Cirrhosis, Non-alcoholic Steatohepatitis, Portal Hypertension
Conditions
Keywords
cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis, Liver cirrhosis
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled trial involving subjects with NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg as determined by the central reader assigned to this study). Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID, 25 mg BID, or 5 mg BID or matching placebo BID.
Interventions
DRUGEmricasan
DRUGPlacebo
Sponsors
Histogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study. * Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.) * Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event * Severe portal hypertension defined as HVPG ≥12 mmHg * Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1 * Willingness to utilize effective contraception (for both males and females of childbearing potential) from Screening to 4 weeks after the last dose of study drug
Exclusion criteria
* Evidence of severe decompensation * Severe hepatic impairment defined as a Child-Pugh score ≥10 * ALT (alanine transaminase) \> 3 times upper limit of normal (ULN) or AST (aspartate transaminase) \>5 times ULN during screening * Estimated creatinine clearance \<30 mL/min * Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure * Known portal vein thrombosis * Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy * Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters * Alpha-fetoprotein \>50 ng/mL * History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of \>500 msec * History of or active malignancies, other than those successfully treated with curative intent and believed to be cured * Prior liver transplant * Change in diabetes medications or vitamin E within 3 months of screening * Uncontrolled diabetes mellitus (HbA1c \>9%) within 3 months of screening * Significant systemic or major illness other than liver disease * HIV infection * Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening * If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding * Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Hepatic Venous Pressure Gradient (HVPG) | Baseline to Week 24 | To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement of HVPG Response Using a 20% Reduction From Baseline | Baseline to Week 24 | To assess subjects who have at least a 20 percent reduction from baseline in HVPG |
| Caspase 3/7 | Baseline to Week 24, Baseline to Week 48 | To assess whether number of Caspase 3/7 biomarkers is affected by emricasan as compared to placebo |
| Alanine Aminotransferase (ALT) | Baseline to Week 24 and Baseline to Week 48 | To assess whether amount of non-specific (ALT) biomarkers are affected by emricasan compared to placebo |
Countries
Germany, Spain, United States
Participant flow
Pre-assignment details
Enrolled participants were excluded from the study and not randomized if they withdrew consent or did not meet inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Emricasan (5 mg) Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day.
Emricasan | 65 |
| Emricasan (25 mg) Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day.
Emricasan | 65 |
| Emricasan (50 mg) Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day.
Emricasan | 66 |
| Matching Placebo Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day.
Placebo | 67 |
| Total | 263 |
Baseline characteristics
| Characteristic | Total | Emricasan (5 mg) | Matching Placebo | Emricasan (50 mg) | Emricasan (25 mg) |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 92 Participants | 18 Participants | 23 Participants | 25 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 171 Participants | 47 Participants | 44 Participants | 41 Participants | 39 Participants |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 8.76 | 60.6 years STANDARD_DEVIATION 8.77 | 61.4 years STANDARD_DEVIATION 7.9 | 59.5 years STANDARD_DEVIATION 9.48 | 62.0 years STANDARD_DEVIATION 8.81 |
