Hepatic Cirrhosis, Liver Cirrhosis, Portal Hypertension
Conditions
Keywords
Liver Cirrhosis, Hepatic Cirrhosis, Portal Hypertension
Brief summary
This is an open-label pilot study to evaluate the safety, tolerability, and efficacy of IDN-6556 in treating portal hypertension in subjects with liver cirrhosis.
Detailed description
Studies in patients with liver disease have demonstrated that cCK18 is elevated in the serum of patients and has been associated with disease severity. Studies have also shown that cCK18 is generally elevated to a higher 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. This suggests that apoptosis and caspase activity are associated with the severity of disease. IDN-6556 and its ability to inhibit inflammation and apoptosis may have a beneficial impact on both the dynamic and structural components associated with the pathogenesis of portal hypertension in cirrhosis.
Interventions
DRUGIDN-6556
25 mg BID
Sponsors
Conatus Pharmaceuticals Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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 * Evidence of portal hypertension as evidenced by any of the following: 1. Splenomegaly, on imaging and/or clinical evaluation, with platelet count of \<120,000 at study entry, or 2. Presence of small sized varices on screening endoscopy and/or collateral circulation on imaging, or 3. Presence of medium/large varices that have never bled and have been obliterated with endoscopic ligation * Portal hypertension defined as a hepatic venous pressure gradient (HVPG) \>5 mmHg at Screening * 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
* Decompensated cirrhosis as defined by the presence of overt ascites (requiring diuretics), overt encephalopathy (requiring specific therapy), or history of variceal hemorrhage. * Known infection with HIV * Hepatic failure defined as total bilirubin ≥12 mg/dL * Other non-liver organ failure, including: 1. Renal failure defined as creatinine ≥ 2.0 mg/dL 2. Cerebral failure defined as hepatic encephalopathy grade III or IV 3. Coagulation failure defined as INR ≥ 2.5 or platelets ≤ 20x109/L 4. Hemodynamic requirement for inotropic support * 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; examples include but are not limited to: 1. β-blockers, including carvedilol 2. Nitrates 3. Vasopressin (or analogues) 4. Phosphodiesterase inhibitors (prescribed daily for pulmonary hypertension; p.r.n. use for erectile dysfunction is permitted) * 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 the following drugs within 2 months of Screening: 1. Systemic corticosteroids 2. Pentoxifylline 3. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) * Concomitant pancreatitis * Evidence of portal vein thrombosis on Doppler ultrasound of the portal vasculature * Active inflammatory bowel disease * Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) * Autoimmune hepatitis * Hepatitis C Virus (HCV) infected subjects receiving or planning on receiving anti-viral therapy during the course of the study * Hepatitis B Virus (HBV) infected subjects who have been on stable anti-HBV therapy for less than 3 months * Hepatocellular carcinoma (HCC) at entry into the study * Active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) * History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QT or QTc interval of \>480 milliseconds (msec) * Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the subject from participating in and completing the study * Any subject that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study * If female, known pregnancy, or has a positive urine or serum pregnancy test, or lactating/breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Venous Pressure Gradient (HVPG) | Baseline to Day 28/EOT (end of treatment) | Mean change of HVPG \[mmHg\] from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
| cCK18/M30 | Change from Baseline to Day 28/EOT | Absolute Mean Change of caspase-cleaved cytokeratin serum levels (cCK18/M30); the statistical analysis is based on the mean change in log-transformed cCK18/M30 from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
