Cirrhosis, NASH - Nonalcoholic Steatohepatitis, Portal Hypertension
Conditions
Brief summary
To validate the ability of the Methacetin Breath Test (MBT) to detect clinically significant portal hypertension (CSPH)/severe portal hypertension (SPH) defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg and HVPG ≥ 12 mmHg respectively, in patients with non-alcoholic steatohepatitis (NASH) during the course of treatment with Conatus's investigational product emricasan/placebo.
Detailed description
This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-14 (NCT02960204).The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled trial in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension. As one of the Conatus' study exploratory objectives, this companion protocol is designed to assess whether emricasan compared to placebo improves liver metabolic function at Weeks 24 and 48 as assessed by the methacetin breath test (at select sites), if relevant.
Interventions
COMBINATION_PRODUCTMethacetin Breath Test
A breath analyzer will be used to measure changes in carbon-12 to carbon-13 ratio as a result of metabolism of the Methacetin substrate before and after treatment.
DRUGEmricasan
Investigational drug for NASH treatment in Main Conatus protocol
DRUGPlacebo oral capsule
Placebo versus emricasan in Conatus NASH treatment trial
Sponsors
Conatus Pharmaceuticals Inc.
Meridian Bioscience, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The collaborator is responsible for the masking process.
Intervention model description
The population performing the MBT at weeks 24 and 48 will have approximately an equal number of subjects from each of the 4 parallel treatment arms (5 mg, 25 mg, 50 mg or placebo).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.) 3. Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event. 4. Severe portal hypertension defined as HVPG ≥12 mmHg 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 childbearing potential) from Screening to 4 weeks after the last dose of study drug
Exclusion criteria
1. Evidence of severe decompensation 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 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. Prior liver transplant 13. Change in diabetes medications or vitamin E within 3 months of screening 14. Uncontrolled diabetes mellitus (HbA1c \>9%) within 3 months of screening 15. Significant systemic or major illness other than liver disease 16. HIV infection 17. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening 18. If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding 19. 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 |
|---|---|---|
| Number of Subjects With Matched Clinically Significant Portal Hypertension Based on Hepatic Venous Pressure Gradient (HVPG) and Methacetin Breath Test (MBT) | 1 hour for MBT related to assessment of this diagnostic primary outcome assesses during screening | Binary diagnosis of clinically significant portal hypertension (CSPH) as determined by HVPG, defined as HVPG ≥ 10mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Matched Subjects With Significant Portal Hypertension (Defined as HVPG>=12mmHg) Based on HVPG and MBT | 1 hour for MBT for assessment of this diagnostic secondary outcome assessed during screening | Binary diagnosis of HVPG\>=12mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies |
Countries
France
Participant flow
Recruitment details
All subjects that met the companion protocol eligibility criteria were enrolled.
Pre-assignment details
Diagnostic endpoints used screening measurements taken prior to study drug administration, therefore no treatment effect was relevant. In addition, for the event prediction endpoints, the treatment covariate was tested for significance, and was found to be non-significant, thus removed from the final predicting model. As such, arms were combined.
Participants by arm
| Arm | Count |
|---|---|
| ACLD With NASH Subjects with advanced chronic liver disease (ACLD) and confirmed nonalcoholic steatohepatitis (NASH) | 343 |
| Total | 343 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 63 |
| Overall Study | Protocol Violation | 19 |
Baseline characteristics
| Characteristic | ACLD With NASH |
|---|---|
| Age, Continuous | 60.4 years STANDARD_DEVIATION 8.78 |
| BMI | 35.3 kg/cm^2 STANDARD_DEVIATION 7.07 |
| Compensated (Liver disease) | 265 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 80 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 255 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race (NIH/OMB) White | 316 Participants |
| Region of Enrollment France | 10 participants |
| Region of Enrollment Spain | 24 participants |
| Region of Enrollment United States | 309 participants |
| Sex: Female, Male Female | 200 Participants |
| Sex: Female, Male Male | 143 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 343 |
| other Total, other adverse events | 2 / 343 |
| serious Total, serious adverse events | 0 / 343 |
Outcome results
Primary
Number of Subjects With Matched Clinically Significant Portal Hypertension Based on Hepatic Venous Pressure Gradient (HVPG) and Methacetin Breath Test (MBT)
Binary diagnosis of clinically significant portal hypertension (CSPH) as determined by HVPG, defined as HVPG ≥ 10mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies
Time frame: 1 hour for MBT related to assessment of this diagnostic primary outcome assesses during screening
Population: Diagnostic endpoints used screening measurements taken prior to study drug administration, therefore no treatment effect was relevant. In addition, for the event prediction endpoints, the treatment covariate was tested for significance, and was found to be non-significant, thus removed from the final predicting model. As such, arms were combined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Subjects With CSPH | Number of Subjects With Matched Clinically Significant Portal Hypertension Based on Hepatic Venous Pressure Gradient (HVPG) and Methacetin Breath Test (MBT) | 190 Participants |
Secondary
Number of Matched Subjects With Significant Portal Hypertension (Defined as HVPG>=12mmHg) Based on HVPG and MBT
Binary diagnosis of HVPG\>=12mmHg and by the MBT derived from an algorithm developed under other Exalenz clinical studies
Time frame: 1 hour for MBT for assessment of this diagnostic secondary outcome assessed during screening
Population: Diagnostic endpoints used screening measurements taken prior to study drug administration, therefore no treatment effect was relevant. In addition, for the event prediction endpoints, the treatment covariate was tested for significance, and was found to be non-significant, thus removed from the final predicting model. As such, arms were combined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Subjects With CSPH | Number of Matched Subjects With Significant Portal Hypertension (Defined as HVPG>=12mmHg) Based on HVPG and MBT | 182 Participants |