| Child-Pugh Classification A | 231 Participants | 56 Participants | 61 Participants | 55 Participants | 59 Participants |
| Child-Pugh Classification B | 29 Participants | 7 Participants | 6 Participants | 11 Participants | 5 Participants |
| Child-Pugh Classification C | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component: Ascites 1 | 238 Participants | 58 Participants | 62 Participants | 57 Participants | 61 Participants |
| Child-Pugh Component: Ascites 2 | 25 Participants | 7 Participants | 5 Participants | 9 Participants | 4 Participants |
| Child-Pugh Component: Ascites 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component Hepatic Encephalopathy 1 | 261 Participants | 63 Participants | 67 Participants | 66 Participants | 65 Participants |
| Child-Pugh Component Hepatic Encephalopathy 2 | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component Hepatic Encephalopathy 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component: Prothrombin Time (or International Normalized Ratio) 1 | 261 Participants | 63 Participants | 67 Participants | 66 Participants | 65 Participants |
| Child-Pugh Component: Prothrombin Time (or International Normalized Ratio) 2 | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component: Prothrombin Time (or International Normalized Ratio) 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Child-Pugh Component: Total Albumin 1 | 209 Participants | 49 Participants | 57 Participants | 51 Participants | 52 Participants |
| Child-Pugh Component: Total Albumin 2 | 52 Participants | 15 Participants | 10 Participants | 14 Participants | 13 Participants |
| Child-Pugh Component: Total Albumin 3 | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Child-Pugh Component: Total Bilirubin 1 | 242 Participants | 58 Participants | 64 Participants | 59 Participants | 61 Participants |
| Child-Pugh Component: Total Bilirubin 2 | 14 Participants | 5 Participants | 2 Participants | 4 Participants | 3 Participants |
| Child-Pugh Component: Total Bilirubin 3 | 7 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants |
| Child-Pugh Score | 5.5 units on a scale STANDARD_DEVIATION 0.82 | 5.5 units on a scale STANDARD_DEVIATION 0.96 | 5.4 units on a scale STANDARD_DEVIATION 0.75 | 5.6 units on a scale STANDARD_DEVIATION 0.86 | 5.5 units on a scale STANDARD_DEVIATION 0.69 |
| Cholecystectomy | 86 Participants | 24 Participants | 26 Participants | 20 Participants | 16 Participants |
| Cirrhosis Baseline Status Compensated Cirrhosis | 201 Participants | 49 Participants | 55 Participants | 48 Participants | 49 Participants |
| Cirrhosis Baseline Status Decompensated Cirrhosis | 62 Participants | 16 Participants | 12 Participants | 18 Participants | 16 Participants |
| Compensated Status with Varices Compensated with medium/large varices | 64 Participants | 17 Participants | 12 Participants | 16 Participants | 19 Participants |
| Compensated Status with Varices Compensated with none/small varices | 135 Participants | 32 Participants | 42 Participants | 32 Participants | 29 Participants |
| Compensated Status with Varices Decompensated with medium/large varices | 19 Participants | 8 Participants | 1 Participants | 6 Participants | 4 Participants |
| Compensated Status with Varices Decompensated with none/small varices | 43 Participants | 8 Participants | 11 Participants | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 60 Participants | 19 Participants | 18 Participants | 12 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 191 Participants | 42 Participants | 47 Participants | 52 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 4 Participants | 2 Participants | 2 Participants | 4 Participants |
| Gallstones | 116 Participants | 30 Participants | 27 Participants | 31 Participants | 28 Participants |
