Non-alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Keywords
NAFLD, NASH
Brief summary
The purpose of this study is to determine the safety and efficacy of IDN-6556 compared to placebo in patients with diagnosed fat deposits in their liver (not caused by alcohol) and with abnormal liver tests
Detailed description
This is a double-blind, randomized study to evaluate the effects of IDN-6556 on serum transaminases and pharmacodynamics of IDN-6556 in subjects with non-alcoholic fatty liver disease with elevated alanine aminotransferase.
Interventions
DRUGIDN-6556
25 mg BID for 28 days
OTHERPlacebo
Placebo BID for 28 Days
Sponsors
Conatus Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
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 understand and comply with the requirements of the study * Diagnosis of non-alcoholic fatty liver disease (NAFLD) as evidenced by imaging or other diagnostic assessments * Alanine aminotransferase (ALT) levels ≥1.5 x ULN on at least two occasions, seven or more days apart, during the Screening period * alpha-fetoprotein (AFP) ≤ 100 ng/mL * Hemoglobin ≥10 g/dL, a platelet count ≥ 100 x 10\^9/L, and a white blood cell count ≥ 3.0 x 10\^9/L * If on metformin, sulfonylureas, statins, or fibrates, subjects must be on a stable dose of these drugs for at least three months prior to Screening and during the study
Exclusion criteria
* Known infection with HIV, HCV, or HBV * Decompensated or severe liver disease as evidenced by one or more of the following: 1. Confirmed cirrhosis or suspicion of cirrhosis 2. Esophageal varices 3. Ascites 4. Suspicion of portal hypertension 5. Hospitalization for liver disease within 60 days of screening 6. Bilirubin \>2 x ULN, or ALT or AST \> 10 x ULN * Inflammatory bowel disease * Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) * Hepatocellular carcinoma (HCC) at entry into the study * History of or active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) * Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal insufficiency, and/or serious psychiatric disease, that, in the opinion of the Investigator would preclude the subject from participating in and completing the study * History or presence of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (the equivalent of 14 4-ounce glasses of wine or 14 12-ounce cans/bottles of beer or wine coolers), or other substance abuse within the prior two years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) | Day 28/ET | Mean change in alanine aminotransferase (ALT) from Baseline to Day 28/ET between IDN-6556 vs Placebo |
| Relative Percent Change in Alanine Aminotransferase (ALT) | Baseline to Day 28/ET | Back transformation from log-transformed analysis results to original scale in alanine aminotransferase (ALT) from Baseline to Day 28/ET between IDN-6556 vs Placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Aspartate Aminotransferase (AST) | Day 28/ET | Difference in the change in aspartate aminotransferase (AST) from Baseline to Day 28/ET in units per liter (U/L) between IDN-6556 and placebo. |
| Levels of cCK18/M30 | Day 28/ET | Difference in the change in Caspase-cleaved cytokeratin serum levels (cCK18/M30) in units per liter (U/L) from baseline to Day 28/ET between IDN-6556 and placebo |
| Levels of Caspase 3/7 RLU | Day 28/ET | Difference in the change of caspase 3/7 (Relative Light Units) from baseline to Day 28/ET between IDN-6556 and Placebo |
| Levels of flCK18/M65 | Day 28/ET | Difference in the change in full-length cytokeratin 18 (flCK18/M65) in units per liter (U/L) from Baseline to Day 28/ET between IDN-6556 and placebo |
Countries
United States
Participant flow
Recruitment details
In total, 71 subjects were screened at 7 sites, and 38 subjects were randomized and treated to a BID treatment with either placebo or IDN-6556 25 mg with 19 subjects in each arm.
Pre-assignment details
38 subjects were randomized and treated (19 each arm). 2 subjects on placebo discontinued before Day 28 and 1 discontinued after Day 28, but returned for their Day 56 visit, so 17 subjects completed the study. However, all 38 were included in the analyses using the last results provided for the 2 subjects at early termination.
