Nonalcoholic Steatohepatitis (NASH), Nonalcoholic Fatty Liver Disease (NAFLD)
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of selonsertib, firsocostat, cilofexor, fenofibrate and/or Vascepa® in adults with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
Interventions
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cohorts 1-6 and 9 will be enrolled sequentially while Cohorts 7 and 8 will be randomized in parallel. Cohorts 10 and 11 will be randomized in parallel. Cohorts 12 and 13 will be randomized in parallel.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Males and females between 18-75 years of age (Cohorts 1-9: 18-75 years and Cohorts 10-13: ≥ 18 years); inclusive based on the date of the screening visit * Willing and able to provide informed consent prior to any study specific procedures being performed * For Cohorts 1 through 6 and 9, individuals must meet the following conditions: * Clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) * Screening FibroTest® \< 0.75, unless a historical liver biopsy within 12 months of Screening does not reveal cirrhosis. In individuals with Gilbert's syndrome or hemolysis, FibroTest® will be calculated using direct bilirubin instead of total bilirubin, * Screening magnetic resonance imaging - proton density fat fraction (MRI-PDFF) with ≥ 10% steatosis, * Screening magnetic resonance elastography (MRE) with liver stiffness ≥ 2.88 kPa, OR * A historical liver biopsy within 12 months of Screening consistent with NASH (defined as the presence of steatosis, inflammation, and ballooning) with stage 2-3 fibrosis according to the NASH Clinical Research Network (CRN) classification (or equivalent), AND * No documented weight loss \> 5% between the date of the liver biopsy and Screening; * For Cohorts 7 and 8, individuals must have a clinical diagnosis of NAFLD and have at least one of the following criteria: * Screening MRE with liver stiffness ≥ 4.67 kPa, * A historical FibroScan® ≥ 14 kPa within 6 months of Screening, * Screening FibroTest® ≥ 0.75, * A historical liver biopsy consistent with stage 4 fibrosis according to the NASH CRN classification (or equivalent); * For Cohorts 10 and 11, individuals must have a clinical diagnosis of NAFLD and meet at least two criteria for metabolic syndrome modified from the NCEP ATP III Guidelines and one of the following criteria at Screening: * A historical liver biopsy within 6 months of Screening consistent with NASH and bridging fibrosis (F3) or within 12 months of Screening consistent with NASH and compensated cirrhosis (F4) in the opinion of the investigator, * Screening liver stiffness by MRE ≥ 3.64 kPa; * Screening liver stiffness by FibroScan® ≥ 9.9 kPa; * For Cohorts 12 and 13, individuals must have a clinical diagnosis of NAFLD/NASH and at least two criteria for metabolic syndrome as modified from the NCEPT ATP III Guidelines, OR one of the following criteria: * A historical liver biopsy within 6 months of Screening consistent with NASH for individuals without compensated cirrhosis (F4); or within 12 months of Screening consistent with NASH for individuals with compensated cirrhosis (F4) in the opinion of the investigator, * A historical MRE with liver stiffness ≥ 2.88 kPa within 6 months of Screening, * A historical FibroScan® with liver stiffness ≥ 9.9 kPa within 6 months of Screening, AND * No documented weight loss \> 5% between the date of the historical liver biopsy, historical MRE, or historical FibroScan® and Screening; * Platelet count ≥ 100,000/µL; * Serum creatinine \< 2 mg/dL (Cohorts 1-9) at Screening; * Estimated glomerular filtration rate (eGFR) ≥ 80 mL/min (Cohorts 10-11) or ≥ 60 mL/min (Cohorts 12-13), as calculated by the Cockcroft-Gault equation at Screening; * For Cohorts 10-13, serum triglyceride level ≥ 150 mg/dL at Screening. Key
Exclusion criteria
* Pregnant or lactating females * Other causes of liver disease including autoimmune, viral, and alcoholic liver disease * Any history of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding * For Cohorts 7-8, 10-13, Child-Pugh-Turcotte (CPT) score \> 6 * History of liver transplantation * History of hepatocellular carcinoma; * Weight reduction surgery in the past 2 years or planned during the study; * Documented weight loss \> 5% between the date of the historical liver biopsy and Screening, if applicable; * Body Mass Index (BMI) \< 18 kg/m2; * ALT \> 5 x ULN at Screening; * For Cohorts 10-13, HbA1c ≥ 9.5% (or serum fructosamine ≥ 381 µmol if HbA1c is unable to be resulted) at Screening; * For Cohorts 10-13, hemoglobin ≤ 10.6 g/dL at Screening; * INR \> 1.2 (Cohorts 1-9) or INR \> 1.4 (Cohorts 10-13) at Screening, unless on anticoagulation therapy; * Total bilirubin \> 1x ULN (Cohorts 1 through 6 and 9), \>1.5 x ULN (Cohorts 7 and 8), or \>1.3 x ULN (Cohorts 10-13) except in confirmed cases of Gilbert's syndrome; * Triglycerides ≥ 500 mg/dL (Cohorts 5-8 and 10-13) or ≥ 250 mg/dL (Cohort 9) at Screening; * Model for End-Stage Liver Disease (MELD) score \> 12 at Screening (Cohorts 10 -13), unless due to an alternate etiology such as therapeutic anticoagulation; * Chronic hepatitis B (HBsAg positive); * Chronic hepatitis C (HCV RNA positive). individuals cured of HCV infection less than 2 years prior to the Screening visit are not eligible (Cohorts 10-13); * HIV Ab positive; * Presence of gallstones within 6 months of Screening (Cohorts 10-13); * Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30 mL of alcohol is present in 1 12oz/360 mL beer, 1 4oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40% proof alcohol); * Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at Screening. Individuals on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Individuals with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator; * Unstable cardiovascular disease; * History of intestinal resection of the extent that would result in malabsorption; * Use of any prohibited concomitant medications as described in the protocol; * History of a malignancy within 5 years of Screening with the following exceptions: * Adequately treated carcinoma in situ of the cervix, * Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. | Treatment-emergent AEs were defined as events that met 1 or both of the following criteria: * Any AEs with onset dates on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug * Any AEs leading to premature discontinuation of study drug |
| Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. | A treatment emergent serious adverse event (SAE) was defined as an event that, at any dose, results in the following: * Death * Life-threatening * In-patient hospitalization or prolongation of existing hospitalization * Persistent or significant disability/incapacity * A congenital anomaly/birth defect * A medically important event or reaction |
| Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If baseline laboratory data were missing, then any abnormality of at least Grade 1 was considered treatment emergent. Graded laboratory abnormalities were defined using the grading scheme in the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for Cohorts 1-9 and CTCAE Version 5.0 for Cohorts 10-13. |
Countries
New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled in study sites in the United States and New Zealand. The first participant was screened on 13 June 2016. The last study visit occurred on 17 December 2020.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: SEL 18 mg (Non-cirrhotic) Non-cirrhotic participants received SEL 18 mg tablet orally once daily for 12 weeks | 10 |
| Cohort 2: FIR 20 mg (Non-cirrhotic) Non-cirrhotic participants received FIR 20 mg tablet orally once daily for 12 weeks | 10 |
| Cohort 3: CILO 30 mg (Non-cirrhotic) Non-cirrhotic participants received CILO 30 mg tablet once daily for 12 weeks | 10 |
| Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) Non-cirrhotic participants received SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks | 20 |
| Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) Non-cirrhotic participants received SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks | 20 |
| Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) Non-cirrhotic participants received CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks | 20 |
| Cohort 7: CILO 20 mg (Cirrhotic) Participants with Child-Pugh-Turcotte Class A cirrhosis received FIR 20 mg tablet once daily for 12 weeks | 10 |
| Cohort 8: CILO 30 mg (Cirrhotic) Participants with Child-Pugh-Turcotte Class A cirrhosis received CILO 30 mg tablet once daily for 12 weeks | 10 |
| Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) Non-cirrhotic participants received SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks | 13 |
| Cohort 10: FIR 20 mg + FENO 48 mg Participants received FENO 48 mg tablet orally for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 48 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH were accepted to participate in this cohort. | 15 |
| Cohort 11: FIR 20 mg + FENO 145 mg Participants received FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 145 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH were accepted to participate in this cohort. | 16 |
| Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g Participants received VAS 2 g capsule orally twice daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + VAS 2 g capsule twice daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH were accepted to participate in this cohort. | 30 |
| Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg Participants received FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + FENO 145 mg tablet orally once daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH were accepted to participate in this cohort. | 32 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre-treatment Phase | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Pre-treatment Phase | Investigator's Discretion | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Treatment Phase | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Phase | Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g | Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg | Total | Cohort 1: SEL 18 mg (Non-cirrhotic) | Cohort 2: FIR 20 mg (Non-cirrhotic) | Cohort 3: CILO 30 mg (Non-cirrhotic) | Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) | Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) | Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) | Cohort 7: CILO 20 mg (Cirrhotic) | Cohort 8: CILO 30 mg (Cirrhotic) | Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) | Cohort 10: FIR 20 mg + FENO 48 mg | Cohort 11: FIR 20 mg + FENO 145 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 11.1 | 52 years STANDARD_DEVIATION 11.5 | 55 years STANDARD_DEVIATION 11.1 | 54 years STANDARD_DEVIATION 7 | 57 years STANDARD_DEVIATION 9.8 | 53 years STANDARD_DEVIATION 12.3 | 56 years STANDARD_DEVIATION 7.8 | 48 years STANDARD_DEVIATION 13.8 | 55 years STANDARD_DEVIATION 10.7 | 60 years STANDARD_DEVIATION 11.1 | 60 years STANDARD_DEVIATION 9.5 | 56 years STANDARD_DEVIATION 8.2 | 59 years STANDARD_DEVIATION 9.7 | 52 years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 17 Participants | 115 Participants | 8 Participants | 9 Participants | 8 Participants | 12 Participants | 5 Participants | 11 Participants | 6 Participants | 3 Participants | 9 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 15 Participants | 101 Participants | 2 Participants | 1 Participants | 2 Participants | 8 Participants | 15 Participants | 9 Participants | 4 Participants | 7 Participants | 4 Participants | 13 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 30 Participants | 205 Participants | 10 Participants | 10 Participants | 10 Participants | 19 Participants | 17 Participants | 17 Participants | 10 Participants | 10 Participants | 12 Participants | 14 Participants | 16 Participants |
| Region of Enrollment New Zealand | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 30 Participants | 32 Participants | 209 Participants | 10 Participants | 10 Participants | 10 Participants | 20 Participants | 17 Participants | 17 Participants | 10 Participants | 10 Participants | 12 Participants | 15 Participants | 16 Participants |
