Fibrosis, Liver, NAFLD - Nonalcoholic Fatty Liver Disease, NASH - Nonalcoholic Steatohepatitis
Conditions
Keywords
Anti-fibrotic
Brief summary
This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects.
Detailed description
This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects. Study will evaluate the safety and tolerability of a once daily 75mg dose and 225mg of CRV431 compared to placebo over 28 days of dosing. Pharmacokinetic parameters of CRV431 and its major metabolites and fraction unbound will also be evaluated. Non-invasive antifibrotic bio-markers will be collected and quantified from presumed NASH F2/F3 subjects dosed with 75mg CRV431 or placebo.
Interventions
DRUGCRV431 75mg
1 x 75mg softgel capsule
DRUGPlacebo (1 softgel)
1 x placebo softgel capsule
DRUGCRV431 225mg
3 x 75mg softgel capsule
DRUGPlacebo (3 softgels)
3 x placebo softgel capsule
Sponsors
Hepion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
placebo-controlled
Intervention model description
Randomized, multi-center, single-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female between 18 and 75 years of age (inclusive). * Capable of giving written informed consent and able to effectively communicate with the investigator and study personnel. * Presumed F2/F3 NASH to include: AST \>20 IU/L, Pro-C3 \>15.5 ng/mL, enhanced liver fibrosis (ELF) score \>9.8, and FibroScan \>8.5 kPa values. Key
Exclusion criteria
* Pregnant or breastfeeding or planning to become pregnant during the study period. * Known allergy to CRV431, cyclosporine, or any of their inactive ingredients. * Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus antibodies (HIVAb). * Well documented causes of chronic liver disease according to standard diagnostic procedures to include any history or presence of decompensated cirrhosis. * Subjects with a platelet count \<150,000/mL. * Subjects with hemoglobin A1c(HbA1c) \>9.5%. * Weight loss of more than 5% within 3 months prior to randomization. * Subjects with a blood pressure to include a systolic pressure \>150 or a diastolic pressure \>90. * At Screening, an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 mL (calculated by the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] method) and/or a Kidney Disease Improving Global Outcomes (KDIGO) category of \>G2. * Subjects with a history of organ transplantation. Corneal transplantation will be allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Time from informed consent to study day 42. | Number of adverse events, serious adverse events, and clinical laboratory abnormalities. |
| Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | Day 1 and Day 28 | The Tmax value is defined as time to reach maximum whole blood concentration. Each value is a median for the cohort along with the standard deviation presented in hours for Day 1 and Day 28. |
| Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | Day 1 and Day 28 | The Cmax value is defined as the maximum whole blood concentration presented as ng/mL. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28. |
| AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | Timepoints for data collection include 0, 2.0 hours, 4.0 hours, 8 hours on both Day 1 and Day 28. | The AUC 0-last value is defined as the area under the whole blood concentration time curve from time 0 to the time of the last measurable concentration. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CRV431 75mg CRV431, softgel capsule, 75mg, QD, 28 days, fasted conditions
CRV431 75mg: 1 x 75mg softgel capsule | 15 |
| Placebo, 75mg Placebo, softgel capsule, QD, 28 days, fasted conditions
Placebo (1 softgel): 1 x placebo softgel capsule | 6 |
| CRV431 225mg CRV431, softgel capsule, 225mg, QD, 28 days, fasted conditions
CRV431 225mg: 3 x 75mg softgel capsule | 17 |
| Placebo, 225mg CRV431, 3 softgel capsules, 225mg, QD, 28 days, fasted conditions
Placebo (3 softgels): 3 x placebo softgel capsule | 9 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo, 225mg | CRV431 75mg | CRV431 225mg | Placebo, 75mg |
|---|---|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 11.94 | 61.1 years STANDARD_DEVIATION 13.8 | 59.1 years STANDARD_DEVIATION 9.9 | 54 years STANDARD_DEVIATION 13.3 | 61.8 years STANDARD_DEVIATION 8.7 |
| ALT | 51.46 IU/mL STANDARD_DEVIATION 32.18 | 52.9 IU/mL STANDARD_DEVIATION 35.6 | 62.5 IU/mL STANDARD_DEVIATION 42.1 | 39.3 IU/mL STANDARD_DEVIATION 18.4 | 75.8 IU/mL STANDARD_DEVIATION 36.8 |
| AST | 43.83 IU/mL STANDARD_DEVIATION 27.71 | 44.7 IU/mL STANDARD_DEVIATION 36 | 51.9 IU/mL STANDARD_DEVIATION 35.3 | 33.1 IU/mL STANDARD_DEVIATION 14.3 | 70.2 IU/mL STANDARD_DEVIATION 40.1 |
| BMI | 37.57 kg/m^2 STANDARD_DEVIATION 7.82 | 39.2 kg/m^2 STANDARD_DEVIATION 10.6 | 37.1 kg/m^2 STANDARD_DEVIATION 8.5 | 37.7 kg/m^2 STANDARD_DEVIATION 6.4 | 36.1 kg/m^2 STANDARD_DEVIATION 6.5 |
| ELF Score | 10.0 units on a scale STANDARD_DEVIATION 0.74 | 9.7 units on a scale STANDARD_DEVIATION 1 | 10.3 units on a scale STANDARD_DEVIATION 0.8 | 9.8 units on a scale STANDARD_DEVIATION 0.9 | 10.1 units on a scale STANDARD_DEVIATION 0.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 6 Participants | 6 Participants | 10 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 3 Participants | 9 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Pro-C3 | 22.70 ng/mL STANDARD_DEVIATION 12.44 | 18.56 ng/mL STANDARD_DEVIATION 5.84 | 23.15 ng/mL STANDARD_DEVIATION 6.88 | 19.94 ng/mL STANDARD_DEVIATION 9.07 | 23.19 ng/mL STANDARD_DEVIATION 10.55 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 45 Participants | 9 Participants | 14 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Female | 23 Participants | 2 Participants | 8 Participants | 10 Participants | 3 Participants |
