Non Alcoholic Steatohepatitis (NASH)
Conditions
Keywords
NASH, Non alcoholic steatohepatitis, Tropifexor, LJN452, Licogliflozin, LIK066, Placebo
Brief summary
Randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor & licogliflozin combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.
Detailed description
The study consisted of 1) a screening period, 2) a treatment period starting from randomization on Day 0 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of study treatment. The study duration from first dose of study medication was 52 weeks.
Interventions
DRUGTropifexor
100mcg+30mcg+10mcg capsules of tropifexor taken orally every day until the 140 mcg capsule of tropifexor taken orally every day is produced, then patients will switch to the single 140mcg capsule taken orally every day
DRUGLicogliflozin
30mg tablet of licoglifozin taken orally every day
OTHERPlacebo
licogliflozin placebo + tropifexor placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
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
Presence of NASH with fibrosis confirmed by central reader's evaluation of liver biopsy obtained no more than 6 months before randomization as demonstrated by the following: 1. NASH using NAFLD Activity Score (NAS) ≥ 4 with at least 1 point each in inflammation and ballooning and 2. Fibrosis stage 2 or 3 using NASH CRN fibrosis criteria
Exclusion criteria
* Type 1 diabetes mellitus * Uncontrolled type 2 diabetes defined as glycated hemoglobin (HbA1c) ≥ 9.0% at screening * HbA1c \< 6.5% at screening in Type 2 diabetics currently treated with insulin or sulfonylureas * Clinical evidence of liver impairment as defined by the presence of any of the following abnormalities: * Platelet count \< LLN (see Central laboratory manual). * Serum albumin \< LLN (see Central laboratory manual). * International Normalized Ratio (INR) \> ULN (see Central laboratory manual). * ALT or AST \> 5× ULN (confirmed by 2 values during screening). * Total bilirubin \> ULN (see Central laboratory manual) (confirmed by 2 values during screening), including Gilbert's syndrome. * Alkaline phosphatase \> 300 IU/L (confirmed by 2 values during screening). * History of esophageal varices, ascites or hepatic encephalopathy * Splenomegaly * MELD score \>12
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | Baseline, Week 48 | Response was defined as at least a one-stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH) Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. |
| Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | 48 weeks | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | Baseline, Week 48 | Change in liver fat content based on MRI-PDFF. |
| Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | 48 weeks | Fibrosis staging and Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. |
| Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | Baseline, Week 48 | Whether the participants had 5% or more reduction in body weight. |
| Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | 48 weeks | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. |
| Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. |
| Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. |
| Change From Baseline in Alanine Transaminase (ALT) Over Time | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. |
| Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | 48 weeks | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Denmark, Estonia, Germany, India, Italy, Japan, Mexico, Puerto Rico, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
234 participants were randomized at 81 sites.
Pre-assignment details
One of the randomized participants in the tropifexor group was not treated due to loss of interest in the study.
Participants by arm
| Arm | Count |
|---|---|
| Tropifexor Monotherapy Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally | 53 |
| Licogliflozin Monotherapy Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally | 55 |
| Combination Therapy Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally | 84 |
| Placebo Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily | 41 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 10 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 | 2 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Study terminated by Sponsor | 22 | 16 | 28 | 17 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Tropifexor Monotherapy | Licogliflozin Monotherapy | Combination Therapy |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 47 Participants | 11 Participants | 16 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 186 Participants | 42 Participants | 39 Participants | 70 Participants |
| Age, Continuous | 54.9 Years STANDARD_DEVIATION 10.22 | 55.0 Years STANDARD_DEVIATION 11.05 | 54.5 Years STANDARD_DEVIATION 11.09 | 56.0 Years STANDARD_DEVIATION 12.13 | 54.7 Years STANDARD_DEVIATION 10.82 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 8 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 41 Participants | 9 Participants | 10 Participants | 17 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 7 Participants | 0 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 32 Participants | 174 Participants | 39 Participants | 40 Participants | 63 Participants |
| Sex: Female, Male Female | 26 Participants | 129 Participants | 26 Participants | 34 Participants | 43 Participants |
| Sex: Female, Male Male | 15 Participants | 104 Participants | 27 Participants | 21 Participants | 41 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 55 | 0 / 84 | 0 / 41 | 0 / 233 |
| other Total, other adverse events | 35 / 53 | 39 / 55 | 54 / 84 | 23 / 41 | 151 / 233 |
| serious Total, serious adverse events | 4 / 53 | 3 / 55 | 4 / 84 | 3 / 41 | 14 / 233 |
Outcome results
Primary
Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline
Response was defined as at least a one-stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH) Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Time frame: Baseline, Week 48
Population: Full Analysis Set (FAS): all participants to whom study treatment has been assigned by randomization and had an assessment of response at Week 48. Efficacy analysis was conducted using the FAS.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | 6 Participants |
| Licogliflozin Monotherapy | Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | 9 Participants |
| Combination Therapy | Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | 10 Participants |
| Placebo | Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | 4 Participants |
Primary
Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis
Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Time frame: 48 weeks
Population: Full Analysis Set (FAS): all participants to whom study treatment has been assigned by randomization. Efficacy analysis was conducted using the FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | 5 Participants |
| Licogliflozin Monotherapy | Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | 3 Participants |
| Combination Therapy | Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | 10 Participants |
| Placebo | Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | 2 Participants |
Secondary
Change From Baseline in Alanine Transaminase (ALT) Over Time
To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.
