiana
United States	Columbia University Medical Center / Center for Liver Disease and Transplantation	New York	New York
United States	Concorde Medical Group PLLC	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	NYU Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Stanford University Medical Center, Division of Gastroenterology and Hepatology	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York
United States	Tampa General Hospital	Tampa	Florida
United States	New York Medical College / Westchester Medical Center	Valhalla	New York
United States	Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Pharma Ireland, Ltd., Dublin Ireland

Country where clinical trial is conducted

United States, 

References & Publications (1)

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, Norri — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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)