Participants by arm
| Arm | Count |
|---|---|
| IDN-6556 IDN-6556 capsules, 25 mg
IDN-6556: 25 mg BID for 28 days | 19 |
| Placebo Placebo
Matching Placebo BID for 28 days | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | IDN-6556 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 17 Participants | 33 Participants |
| Age, Continuous | 55 years | 46 years | 52 years |
| Region of Enrollment United States | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 19 | 8 / 19 |
| serious Total, serious adverse events | 1 / 19 | 1 / 19 |
Outcome results
Primary
Change in Alanine Aminotransferase (ALT)
Mean change in alanine aminotransferase (ALT) from Baseline to Day 28/ET between IDN-6556 vs Placebo
Time frame: Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDN-6556 | Change in Alanine Aminotransferase (ALT) | -37.8 U/L | Standard Deviation 42.7 |
| Placebo | Change in Alanine Aminotransferase (ALT) | -14.9 U/L | Standard Deviation 22.5 |
Comparison: Statistical Analysis for the difference in mean change in alanine aminotransferase (ALT) from Baseline to Day28/ET between IDN-6556 and placebop-value: 0.019595% CI: [-30.7, -2.5]Wilcoxon (Mann-Whitney)
Primary
Relative Percent Change in Alanine Aminotransferase (ALT)
Back transformation from log-transformed analysis results to original scale in alanine aminotransferase (ALT) from Baseline to Day 28/ET between IDN-6556 vs Placebo
Time frame: Baseline to Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDN-6556 | Relative Percent Change in Alanine Aminotransferase (ALT) | -39.2 Relative percent change | Standard Deviation 26.2 |
| Placebo | Relative Percent Change in Alanine Aminotransferase (ALT) | -13.9 Relative percent change | Standard Deviation 21.8 |
Secondary
Change in Aspartate Aminotransferase (AST)
Difference in the change in aspartate aminotransferase (AST) from Baseline to Day 28/ET in units per liter (U/L) between IDN-6556 and placebo.
Time frame: Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IDN-6556 | Change in Aspartate Aminotransferase (AST) | -6.7 U/L |
| Placebo | Change in Aspartate Aminotransferase (AST) | -5.2 U/L |
Comparison: Statistical Analysis for the difference in change in aspartate aminotransferase (AST) from baseline to Day 28/ET between IDN-6556 and placebop-value: 0.872495% CI: [-14.5, 11.2]Wilcoxon (Mann-Whitney)
Secondary
Levels of Caspase 3/7 RLU
Difference in the change of caspase 3/7 (Relative Light Units) from baseline to Day 28/ET between IDN-6556 and Placebo
Time frame: Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IDN-6556 | Levels of Caspase 3/7 RLU | -287.0 RLU |
| Placebo | Levels of Caspase 3/7 RLU | 68.0 RLU |
Comparison: Statistical Analysis for the difference in change for caspase 3/7 from Baseline to Day 28/ET between IDN-6556 and Placebop-value: 0.136595% CI: [-590, 63]Wilcoxon (Mann-Whitney)
Secondary
Levels of cCK18/M30
Difference in the change in Caspase-cleaved cytokeratin serum levels (cCK18/M30) in units per liter (U/L) from baseline to Day 28/ET between IDN-6556 and placebo
Time frame: Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IDN-6556 | Levels of cCK18/M30 | -183.0 U/L |
| Placebo | Levels of cCK18/M30 | 14.0 U/L |
Comparison: Statistical Analysis for the difference in change for cCK18/M30 from Baseline to Day 28/ET between IDN-6556 and Placebop-value: 0.114995% CI: [-336, 55]Wilcoxon (Mann-Whitney)
Secondary
Levels of flCK18/M65
Difference in the change in full-length cytokeratin 18 (flCK18/M65) in units per liter (U/L) from Baseline to Day 28/ET between IDN-6556 and placebo
Time frame: Day 28/ET
Population: The full analysis set (FAS) included all subjects who were randomized and received at least one dose of study drug. For the FAS, subjects were assigned to the treatment group based on the randomization schedule, regardless of the treatment they actually received. All efficacy analyses were conducted on the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IDN-6556 | Levels of flCK18/M65 | -296.0 U/L |
| Placebo | Levels of flCK18/M65 | 4.0 U/L |
Comparison: Statistical Analysis of the difference in the change in full-length cytokeratine 18 (flCK18/M65) from Baseline to Day 28/ET between IDN-6556 and placebop-value: 0.047195% CI: [-628, -7]Wilcoxon (Mann-Whitney)