Time frame: Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)
Population: The safety analysis set included all participants who received at least one dose of study treatment. At each time point, only participants with a value at both Baseline and that time point were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 2 | -17.4 units per liter (U/L) | Standard Deviation 28.3 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 12 | -13.8 units per liter (U/L) | Standard Deviation 28.48 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 32 | -18.2 units per liter (U/L) | Standard Deviation 30.97 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 4 | -16.1 units per liter (U/L) | Standard Deviation 18.41 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 24 | -15.1 units per liter (U/L) | Standard Deviation 28.34 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 16 | -15.4 units per liter (U/L) | Standard Deviation 26.94 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 8 | -9.9 units per liter (U/L) | Standard Deviation 20.02 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Follow-up | -1.5 units per liter (U/L) | Standard Deviation 37.77 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 48 | -11.7 units per liter (U/L) | Standard Deviation 49.32 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 20 | -14.5 units per liter (U/L) | Standard Deviation 27.92 |
| Tropifexor Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 40 | -12.7 units per liter (U/L) | Standard Deviation 39.35 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 20 | -14.6 units per liter (U/L) | Standard Deviation 24.96 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 40 | -15.2 units per liter (U/L) | Standard Deviation 26.91 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 24 | -17.0 units per liter (U/L) | Standard Deviation 22.43 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 32 | -13.0 units per liter (U/L) | Standard Deviation 28.01 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 8 | -7.9 units per liter (U/L) | Standard Deviation 19.82 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Follow-up | -9.4 units per liter (U/L) | Standard Deviation 27.94 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 12 | -11.3 units per liter (U/L) | Standard Deviation 16.57 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 48 | -12.0 units per liter (U/L) | Standard Deviation 28.99 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 16 | -12.4 units per liter (U/L) | Standard Deviation 20.38 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 4 | -4.2 units per liter (U/L) | Standard Deviation 19.84 |
| Licogliflozin Monotherapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 2 | -3.2 units per liter (U/L) | Standard Deviation 15.52 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 48 | -36.9 units per liter (U/L) | Standard Deviation 30.2 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 2 | -13.5 units per liter (U/L) | Standard Deviation 24.47 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 4 | -14.5 units per liter (U/L) | Standard Deviation 25.78 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 8 | -17.6 units per liter (U/L) | Standard Deviation 23.47 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 12 | -21.0 units per liter (U/L) | Standard Deviation 24.91 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 16 | -24.4 units per liter (U/L) | Standard Deviation 26.13 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 20 | -25.0 units per liter (U/L) | Standard Deviation 28.95 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 24 | -35.2 units per liter (U/L) | Standard Deviation 30.61 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 32 | -33.8 units per liter (U/L) | Standard Deviation 37.21 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 40 | -36.1 units per liter (U/L) | Standard Deviation 27.42 |
| Combination Therapy | Change From Baseline in Alanine Transaminase (ALT) Over Time | Follow-up | -17.0 units per liter (U/L) | Standard Deviation 27.97 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 20 | -5.7 units per liter (U/L) | Standard Deviation 20.2 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Follow-up | -8.8 units per liter (U/L) | Standard Deviation 28.88 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 40 | -8.7 units per liter (U/L) | Standard Deviation 40.7 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 16 | -3.2 units per liter (U/L) | Standard Deviation 24.57 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 12 | -2.5 units per liter (U/L) | Standard Deviation 25.05 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 8 | -5.6 units per liter (U/L) | Standard Deviation 19.67 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 48 | -19.5 units per liter (U/L) | Standard Deviation 30.16 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 4 | -3.2 units per liter (U/L) | Standard Deviation 17.81 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 2 | -4.3 units per liter (U/L) | Standard Deviation 18.94 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 32 | -1.0 units per liter (U/L) | Standard Deviation 41.32 |
| Placebo | Change From Baseline in Alanine Transaminase (ALT) Over Time | Week 24 | -4.0 units per liter (U/L) | Standard Deviation 28.28 |
Secondary
Change From Baseline in Aspartate Aminotransferase (AST) Over Time
To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.