| Change in cCK18/M30 | Baseline to Day 28/EOT (end of treatment) | Median change of caspase-cleaved cytokeratin serum levels (cCK18/M30) from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) | Baseline to 28 days/EOT | Median change of ALT from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
| Change in Aspartate Aminotransferase (AST) | Baseline to 28 days/EOT | Median change of AST from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
| Concentration of Caspase 3/7 RLU | Baseline to 28 days/EOT | Median change of concentration of Caspase 3/7 Relative Light Units from Baseline to Day 28/EOT (end of treatment) for IDN-6556 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IDN-6556 IDN-6556 25 mg Dosed twice daily | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | IDN-6556 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Gender Female | 7 Participants |
| Gender Male | 16 Participants |
| Region of Enrollment United States | 23 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
cCK18/M30
Absolute Mean Change of caspase-cleaved cytokeratin serum levels (cCK18/M30); the statistical analysis is based on the mean change in log-transformed cCK18/M30 from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Change from Baseline to Day 28/EOT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDN-6556 - Overall Population | cCK18/M30 | -47.1 U/L | Standard Deviation 122.23 |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | cCK18/M30 | -74.3 U/L | Standard Deviation 99.02 |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | cCK18/M30 | -26.2 U/L | Standard Deviation 137.64 |
Comparison: Statistical Analysis for the mean change in log-transformed caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT for the overall evaluable population treated with IDN-6556 25 mg twice dailyp-value: 0.02695% CI: [-0.42, -0.03]ANCOVA
Comparison: Statistical Analysis for the mean change in log-transformed caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT in the HVPG \< 12 mmHg subgroup population treated with IDN-6556 25 mg twice dailyp-value: 0.00195% CI: [-0.72, -0.21]ANCOVA
Comparison: Statistical Analysis for the median change in log-transformed caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT in the HVPG ≥ 12 mmHg subgroup population treated with IDN-6556 25 mg twice dailyp-value: 0.7295% CI: [-0.26, 0.18]ANCOVA
Primary
Change in cCK18/M30
Median change of caspase-cleaved cytokeratin serum levels (cCK18/M30) from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Baseline to Day 28/EOT (end of treatment)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 - Overall Population | Change in cCK18/M30 | Day 28/EOT | 143.0 U/L |
| IDN-6556 - Overall Population | Change in cCK18/M30 | Baseline | 191.0 U/L |
| IDN-6556 - Overall Population | Change in cCK18/M30 | Change From Baseline at Day 28 | -21.0 U/L |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Change in cCK18/M30 | Day 28/EOT | 124.5 U/L |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Change in cCK18/M30 | Baseline | 189.0 U/L |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Change in cCK18/M30 | Change From Baseline at Day 28 | -52.5 U/L |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Change in cCK18/M30 | Baseline | 221.0 U/L |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Change in cCK18/M30 | Change From Baseline at Day 28 | 12.0 U/L |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Change in cCK18/M30 | Day 28/EOT | 186.0 U/L |
Comparison: Statistical Analysis for the median change of caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT for the overall evaluable population treated with IDN-6556 25 mg twice dailyp-value: 0.10595% CI: [-60, 13]Wilcoxon (Mann-Whitney)
Comparison: Statistical Analysis for the median change of caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT in the HVPG \< 12 mmHg subgroup population treated with IDN-6556 25 mg twice dailyp-value: 0.01695% CI: [-109, -6]Wilcoxon (Mann-Whitney)
Comparison: Statistical Analysis for the median change of caspase-cleaved cytokeratin serum levels from Baseline to Day 28/EOT in the HVPG ≥ 12 mmHg subgroup population treated with IDN-6556 25 mg twice dailyp-value: 0.83995% CI: [-60, 13]Wilcoxon (Mann-Whitney)