| Hepatic Venous Pressure Gradient | 16.96 mmHg STANDARD_DEVIATION 3.586 | 16.88 mmHg STANDARD_DEVIATION 3.573 | 16.81 mmHg STANDARD_DEVIATION 3.724 | 16.91 mmHg STANDARD_DEVIATION 3.545 | 17.25 mmHg STANDARD_DEVIATION 3.3 |
| MELD Classification (Median Cut) <= 8 | 138 Participants | 33 Participants | 44 Participants | 30 Participants | 31 Participants |
| MELD Classification (Median Cut) >= 9 | 125 Participants | 32 Participants | 23 Participants | 36 Participants | 34 Participants |
| MELD Component: International Normalized Ratio | 1.16 mg/dL STANDARD_DEVIATION 0.128 | 1.18 mg/dL STANDARD_DEVIATION 0.167 | 1.14 mg/dL STANDARD_DEVIATION 0.113 | 1.16 mg/dL STANDARD_DEVIATION 0.115 | 1.16 mg/dL STANDARD_DEVIATION 0.167 |
| MELD Component: Serum Creatine | 1.02 mg/dL STANDARD_DEVIATION 0.102 | 1.02 mg/dL STANDARD_DEVIATION 0.079 | 1.02 mg/dL STANDARD_DEVIATION 0.086 | 1.04 mg/dL STANDARD_DEVIATION 0.16 | 1.01 mg/dL STANDARD_DEVIATION 0.053 |
| MELD Component: Total Bilirubin | 1.29 mg/dL STANDARD_DEVIATION 0.696 | 1.27 mg/dL STANDARD_DEVIATION 0.514 | 1.20 mg/dL STANDARD_DEVIATION 0.6 | 1.39 mg/dL STANDARD_DEVIATION 0.725 | 1.31 mg/dL STANDARD_DEVIATION 0.482 |
| Model for End-Stage Liver Disease (MELD) Score | 8.97 units on a scale STANDARD_DEVIATION 2.489 | 9.17 units on a scale STANDARD_DEVIATION 2.673 | 8.40 units on a scale STANDARD_DEVIATION 2.511 | 9.24 units on a scale STANDARD_DEVIATION 2.512 | 9.06 units on a scale STANDARD_DEVIATION 2.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 7 Participants | 3 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 240 Participants | 58 Participants | 64 Participants | 60 Participants | 58 Participants |
| Region of Enrollment France | 14 participants | 5 participants | 2 participants | 4 participants | 3 participants |
| Region of Enrollment Germany | 7 participants | 3 participants | 3 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 20 participants | 4 participants | 5 participants | 4 participants | 7 participants |
| Region of Enrollment Switzerland | 9 participants | 2 participants | 3 participants | 0 participants | 4 participants |
| Region of Enrollment United States | 212 participants | 51 participants | 54 participants | 57 participants | 50 participants |
| Sex: Female, Male Female | 150 Participants | 37 Participants | 45 Participants | 33 Participants | 35 Participants |
| Sex: Female, Male Male | 113 Participants | 28 Participants | 22 Participants | 33 Participants | 30 Participants |
| Taking Non-Selective Beta Blockers at Baseline No | 156 Participants | 37 Participants | 40 Participants | 40 Participants | 39 Participants |
| Taking Non-Selective Beta Blockers at Baseline Yes | 107 Participants | 28 Participants | 27 Participants | 26 Participants | 26 Participants |
| Varices None | 71 Participants | 19 Participants | 19 Participants | 19 Participants | 14 Participants |
| Varices Present - Large | 26 Participants | 4 Participants | 7 Participants | 8 Participants | 7 Participants |
| Varices Present - Medium | 57 Participants | 21 Participants | 6 Participants | 14 Participants | 16 Participants |
| Varices Present - Not Specified | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Varices Present - Small | 107 Participants | 21 Participants | 34 Participants | 25 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 65 | 2 / 65 | 1 / 66 | 0 / 67 |
| other Total, other adverse events | 59 / 65 | 62 / 65 | 57 / 66 | 61 / 67 |
| serious Total, serious adverse events | 15 / 65 | 23 / 65 | 21 / 66 | 16 / 67 |
Outcome results
Primary
Mean Change in Hepatic Venous Pressure Gradient (HVPG)
To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG)
Time frame: Baseline to Week 24
Population: Full analysis set (Multiple Imputation)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Emricasan (5 mg) | Mean Change in Hepatic Venous Pressure Gradient (HVPG) | -0.48 mmHg | Standard Deviation 3.356 |
| Emricasan (25 mg) | Mean Change in Hepatic Venous Pressure Gradient (HVPG) | -0.81 mmHg | Standard Deviation 3.669 |
