CirrhosisPhase 2HALT-HENCT00999167
A Study of Safety and Efficacy of HPN-100 in Subjects With Cirrhosis and Episodic Hepatic Encephalopathy
A Phase 2 study testing HPN-100 in people with Cirrhosis and Hepatic Encephalopathy, run by Amgen at 28 sites in United States.
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cirrhosis, Hepatic Encephalopathy
- What is being tested?
- HPN-100
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 189 participants
- Where
- 28 sitesUnited States
- Study dates
- Dec 2009to Apr 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
28 sites in 1 country.
28 sites in 1 country
United States28 sites
University of Maryland
Baltimore, Maryland, 21201
University of Virginia Health System
Charlottesville, Virginia, 22908
The University of Chicago Medical Center
Chicago, Illinois, 60637
University of Cincinnati / Division of Digestive Diseases
Cincinnati, Ohio, 45267
Cleveland Clinic
Cleveland, Ohio, 44195
Methodist Dallas Medical Center
Dallas, Texas, 75203
UT Southwestern Medical Center
Dallas, Texas, 75390
Henry Ford Hospital / Department of Gastroenterology
Detroit, Michigan, 48202
Baylor College of Medicine-St. Luke's Episcopal Hospital
Houston, Texas, 77030
Indiana University
Indianapolis, Indiana, 46202
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
University of Kansas Medical Center
Kansas City, Kansas, 66160
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
University of Wisconsin Hospital & Clinics
Madison, Wisconsin, 53792
University of Miami / Center for Liver Diseases
Miami, Florida, 33136
The Digestive Disease Center at Vanderbilt
Nashville, Tennessee, 37232
Tulane University Health Science Center
New Orleans, Louisiana, 70112
Concorde Medical Group PLLC
New York, New York, 10016
NYU Medical Center
New York, New York, 10016
Mount Sinai Medical Center
New York, New York, 10029
Columbia University Medical Center / Center for Liver Disease and Transplantation
New York, New York, 10032
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Stanford University Medical Center, Division of Gastroenterology and Hepatology
Palo Alto, California, 94304
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Rochester Medical Center
Rochester, New York, 14642
Tampa General Hospital
Tampa, Florida, 33606
New York Medical College / Westchester Medical Center
Valhalla, New York, 10595
Georgetown University Hospital
Washington D.C., District of Columbia, 20007
About this study
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
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).
Read the 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.
- Conditions
- Cirrhosis, Hepatic Encephalopathy
- Being tested
- HPN-100, Placebo
- Keywords
- Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate
- Medical subject headings
- Fibrosis, Hepatic Encephalopathy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HPN-100Drug
Also called GT4P
Part B: 6 mL BID for 16 weeks.
PlaceboDrug
Part B: same as experimental arm
| Study group | Role | What they receive |
|---|---|---|
| HPN-100 | Experimental | Not described Receives: Drug: HPN-100 |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: Part B: 112 Days
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: Day 56, Final Visit (D112)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2009 (estimated)
- Study startDec 2009
- Primary completionApr 2012
- Study completionApr 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for CirrhosisStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 189 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00999167
- Sponsor's protocol ID
- HPN-100-008
- Acronym
- HALT-HE
- Status last verified
- Jun 2024
- First submitted
- 8 Oct 2009
- Last updated
- 10 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Publications
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.
PubMed 23847109Mokhtarani 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.
PubMed 24144944
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00999167
- Acronym / sponsor ID
- HALT-HE / HPN-100-008
- Conditions
- Cirrhosis, Hepatic Encephalopathy
- Keywords
- Cirrhosis, Episodic Hepatic Encephalopathy, HE, HPN-100, GT4P, glycerol phenylbutyrate
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 189 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Study start
- Dec 2009
- Primary completion
- Apr 2012 (actual)
- Study completion
- Apr 2012 (actual)
- First posted
- 21 Oct 2009 (estimated)
- Results
- Posted 30 Sep 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| HPN-100 | Experimental | Drug: HPN-100 |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HPN-100Also: GT4PPart B: 6 mL BID for 16 weeks. | Drug | HPN-100 |
| PlaceboPart B: same as experimental arm | Drug | Placebo |
Primary outcome
Part A: The Rate of AEs and Tolerability of HPN-100
Time frame: 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
Time frame: 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
3 secondary outcomes
Total Number of HE Events
Time frame: 112 Days
Time to Meeting the Primary Endpoint
Time frame: 112 Days
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score
Time frame: Day 56, Final Visit (D112)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23847109Rockey 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.
- Derived from this study: PubMed 24144944Mokhtarani 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.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
28 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing HPN-100 in people with Cirrhosis and Hepatic Encephalopathy, run by Amgen at 28 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 28 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Sep 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: The Rate of AEs and Tolerability of HPN-100 (time frame: Part A: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00999167, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2024.