Primary
Hepatic Venous Pressure Gradient (HVPG)
Mean change of HVPG \[mmHg\] from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Baseline to Day 28/EOT (end of treatment)
Population: 23 subjects were enrolled, of whom 22 were evaluable for the HVPG endpoint. 1 subject discontinued at day 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IDN-6556 - Overall Population | Hepatic Venous Pressure Gradient (HVPG) | Day 28/EOT | 14.1 mmHg | Standard Deviation 6.4 |
| IDN-6556 - Overall Population | Hepatic Venous Pressure Gradient (HVPG) | Baseline | 15.2 mmHg | Standard Deviation 7.68 |
| IDN-6556 - Overall Population | Hepatic Venous Pressure Gradient (HVPG) | Change From Baseline | -1.14 mmHg | Standard Deviation 4.57 |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Day 28/EOT | 10.0 mmHg | Standard Deviation 3.86 |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Baseline | 8.05 mmHg | Standard Deviation 1.88 |
| IDN-6556 - Subgroup With HVPG < 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Change From Baseline | 1.90 mmHg | Standard Deviation 3.15 |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Baseline | 20.62 mmHg | Standard Deviation 5.59 |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Change From Baseline | -3.67 mmHg | Standard Deviation 4.05 |
| IDN-6556 - Subgroup HVPG ≥ 12 mmHg | Hepatic Venous Pressure Gradient (HVPG) | Day 28/EOT | 17.6 mmHg | Standard Deviation 6.1 |
Comparison: Statistical Analysis for the mean change of the Hepatic Venous Pressure Gradient from Baseline to Day 28/EOT for the overall evaluable population treated with IDN-6556 25 mg twice dailyp-value: 0.25795% CI: [-3.16, 0.89]Paired t-test
Comparison: Statistical Analysis for the mean change of the Hepatic Venous Pressure Gradient from Baseline to Day 28/EOT in the HVPG \< 12 mmHg subgroupp-value: 0.117495% CI: [-0.52, 4.32]ANCOVA
Comparison: Statistical Analysis for the mean change of the Hepatic Venous Pressure Gradient from Baseline to Day 28/EOT in the HVPG ≥ 12 mmHg subgroupp-value: 0.002595% CI: [-5.88, -1.46]ANCOVA
Secondary
Change in Alanine Aminotransferase (ALT)
Median change of ALT from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Baseline to 28 days/EOT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 - Overall Population | Change in Alanine Aminotransferase (ALT) | Baseline | 25.0 U/L |
| IDN-6556 - Overall Population | Change in Alanine Aminotransferase (ALT) | Day 28/EOT | 23.0 U/L |
| IDN-6556 - Overall Population | Change in Alanine Aminotransferase (ALT) | Change from Baseline at Day 28 | -4.0 U/L |
Comparison: Statistical Analysis for the median change in Alanine Aminotransferase (ALT) from Baseline to Day 28/EOTp-value: 0.008495% CI: [-7, 0]Wilcoxon (Mann-Whitney)
Secondary
Change in Aspartate Aminotransferase (AST)
Median change of AST from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Baseline to 28 days/EOT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 - Overall Population | Change in Aspartate Aminotransferase (AST) | Baseline | 35.0 U/L |
| IDN-6556 - Overall Population | Change in Aspartate Aminotransferase (AST) | Day 28/EOT | 27.0 U/L |
| IDN-6556 - Overall Population | Change in Aspartate Aminotransferase (AST) | Change from Baseline at Day 28 | -4.0 U/L |
Comparison: Statistical Analysis for the median change in Aspartate Aminotransferase (AST) from Baseline to Day 28/EOTp-value: 0.013195% CI: [-7, -1]Wilcoxon (Mann-Whitney)
Secondary
Concentration of Caspase 3/7 RLU
Median change of concentration of Caspase 3/7 Relative Light Units from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Time frame: Baseline to 28 days/EOT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 - Overall Population | Concentration of Caspase 3/7 RLU | Baseline | 1997 RLU |
| IDN-6556 - Overall Population | Concentration of Caspase 3/7 RLU | Day 28/EOT | 1518 RLU |
| IDN-6556 - Overall Population | Concentration of Caspase 3/7 RLU | Change from Baseline at Day 28 | -772 RLU |
Comparison: Statistical Analysis for the median change in concentration of Caspase 3/7 Relative Light Units from baseline to Day 28/EOTp-value: 0.00395% CI: [-1188, -19]Wilcoxon (Mann-Whitney)