| Emricasan (50 mg) | Mean Change in Hepatic Venous Pressure Gradient (HVPG) | -0.70 mmHg | Standard Deviation 3.4 |
| Matching Placebo | Mean Change in Hepatic Venous Pressure Gradient (HVPG) | -0.18 mmHg | Standard Deviation 3.028 |
Secondary
Alanine Aminotransferase (ALT)
To assess whether amount of non-specific (ALT) biomarkers are affected by emricasan compared to placebo
Time frame: Baseline to Week 24 and Baseline to Week 48
Population: Full Analysis Set (Observed Cases)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Emricasan (5 mg) | Alanine Aminotransferase (ALT) | Week 24 | -7.83 U/L | Standard Deviation 10.65 |
| Emricasan (5 mg) | Alanine Aminotransferase (ALT) | Week 48 | -6.54 U/L | Standard Deviation 11.917 |
| Emricasan (25 mg) | Alanine Aminotransferase (ALT) | Week 48 | -4.16 U/L | Standard Deviation 9.85 |
| Emricasan (25 mg) | Alanine Aminotransferase (ALT) | Week 24 | -8.06 U/L | Standard Deviation 10.542 |
| Emricasan (50 mg) | Alanine Aminotransferase (ALT) | Week 24 | -7.06 U/L | Standard Deviation 12.01 |
| Emricasan (50 mg) | Alanine Aminotransferase (ALT) | Week 48 | -5.34 U/L | Standard Deviation 11.153 |
| Matching Placebo | Alanine Aminotransferase (ALT) | Week 24 | -1.69 U/L | Standard Deviation 12.907 |
| Matching Placebo | Alanine Aminotransferase (ALT) | Week 48 | -2.97 U/L | Standard Deviation 12.457 |
Secondary
Caspase 3/7
To assess whether number of Caspase 3/7 biomarkers is affected by emricasan as compared to placebo
Time frame: Baseline to Week 24, Baseline to Week 48
Population: Full Analysis Set (Observed Cases)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Emricasan (5 mg) | Caspase 3/7 | Week 24 | -0.01 RLU | Standard Deviation 0.475 |
| Emricasan (5 mg) | Caspase 3/7 | Week 48 | 0.13 RLU | Standard Deviation 0.541 |
| Emricasan (25 mg) | Caspase 3/7 | Week 48 | -0.18 RLU | Standard Deviation 0.665 |
| Emricasan (25 mg) | Caspase 3/7 | Week 24 | -0.40 RLU | Standard Deviation 0.597 |
| Emricasan (50 mg) | Caspase 3/7 | Week 24 | -0.46 RLU | Standard Deviation 0.663 |
| Emricasan (50 mg) | Caspase 3/7 | Week 48 | -0.48 RLU | Standard Deviation 0.564 |
| Matching Placebo | Caspase 3/7 | Week 24 | -0.04 RLU | Standard Deviation 0.339 |
| Matching Placebo | Caspase 3/7 | Week 48 | 0.05 RLU | Standard Deviation 0.373 |
Secondary
Improvement of HVPG Response Using a 20% Reduction From Baseline
To assess subjects who have at least a 20 percent reduction from baseline in HVPG
Time frame: Baseline to Week 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Emricasan (5 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% reduction in HVPG: Yes | 8 participants |
| Emricasan (5 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | Unknown | 4 participants |
| Emricasan (5 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% Reduction in HVPG: No | 53 participants |
| Emricasan (25 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% reduction in HVPG: Yes | 14 participants |
| Emricasan (25 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | Unknown | 3 participants |
| Emricasan (25 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% Reduction in HVPG: No | 48 participants |
| Emricasan (50 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% Reduction in HVPG: No | 46 participants |
| Emricasan (50 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% reduction in HVPG: Yes | 10 participants |
| Emricasan (50 mg) | Improvement of HVPG Response Using a 20% Reduction From Baseline | Unknown | 10 participants |
| Matching Placebo | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% reduction in HVPG: Yes | 9 participants |
| Matching Placebo | Improvement of HVPG Response Using a 20% Reduction From Baseline | Unknown | 3 participants |
| Matching Placebo | Improvement of HVPG Response Using a 20% Reduction From Baseline | >= 20% Reduction in HVPG: No | 55 participants |