Clinical trial NCT00999167: A Study of Safety and Efficacy of HPN-100 in Subjects With Cirrhosis and Episodic Hepatic Encephalopathy
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cirrhosis
Hepatic Encephalopathy
Keywords: Cirrhosis
Episodic Hepatic Encephalopathy
HE
HPN-100
GT4P
glycerol phenylbutyrate
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2009-10-21
Enrollment: 189
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Study acquired from Horizon in 2024.

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

Primary outcomes:
measure: Part A: The Rate of AEs and Tolerability of HPN-100
timeFrame: Part A: 28 days
measure: 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
timeFrame: Part B: 112 Days
Secondary outcomes:
measure: Total Number of HE Events
timeFrame: 112 Days
measure: Time to Meeting the Primary Endpoint
timeFrame: 112 Days
measure: Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score
timeFrame: Day 56, Final Visit (D112)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center, Division of Gastroenterology and Hepatology
state: California
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: University of Miami / Center for Liver Diseases
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane University Health Science Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Hospital / Department of Gastroenterology
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: New York
country: United States
facility: Concorde Medical Group PLLC
state: New York
city: New York
country: United States
facility: NYU Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center / Center for Liver Disease and Transplantation
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College / Westchester Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati / Division of Digestive Diseases
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: The Digestive Disease Center at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine-St. Luke's Episcopal Hospital
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital & Clinics
state: Wisconsin
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
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.
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.