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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Cirrhosis, Hepatic Encephalopathy

Intervention / Treatment
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* Drug: HPN-100
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate