Cirrhosis, Hepatic Encephalopathy
Conditions
Keywords
Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate
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.
Interventions
DRUGHPN-100
Part B: 6 mL BID for 16 weeks.
DRUGPlacebo
Part B: same as experimental arm
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: The Rate of AEs and Tolerability of HPN-100 | Part A: 28 days | 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 | Part B: 112 Days | 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
| Measure | Time frame | Description |
|---|---|---|
| Total Number of HE Events | 112 Days | 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 | 112 Days | 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 | Day 56, Final Visit (D112) | 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. |
Countries
United States
Participant flow
Recruitment details
Part A enrollment: 01 December 2009 to 24 February 2010 Part B enrollment: 01 June 2010 to 31 October 2011
Pre-assignment details
The study consisted of Part A, an open-label, dose-escalation lead-in to assess HPN-100 safety and PK, followed by Part B, a randomized, placebo controlled study to assess safety and efficacy of HPN-100.
Participants by arm
| Arm | Count |
|---|---|
| HPN-100 6 mL BID | 90 |
| Placebo 6 mL BID | 88 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A: Open Label Safety run-in | Adverse Event | 3 | 0 | 0 |
| Part A: Open Label Safety run-in | Met protocol defined stopping rule | 4 | 0 | 0 |
| Part B: Randomized, Placebo Controlled | Adverse Event | 0 | 6 | 1 |
| Part B: Randomized, Placebo Controlled | Met protocol defined stopping rule | 0 | 19 | 16 |
| Part B: Randomized, Placebo Controlled | Noncompliance | 0 | 1 | 0 |
| Part B: Randomized, Placebo Controlled | Physician Decision | 0 | 1 | 0 |
| Part B: Randomized, Placebo Controlled | Physician stopped drug | 0 | 1 | 0 |
| Part B: Randomized, Placebo Controlled | Withdrawal by Subject | 0 | 7 | 4 |
Baseline characteristics
| Characteristic | HPN-100 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 10 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 78 Participants | 163 Participants |
| Age, Continuous | 53.8 years STANDARD_DEVIATION 8.94 | 55.4 years STANDARD_DEVIATION 8.85 | 54.6 years STANDARD_DEVIATION 8.85 |
| Region of Enrollment Russian Federation | 26 participants | 24 participants | 50 participants |
| Region of Enrollment Ukraine | 20 participants | 20 participants | 40 participants |
| Region of Enrollment United States | 44 participants | 44 participants | 88 participants |
| Sex: Female, Male Female | 45 Participants | 29 Participants | 74 Participants |
| Sex: Female, Male Male | 45 Participants | 59 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 15 | 71 / 90 | 67 / 88 |
| serious Total, serious adverse events | 5 / 15 | 20 / 90 | 12 / 88 |
Outcome results
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.
Time frame: Part A: 28 days
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Death | 2 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Any AE | 11 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Gastrointestinal disorders | 9 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Metabolism and nutrition disorders | 7 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Infection and infestations | 4 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Nervous system disorders | 4 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Blood and lymphatic system disorders | 2 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Injury, poisoning and procedural complications | 2 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Musculoskeletal and connective tissue disorders | 2 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Psychiatric disorders | 2 Subjects |
| HPN-100 BID | Part A: The Rate of AEs and Tolerability of HPN-100 | Any SAE | 5 Subjects |
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
Time frame: Part B: 112 Days
Population: Intent to Treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HPN-100 BID | 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 | 19 participants |
| Placebo | 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 | 32 participants |
p-value: 0.0214Cochran-Mantel-Haenszel
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.
Time frame: Day 56, Final Visit (D112)
Population: Intent to treat (ITT)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| HPN-100 BID | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | Change from Baseline to D56 (Total Score) | -0.5 units on a scale | Standard Error 1.54 |
| HPN-100 BID | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | Change from Baseline to Final Visit (Total Score) | -10.7 units on a scale | Standard Error 2.85 |
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | Change from Baseline to D56 (Total Score) | 3.2 units on a scale | Standard Error 1.37 |
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score | Change from Baseline to Final Visit (Total Score) | -9.7 units on a scale | Standard Error 3.33 |
Comparison: Changes in the Total Index Score from Baseline and Day 56.p-value: 0.0713ANCOVA
Comparison: Changes in the Total Index Score from Baseline and the Final Visit.p-value: 0.252ANCOVA
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.
Time frame: 112 Days
Population: Intent to treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HPN-100 BID | Time to Meeting the Primary Endpoint | NA Days |
| Placebo | Time to Meeting the Primary Endpoint | NA Days |
p-value: 0.047Regression, Cox
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.
Time frame: 112 Days
Population: Intent to treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HPN-100 BID | Total Number of HE Events | 35 HE event |
| Placebo | Total Number of HE Events | 57 HE event |
p-value: 0.0354Poisson regression adjusting for country