Time frame: Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)
Population: The safety analysis set included all participants who received at least one dose of study treatment. At each time point, only participants with a value at both Baseline and that time point were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 2 | -7.9 U/L | Standard Deviation 14.93 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 12 | 0.4 U/L | Standard Deviation 21.34 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 32 | -2.0 U/L | Standard Deviation 32 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 4 | -1.7 U/L | Standard Deviation 17.43 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 24 | -1.4 U/L | Standard Deviation 19.96 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 16 | -0.7 U/L | Standard Deviation 21.71 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 8 | 1.2 U/L | Standard Deviation 23.71 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Follow-up | -2.0 U/L | Standard Deviation 21.21 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 48 | -0.7 U/L | Standard Deviation 31.34 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 20 | -1.0 U/L | Standard Deviation 22.46 |
| Tropifexor Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 40 | 3.2 U/L | Standard Deviation 34.4 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 20 | -10.0 U/L | Standard Deviation 19.81 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 40 | -11.9 U/L | Standard Deviation 20.22 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 24 | -13.8 U/L | Standard Deviation 19.81 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 32 | -11.2 U/L | Standard Deviation 20.12 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 8 | -7.4 U/L | Standard Deviation 14.12 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Follow-up | -8.2 U/L | Standard Deviation 24.01 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 12 | -10.3 U/L | Standard Deviation 13.25 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 48 | -11.3 U/L | Standard Deviation 23.53 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 16 | -10.8 U/L | Standard Deviation 16.37 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 4 | -2.4 U/L | Standard Deviation 20.49 |
| Licogliflozin Monotherapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 2 | -3.9 U/L | Standard Deviation 12.98 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 48 | -20.4 U/L | Standard Deviation 24.19 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 2 | -5.5 U/L | Standard Deviation 19.38 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 4 | -4.9 U/L | Standard Deviation 22.19 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 8 | -6.7 U/L | Standard Deviation 20.13 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 12 | -10.4 U/L | Standard Deviation 21.42 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 16 | -12.9 U/L | Standard Deviation 20.98 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 20 | -10.8 U/L | Standard Deviation 25.98 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 24 | -18.3 U/L | Standard Deviation 23.26 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 32 | -15.4 U/L | Standard Deviation 34.92 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 40 | -20.6 U/L | Standard Deviation 22.57 |
| Combination Therapy | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Follow-up | -10.6 U/L | Standard Deviation 21.27 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 20 | -3.9 U/L | Standard Deviation 14.23 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Follow-up | -3.3 U/L | Standard Deviation 23.64 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 40 | -5.9 U/L | Standard Deviation 23.21 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 16 | -2.4 U/L | Standard Deviation 17.42 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 12 | -1.4 U/L | Standard Deviation 19.08 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 8 | -1.6 U/L | Standard Deviation 15.19 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 48 | -12.8 U/L | Standard Deviation 17.01 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 4 | -2.2 U/L | Standard Deviation 15.35 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 2 | -1.8 U/L | Standard Deviation 13.46 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 32 | -1.1 U/L | Standard Deviation 29.62 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) Over Time | Week 24 | -2.2 U/L | Standard Deviation 21.96 |
Secondary
Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time
To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.
