| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cirrhosis due to NASH and Severe Portal Hypertension |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036200 |
| E.1.2 | Term | Portal hypertension |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess whether emricasan compared to placebo leads to a mean decrease in hepatic
venous pressure gradient (HVPG) at Week 24 in subjects with NASH cirrhosis and severe portal hypertension. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of emricasan
- To evaluate the dose response of emricasan on portal pressure as assessed by HVPG at week 24
- To assess whether emricasan compared to placebo improves HVPG response using a 20% reduction from baseline response deifinition at week 24
- To assess whether emricasan compared to placebo decreases mechanism specific (caspase 3/7) and non-specific (ALT) biomarkers at weeks 24 and 48 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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.
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
Diagnosis of cirrhosis is based on:
- Biopsy OR
- Clinical evidence: platelet count < 150,000, AST > ALT, and either nodular liver surface on imaging or splenomegaly
NASH is based on at least 1 of the following:
- Prior or current biopsy showing some but not all diagnostic features of NASH (e.g. only fat or ballooning degeneration or inflammation) but with no evidence for viral hepatitis or other liver disease AND either fatty
liver disease on prior imaging or at least 1 metabolic risk factor (as above) for at least 5 years preceding the diagnosis of cirrhosis
Note: Previous viral hepatitis that was curatively treated (with sustained viral response) is not an exclusion as long as: 1) viral eradication was achieved at least 3 years prior to the diagnosis of cirrhosis and 2) all other criteria are met for NASH as the etiology of cirrhosis
3. Compensated cirrhosis (no history of or presence of clinically evident ascites, variceal hemorrhage, or encephalopathy, and on no medications to treat these complications)
OR
Decompensated cirrhosis with no more than 1 prior significant decompensating event:
a. If prior decompensating event was variceal hemorrhage, event must have occurred at least 3 months prior to Day 1
b. If prior decompensating event was ascites requiring chronic diuretics, ascites should be well controlled (not clinically evident, i.e. no ascites or ascites only detectable by ultrasound examination) on a stable dose of diuretics for at least 3 months prior to Day 1
c. If prior decompensating event was hepatic encephalopathy ≥ grade II or requiring hospitalization, encephalopathy should be well-controlled (Stage 0 or 1) on stable medication for at least 3 months prior to Day 1
Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently stable without clinically evident ascites or encephalopathy and on no medications for these conditions does not count as a prior significant decompensating event
4. Severe portal hypertension defined as HVPG ≥12 mmHg (see Section 8.4.1 for recommendations to identify subjects more likely to meet the HVPG criteria)
5. 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
6.Willingness to utilize effective contraception (for both males and females of reproductive potential) from Screening to 4 weeks after the last dose of study drug
7. Platelet count ≤125 k/mm3 or transient elastography ≥ 20 kPa during screening
8. If on therapeutic dose of vitamin E, stable for 6 months prior to Day 1. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of severe decompensation, defined as:
a. Presence or history of more than one type of significant decompensating event (clinically evident ascites requiring chronic diuretics, variceal hemorrhage, and/or overt encephalopathy)
Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently stable without clinically evident ascites or encephalopathy and on no medications for these conditions does not count towards this exclusion (see Inclusion Criteria #4).
b. One type of decompensating event with the following characteristics:
- More than 1 episode of variceal hemorrhage or bleeding from a portal hypertensive source (e.g. portal hypertensive gastropathy)
- Ascites that has required more than 1 large-volume paracentesis (>5 L) for treatment or that has been complicated by spontaneous bacterial peritonitis, hyponatremia (serum Na <130), and/or hepatorenal syndrome
- More than 1 episode of overt hepatic encephalopathy requiring hospitalization
2. Severe hepatic impairment defined as a Child-Pugh score ≥10
3. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening
4. Estimated creatinine clearance <30 mL/min
5. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure
6. Known portal vein thrombosis
7. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy , other definitive treatment (e.g., sphincterotomy), or medical management (e.g. ursodeoxycholic acid)
8. Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, indinavir, lopinavir, ritonavir, rifampin, saquinavir, simeprevir, telaprevir, tipranovir, or some combination of these medications
9. Alpha-fetoprotein >50 ng/mL
10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec
11. History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
12. Significant systemic or major illness other than liver disease that in the opinion of the investigator would preclude the subject from participating in and completing the study, including but not limited to acute coronary syndrome or stroke within 6 months of screening or major surgery within 3 months of screening
13. Prior liver transplant
14. Change in diabetes medications within 3 months of screening, including initiation, discontinuation, or change in dose except for medications titrated according to blood glucose
15. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening
16. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery
17. Known human immunodeficiency virus infection
18. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening to the point of interfering with the subject's ability to comply with study procedures and study drug administration in the investigator's judgement
19. History of significant alcohol consumption (>20 g/day for females and >30 g/day for males on average) within the past 5 years
20. If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
21. Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean Change from Baseline at Week 25 in Hepatic Venous Pressure Gradient (HVPG) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The change from baseline at Weeks 24 and 48 in Caspase 3/7 and ALT
measurements and HVPG response (20% reduction from baseline) at
Week 24. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Spain |
| Switzerland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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