| Sex: Female, Male Male | 24 Participants | 7 Participants | 7 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 6 | 0 / 17 | 0 / 9 |
| other Total, other adverse events | 5 / 15 | 3 / 6 | 10 / 17 | 3 / 9 |
| serious Total, serious adverse events | 0 / 15 | 0 / 6 | 0 / 17 | 0 / 9 |
Outcome results
Primary
AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects.
The AUC 0-last value is defined as the area under the whole blood concentration time curve from time 0 to the time of the last measurable concentration. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28.
Time frame: Timepoints for data collection include 0, 2.0 hours, 4.0 hours, 8 hours on both Day 1 and Day 28.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo, 75mg | AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 2251.32 h*ng/mL | Standard Deviation 1054.2 |
| CRV431 75mg | AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 8851.96 h*ng/mL | Standard Deviation 2132.29 |
| Placebo, 225mg | AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 6348.85 h*ng/mL | Standard Deviation 2819.58 |
| CRV431 225mg | AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 13784.34 h*ng/mL | Standard Deviation 4656.34 |
Primary
Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects.
The Cmax value is defined as the maximum whole blood concentration presented as ng/mL. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28.
Time frame: Day 1 and Day 28
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo, 75mg | Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 347.24 ng/mL | Standard Deviation 168.26 |
| CRV431 75mg | Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 1147.31 ng/mL | Standard Deviation 389.09 |
| Placebo, 225mg | Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 1218.88 ng/mL | Standard Deviation 302.25 |
| CRV431 225mg | Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 1876.9 ng/mL | Standard Deviation 118.19 |
Primary
Number of Safety and Tolerability Events of CRV431 Versus Placebo.
Number of adverse events, serious adverse events, and clinical laboratory abnormalities.
Time frame: Time from informed consent to study day 42.
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Severe Grade 3 | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Moderate Grade2 | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events leading to study withdrawl | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-probably related | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-possibly related | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-unrelated | 4 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Grade 4 | 0 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Mild Grade 1 | 4 Number of treatment emergent AE |
| Placebo, 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events | 4 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Mild Grade 1 | 3 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Severe Grade 3 | 0 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Moderate Grade2 | 5 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-unrelated | 6 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events | 8 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-possibly related | 0 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events leading to study withdrawl | 1 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Grade 4 | 0 Number of treatment emergent AE |
| CRV431 75mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-probably related | 2 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Mild Grade 1 | 2 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events | 3 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-unrelated | 2 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-possibly related | 1 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-probably related | 0 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Moderate Grade2 | 1 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Severe Grade 3 | 0 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Grade 4 | 0 Number of treatment emergent AE |
| Placebo, 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events leading to study withdrawl | 0 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Severe Grade 3 | 1 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-probably related | 7 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-possibly related | 1 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events leading to study withdrawl | 0 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Grade 4 | 0 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Relationship-unrelated | 13 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Moderate Grade2 | 4 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Severity-Mild Grade 1 | 16 Number of treatment emergent AE |
| CRV431 225mg | Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of Treatment Emergent Adverse Events | 21 Number of treatment emergent AE |
Primary
Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects.
The Tmax value is defined as time to reach maximum whole blood concentration. Each value is a median for the cohort along with the standard deviation presented in hours for Day 1 and Day 28.
Time frame: Day 1 and Day 28
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo, 75mg | Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 4.41 hours | Standard Deviation 1.6 |
| CRV431 75mg | Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 4 hours | Standard Deviation 2.05 |
| Placebo, 225mg | Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 2.59 hours | Standard Deviation 1.54 |
| CRV431 225mg | Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | 2 hours | Standard Deviation 0.73 |