Time frame: Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)
Population: The safety analysis set included all participants who received at least one dose of study treatment. At each time point, only participants with a value at both Baseline and that time point were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 4 | -43.6 U/L | Standard Deviation 60.28 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 40 | -38.8 U/L | Standard Deviation 42.89 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 24 | -32.0 U/L | Standard Deviation 45.55 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 12 | -37.4 U/L | Standard Deviation 96.36 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 32 | -34.5 U/L | Standard Deviation 37.31 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 20 | -32.9 U/L | Standard Deviation 37.55 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 48 | -31.6 U/L | Standard Deviation 46 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 16 | -39.4 U/L | Standard Deviation 41.77 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 2 | -34.8 U/L | Standard Deviation 46.06 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Follow-up | 14.8 U/L | Standard Deviation 69.63 |
| Tropifexor Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 8 | -37.9 U/L | Standard Deviation 37.85 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 40 | -20.6 U/L | Standard Deviation 30.99 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 24 | -22.3 U/L | Standard Deviation 28.06 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 4 | -7.0 U/L | Standard Deviation 20.56 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 32 | -19.4 U/L | Standard Deviation 28.68 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 8 | -15.3 U/L | Standard Deviation 28.06 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 2 | -2.8 U/L | Standard Deviation 21.81 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 48 | -20.1 U/L | Standard Deviation 29.1 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 12 | -17.5 U/L | Standard Deviation 33.83 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 16 | -15.5 U/L | Standard Deviation 33.94 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Follow-up | -9.4 U/L | Standard Deviation 42.96 |
| Licogliflozin Monotherapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 20 | -14.8 U/L | Standard Deviation 41.11 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 48 | -44.1 U/L | Standard Deviation 67.27 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 2 | -30.6 U/L | Standard Deviation 45.85 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 4 | -41.7 U/L | Standard Deviation 60.81 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 8 | -45.0 U/L | Standard Deviation 69.45 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 12 | -48.0 U/L | Standard Deviation 76.04 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 16 | -52.2 U/L | Standard Deviation 78.29 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 20 | -50.1 U/L | Standard Deviation 79.3 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 24 | -58.1 U/L | Standard Deviation 82.45 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 32 | -55.1 U/L | Standard Deviation 76.85 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 40 | -50.0 U/L | Standard Deviation 72.08 |
| Combination Therapy | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Follow-up | 5.6 U/L | Standard Deviation 139.33 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 16 | 2.2 U/L | Standard Deviation 36.71 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Follow-up | 7.3 U/L | Standard Deviation 43.69 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 40 | 0.2 U/L | Standard Deviation 54.04 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 12 | 5.2 U/L | Standard Deviation 25.03 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 8 | -0.9 U/L | Standard Deviation 33.16 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 32 | 8.2 U/L | Standard Deviation 45.21 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 48 | -11.1 U/L | Standard Deviation 38.01 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 4 | -1.1 U/L | Standard Deviation 31.63 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 24 | 3.3 U/L | Standard Deviation 44.08 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 2 | 3.8 U/L | Standard Deviation 34.6 |
| Placebo | Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | Week 20 | -0.8 U/L | Standard Deviation 45.84 |
Secondary
Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF)
Change in liver fat content based on MRI-PDFF.
Time frame: Baseline, Week 48
Population: FAS: all participants to whom study treatment has been assigned by randomization and had an assessment at Week 48. This analysis was performed in 40% of participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tropifexor Monotherapy | Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | -6.57 Percent liver fat | Standard Deviation 5.913 |
| Licogliflozin Monotherapy | Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | -2.64 Percent liver fat | Standard Deviation 5.866 |
| Combination Therapy | Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | -7.69 Percent liver fat | Standard Deviation 6.702 |
| Placebo | Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | -2.58 Percent liver fat | Standard Deviation 3.599 |
Secondary
Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline
Whether the participants had 5% or more reduction in body weight.
Time frame: Baseline, Week 48
Population: Data are reported for the total number of participants in the treatment group with response variable defined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | 12 Participants |
| Licogliflozin Monotherapy | Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | 9 Participants |
| Combination Therapy | Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | 28 Participants |
| Placebo | Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | 3 Participants |
Secondary
Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH
Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Time frame: 48 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | 8 Participants |
| Licogliflozin Monotherapy | Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | 10 Participants |
| Combination Therapy | Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | 14 Participants |
| Placebo | Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | 5 Participants |
Secondary
Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis
Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Time frame: 48 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | 6 Participants |
| Licogliflozin Monotherapy | Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | 10 Participants |
| Combination Therapy | Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | 11 Participants |
| Placebo | Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | 4 Participants |
Secondary
Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH
Fibrosis staging and Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Time frame: 48 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tropifexor Monotherapy | Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | 3 Participants |
| Licogliflozin Monotherapy | Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | 4 Participants |
| Combination Therapy | Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | 3 Participants |
| Placebo | Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | 3 Participants |