| Sex: Female, Male Female | 24 Participants | 22 Participants | 148 Participants | 9 Participants | 5 Participants | 9 Participants | 13 Participants | 11 Participants | 12 Participants | 7 Participants | 6 Participants | 11 Participants | 10 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 68 Participants | 1 Participants | 5 Participants | 1 Participants | 7 Participants | 9 Participants | 8 Participants | 3 Participants | 4 Participants | 2 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 10 | 0 / 10 | 0 / 13 | 0 / 15 | 0 / 16 | 0 / 30 | 0 / 32 |
| other Total, other adverse events | 5 / 10 | 6 / 10 | 5 / 10 | 5 / 20 | 8 / 20 | 10 / 20 | 8 / 10 | 7 / 10 | 10 / 13 | 13 / 15 | 14 / 16 | 7 / 30 | 9 / 32 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 1 / 20 | 1 / 20 | 1 / 20 | 1 / 10 | 0 / 10 | 1 / 13 | 0 / 15 | 0 / 16 | 1 / 30 | 1 / 32 |
Outcome results
Primary
Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If baseline laboratory data were missing, then any abnormality of at least Grade 1 was considered treatment emergent. Graded laboratory abnormalities were defined using the grading scheme in the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for Cohorts 1-9 and CTCAE Version 5.0 for Cohorts 10-13.
Time frame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Population: The Safety Analysis Set included all participants who were administered at least 1 dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: SEL 18 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 20 percentage of participants |
| Cohort 2: FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 20 percentage of participants |
| Cohort 3: CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 40 percentage of participants |
| Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 10 percentage of participants |
| Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 20 percentage of participants |
| Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 10 percentage of participants |
| Cohort 7: CILO 20 mg (Cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 40 percentage of participants |
| Cohort 8: CILO 30 mg (Cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 30 percentage of participants |
| Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 15.4 percentage of participants |
| Cohort 10: FIR 20 mg + FENO 48 mg | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 6.7 percentage of participants |
| Cohort 11: FIR 20 mg + FENO 145 mg | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 12.5 percentage of participants |
| Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 6.7 percentage of participants |
| Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg | Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | 6.3 percentage of participants |
Primary
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Treatment-emergent AEs were defined as events that met 1 or both of the following criteria: * Any AEs with onset dates on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug * Any AEs leading to premature discontinuation of study drug
Time frame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Population: The Safety Analysis Set included all participants who were administered at least 1 dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: SEL 18 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 50 percentage of participants |
| Cohort 2: FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 60 percentage of participants |
| Cohort 3: CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 50 percentage of participants |
| Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 25 percentage of participants |
| Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 40 percentage of participants |
| Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 50 percentage of participants |
| Cohort 7: CILO 20 mg (Cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 80 percentage of participants |
| Cohort 8: CILO 30 mg (Cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 70 percentage of participants |
| Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 76.92 percentage of participants |
| Cohort 10: FIR 20 mg + FENO 48 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 86.67 percentage of participants |
| Cohort 11: FIR 20 mg + FENO 145 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 87.5 percentage of participants |
| Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 40 percentage of participants |
| Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 37.5 percentage of participants |
Primary
Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events
A treatment emergent serious adverse event (SAE) was defined as an event that, at any dose, results in the following: * Death * Life-threatening * In-patient hospitalization or prolongation of existing hospitalization * Persistent or significant disability/incapacity * A congenital anomaly/birth defect * A medically important event or reaction
Time frame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Population: The Safety Analysis Set included all participants who were administered at least 1 dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: SEL 18 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 2: FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 3: CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 5 percentage of participants |
| Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 5 percentage of participants |
| Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 5 percentage of participants |
| Cohort 7: CILO 20 mg (Cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 10 percentage of participants |
| Cohort 8: CILO 30 mg (Cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 7.69 percentage of participants |
| Cohort 10: FIR 20 mg + FENO 48 mg | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 11: FIR 20 mg + FENO 145 mg | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 0 percentage of participants |
| Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 3.33 percentage of participants |
| Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg | Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | 3.12 percentage of participants |