Decompensated Cirrhosis
Conditions
Brief summary
This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-17.The IDN-6556-17 study is a Phase 2, multicenter, double-blind, placebo-controlled trial of Emricasan in subjects with decompensated non-alcoholic steatohepatitis (NASH) cirrhosis.
Detailed description
The protocol is intended to validate the ability of the MBT to predict deterioration by 48 weeks for all subjects, and at later time points for those followed longer, for subjects with decompensated NASH cirrhosis in the placebo treatment arm of Conatus' study IDN-6556-17. As one of the Conatus' study secondary objectives, this companion protocol is designed to assess improvement in liver metabolic function as measured by Methacetin Breath Test (MBT) \[ Time Frame: Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) \].
Interventions
COMBINATION_PRODUCTMethacetin Breath Test
A breath analyzer will be used to measure changes in carbon 12 to carbon13 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 study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. All subjects will continue treatment until the last subject in the study reaches 48 weeks in the study. At least 30% of subjects randomized should have baseline MELD score ≥15 and ≤20. For each subject, the study will consist of: * Screening period of up to 4 weeks * Randomized, double-blind treatment period of at least 48 weeks * A follow-up visit 2 weeks after completion of study drug treatment The duration of each subject's participation will be at least 54 weeks for those completing the entire study.
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. At least one of the following: a) history of variceal hemorrhage (more than 3 months prior to day 1) documented on endoscopy and requiring blood transfusion, b) history of at least moderate ascites (on physical exam or imaging) currently treated with diuretics. 4. MELD score ≥12 and ≤20 during screening 5. Albumin ≥2.5 g/dL during screening 6. Serum creatinine ≤1.5 mg/dL during screening
Exclusion criteria
1. Evidence of severe decompensation 2. Non-cirrhotic portal hypertension 3. Child-Pugh score ≥10 4. Current use of anticoagulants that affect prothrombin time or international normalized ratio 5. ALT \>3 times upper limit of normal (ULN) or AST \>5 times ULN during screening 6. Initiation or discontinuation of non-selective beta blockers within 1 month of screening 7. Transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure within 1 year of screening or previously requiring revision 8. Alpha-fetoprotein \>50 ng/mL in the last year 9. History of hepatocellular carcinoma (HCC) or evidence of HCC 10. History of malignancies other than HCC, unless successfully treated with curative intent and believed to be cured 11. Prior liver transplant 12. Uncontrolled diabetes mellitus (HbA1c \>9%) 13. Change in diabetes medications or vitamin E within 3 months of screening 14. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery 15. Symptoms of biliary colic unless resolved following cholecystectomy 16. History of significant alcohol consumption within the past 5 years 17. Current use of medications that are considered inhibitors of organic anion transporting polypeptide OATP1B1 and OATP1B3 transporters 18. Prolongation of screening (pre-treatment) QTcF interval of \>500 msecs, or history or presence of clinically concerning cardiac arrhythmias 19. Significant systemic or major illness other than liver disease 20. Human immunodeficiency virus infection 21. Use of alcohol, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | 1 hour for MBT for assessment of this diagnostic outcome assessed during screening | Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of \< 5.5%/hour. The data was collected and analyzed agnostic to the intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | 1 hour for MBT for assessment of this diagnostic outcome assessed during screening | Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of \< 7.5%/hour.The data was collected and analyzed agnostic to the intervention. |
Countries
United States
Participant flow
Pre-assignment details
60 subjects were disqualified at baseline before being divided into arms due to screen failure.
Participants by arm
| Arm | Count |
|---|---|
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm Arm 1. The number of subjects that experience a decompensation event as described in the protocol in the arm treated with 25 mg of Emricasan. | 46 |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm Arm 2. The number of subjects that experience a decompensation event as described in the protocol in the arm treated with 5 mg of Emricasan. | 48 |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm Arm 3. The number of subjects that experience a decompensation event as described in the protocol in the placebo arm . | 45 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Device Malfunction | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 5 | 11 | 7 |
Baseline characteristics
| Characteristic | Number of Subjects Experiencing a High Risk Event in Placebo Arm | Total | Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm |
|---|---|---|---|---|
| Age, Continuous | 62.864 years STANDARD_DEVIATION 7.135 | 61.1 years STANDARD_DEVIATION 8.48 | 59.674 years STANDARD_DEVIATION 9.307 | 60.875 years STANDARD_DEVIATION 8.668 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 127 Participants | 43 Participants | 43 Participants |
| Region of Enrollment United States | 44 Participants | 138 Participants | 46 Participants | 48 Participants |
| Sex: Female, Male Female | 27 Participants | 72 Participants | 26 Participants | 19 Participants |
| Sex: Female, Male Male | 17 Participants | 66 Participants | 20 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 48 | 0 / 45 |
| other Total, other adverse events | 1 / 46 | 1 / 48 | 0 / 45 |
| serious Total, serious adverse events | 0 / 46 | 0 / 48 | 0 / 45 |
Outcome results
Primary
Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off
Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of \< 5.5%/hour. The data was collected and analyzed agnostic to the intervention.
Time frame: 1 hour for MBT for assessment of this diagnostic outcome assessed during screening
Population: The population analyzed is Intent to Diagnose (ITD)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects below cut-off | 3 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects below cut-off | 1 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects above cut-off | 15 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects above cut-off | 27 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects above cut-off | 28 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects below cut-off | 4 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects above cut-off | 14 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects below cut-off | 2 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects above cut-off | 22 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | No event recorded in subjects below cut-off | 5 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects above cut-off | 11 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 5.5%/Hour Cut-off | Events in subjects below cut-off | 6 Participants |
Secondary
Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off
Binary diagnosis of subjects that are at high risk to develop a deterioration event as determined by the Methacetin Breath Test (MBT) derived from an algorithm developed under other Exalenz clinical studies using a pre-designed cutoff of Percentage Dose Recovery (PDR) peak of \< 7.5%/hour.The data was collected and analyzed agnostic to the intervention.
Time frame: 1 hour for MBT for assessment of this diagnostic outcome assessed during screening
Population: The population analyzed is Intent to Diagnose (ITD).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects below cut-off | 4 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects below cut-off | 4 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects above cut-off | 14 Participants |
| Number of Subjects Experiencing a High Risk Event in 25 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects above cut-off | 24 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects above cut-off | 26 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects below cut-off | 8 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects above cut-off | 10 Participants |
| Number of Subjects Experiencing a High Risk Event in 5 mg Treatment Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects below cut-off | 4 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects above cut-off | 21 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | No event recorded in subjects below cut-off | 6 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects above cut-off | 8 Participants |
| Number of Subjects Experiencing a High Risk Event in Placebo Arm | Number of Subjects Experiencing a High Risk Event Based on a 7.5 %/Hour Cut-off | Events in subjects below cut-off | 9 Participants |