Hepatic Cirrhosis, Liver Cirrhosis
Conditions
Keywords
Liver Cirrhosis, Hepatic Cirrhosis
Brief summary
This is a multicenter study to see if treatment with IDN-6556 can help improve the liver function of patients with liver cirrhosis with Model for End-Stage Liver Disease scores between 11-18.
Detailed description
Numerous studies have shown that caspase cleaved cytokeratin 18 (cCK18) is elevated in the serum of liver disease patients and has been associated with disease severity, thus associating both excessive apoptosis and caspase activity with disease. Studies have also shown that caspase cleaved cytokeratin 18 is generally elevated to an even greater degree in cirrhosis than in other liver diseases. In addition, increasing stages of cirrhosis from Child-Pugh A, Child-Pugh B to Child-Pugh C are associated with progressively higher levels of caspase cleaved cytokeratin 18. Therefore, it appears that apoptosis and caspase activity tend to correlate with the stage of cirrhosis. A caspase inhibitor like IDN-6556 could have clinical utility by reducing the rate of apoptosis in cirrhotic patients and potentially reduce the progression of disease as determined by clinical markers of progression.
Interventions
DRUGIDN-6556
25 mg BID
DRUGPlacebo
Sponsors
Conatus Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and able to understand and willing to comply with the requirements of the study * Clinical, radiological, or biochemical evidence of liver cirrhosis * Model for End-Stage Liver Disease (MELD) Score of 11 to 18 during the Screening period * Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug.
Exclusion criteria
* Known infection with human immunodeficiency virus (HIV) * Auto-immune hepatitis * Subjects with evidence of uncontrolled infection, defined as persistent bacterial culture positivity despite adequate antibiotic therapy * HCV infected subjects who are receiving or plan to receive anti-viral therapy during the study * Untreated esophageal varices with high risk stigmata for hemorrhage * Variceal hemorrhage within 3 months of Screening * Ascites not adequately controlled on stable background medication * Other non-liver organ failure * Child-Pugh score of 10-15 (Child-Pugh C classification) * Use of vasoactive drugs (at or within 3 months of Screening) that may impair hepatic blood flow * Change in dose or regimen within 3 months of Screening of: 1. Fibrates or statins 2. Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE) inhibitor * Use of chronic anticoagulation therapy including but not limited to Vitamin K/Factor Xa antagonists/inhibitors * Use of the following drugs within 2 months of Screening: 1. Systemic corticosteroids 2. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) * Concomitant pancreatitis * Active inflammatory bowel disease * Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) * Subjects with active or history of malignancies other than hepatocellular carcinoma (HCC) within Milan criteria or curatively treated skin cancer (basal cell or squamous cell carcinomas), unless adequately treated or in complete remission for five or more years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Month 3 in cCK18/M30 | 3 months | Baseline, Month 3, and change between for cCK18/M30 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 3 in MELD Score | 3 Months | The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease and uses the subject's values for total bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. MELD is calculated according to the following formula: MELD = 3.78×ln\[serum bilirubin (mg/dL)\] + 11.2×ln\[INR\] + 9.57×ln\[serum creatinine (mg/dL)\] + 6.43 MELD scores are reported as whole numbers, so the result of the equation above is rounded. Notes: If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0. Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any value below 1 would yield a negative result). The higher the MELD score the more severe the disease state. |
Countries
United States
Participant flow
Recruitment details
A total of 140 subjects from 26 US sites were screened, of whom 87 subjects were randomized. One subject randomized to placebo withdrew from the study before taking study drug. Disposition data is provided for the initial 3-month randomized, placebo-controlled phase on which the primary efficacy and safety analyses were based
Participants by arm
| Arm | Count |
|---|---|
| IDN-6556 25 mg BID of IDN-6556
IDN-6556: 25 mg BID | 44 |
| Placebo Placebo BID
Placebo | 42 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Progression to Child-Pugh C | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | IDN-6556 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 8 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 34 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 11 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 30 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 39 Participants | 37 Participants | 76 Participants |
| Sex: Female, Male Female | 20 Participants | 12 Participants | 32 Participants |
| Sex: Female, Male Male | 24 Participants | 30 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 42 |
| other Total, other adverse events | 34 / 44 | 30 / 42 |
| serious Total, serious adverse events | 6 / 44 | 5 / 42 |
Outcome results
Primary
Change From Baseline at Month 3 in cCK18/M30
Baseline, Month 3, and change between for cCK18/M30
Time frame: 3 months
Population: FAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 | Change From Baseline at Month 3 in cCK18/M30 | Baseline | 293.5 U/L |
| IDN-6556 | Change From Baseline at Month 3 in cCK18/M30 | Month 3 | 288.5 U/L |
| Placebo | Change From Baseline at Month 3 in cCK18/M30 | Baseline | 257.5 U/L |
| Placebo | Change From Baseline at Month 3 in cCK18/M30 | Month 3 | 285.0 U/L |
Primary
Change From Baseline at Month 3 in cCK18/M30
Data was log-transformed for analysis purposes
Time frame: 3 months
Population: Full analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| IDN-6556 | Change From Baseline at Month 3 in cCK18/M30 | Percent (%) Relative Change | -4.6 U/L | Standard Error 5.9 |
| IDN-6556 | Change From Baseline at Month 3 in cCK18/M30 | Log-transformed Values | -0.049 U/L | Standard Error 0.057 |
| Placebo | Change From Baseline at Month 3 in cCK18/M30 | Percent (%) Relative Change | 9.3 U/L | Standard Error 5.9 |
| Placebo | Change From Baseline at Month 3 in cCK18/M30 | Log-transformed Values | 0.090 U/L | Standard Error 0.058 |
Comparison: Analysis was conducted using an ANCOVA model adjusting for baseline value.p-value: 0.09195% CI: [-0.302, 0.023]ANCOVA
Comparison: The analysis was conducted using an ANCOVA model adjusting for baseline value, baseline MELD score, and etiology. The significance was assessed using Type II Sums of Squares from this ANCOVA model.p-value: 0.04195% CI: [-0.41, 0.01]ANCOVA
Secondary
Change From Baseline to Month 3 in MELD Score
The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease and uses the subject's values for total bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. MELD is calculated according to the following formula: MELD = 3.78×ln\[serum bilirubin (mg/dL)\] + 11.2×ln\[INR\] + 9.57×ln\[serum creatinine (mg/dL)\] + 6.43 MELD scores are reported as whole numbers, so the result of the equation above is rounded. Notes: If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0. Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any value below 1 would yield a negative result). The higher the MELD score the more severe the disease state.
Time frame: 3 Months
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDN-6556 | Change From Baseline to Month 3 in MELD Score | -0.10 units on a scale | Standard Error 0.234 |
| Placebo | Change From Baseline to Month 3 in MELD Score | 0.15 units on a scale | Standard Error 0.239 |
Comparison: Analysis was conducted using an ANCOVA model adjusting for baseline value.p-value: 0.46695% CI: [-0.91, 0.42]ANCOVA
Comparison: BL MELD \>= 15 subgroup results (N=19), as analyzed from the adjusted analysis ANCOVA model adjusting for baseline value, baseline MELD score, and etiology.p-value: 0.00395% CI: [-3.61, -0.77]ANCOVA
Comparison: NASH Etiology subgroup results (N=20), as analyzed from the adjusted analysis ANCOVA model adjusting for baseline value, baseline MELD score, and etiology.p-value: 0.02995% CI: [-3.09, -0.17]ANCOVA