Nonalcoholic Steatohepatitis
Conditions
Brief summary
The purpose of this study is to see if the study drug, tirzepatide administered once weekly, is safe and effective as a treatment for Nonalcoholic Steatohepatitis (NASH).
Interventions
DRUGTirzepatide
Administered SC
DRUGPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participants must have a body mass index (BMI) ≥27 kilograms per square meter (kg/m²) and ≤50 kg/m² with stable body weight for at least 3 months * Participants with or without type 2 diabetes mellitus (T2DM) * If with T2DM, hemoglobin A1c (HbA1c) ≤9.5% * Participants must be willing to undergo baseline and endpoint liver biopsies * Participants must have histologic diagnosis of NASH with stage 2 or 3 fibrosis by liver biopsy * Participants must not have known or suspected alcohol abuse (\>14 units/week for women and \>21 units/week for men) or active substance abuse * Participants must not have evidence of cirrhosis or other forms of liver disease * Participants must not have heart attack, stroke, or hospitalization for congestive heart failure in the past 6 months * Participants must not have active cancer within the last 5 years * Participants must not have uncontrolled high blood pressure * Participants must not have renal impairment with estimated glomerular filtration rate (eGFR) \<30 milliters/minute/1.73m²; for participants on metformin, eGFR \<45 mL/min/1.73m² * Participants must not have a diagnosis of type 1 diabetes * Participants must not have a history of pancreatitis (acute or chronic) * Participants must not have calcitonin ≥35 nanograms per liter * Participant must not have family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma (family is defined as a first degree relative) * Female participants must not be pregnant, breast-feeding, or intend to become pregnant or of childbearing potential and not using adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology | Week 52 | NASH resolution is defined as the absence of fatty liver disease or simple steatosis without steatohepatitis; the absence of hepatocellular ballooning (nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) 0 for ballooning); with or without mild lobular inflammation (NAS 0 or 1 for inflammation); and any value for steatosis. No worsening of fibrosis is defined as no increase in fibrosis stage from baseline to Week 52. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology | Week 52 | NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Participants were evaluated with the NASH CRN scoring system with ≥1-point reduction without worsening of NASH (defined as no increase in the NAS score). |
| Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology | Week 52 | Participants were evaluated with the NASH CRN scoring system with ≥1 stage increase in fibrosis. |
| Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components | Week 52 | Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in at least 2 NAS components (lobular inflammation, hepatocellular ballooning or steatosis). The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8, with the higher score indicating more aggressive disease. |
| Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | Baseline to Week 52 | MRI-PDFF is an established method that enables quantification of fat content in the liver. The value of whole liver fat as assessed by MRI-PDFF is expressed in percentage (%) and ranges from 0 to 100% with higher values representing higher liver fat level. Least square (LS) mean was calculated using mixed model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Diabetes Flag (DIABFL) + REGION1 + Treatment + Time + Treatment\*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured. |
| Mean Change From Baseline in Body Weight | Baseline to Week 52 | Change in body weight at the end of 52 weeks measured in kilogram (kg) using a calibrated scale. LS mean was calculated using MMRM model for post-baseline measures: Variable = Baseline + DIABFL + REGION1 + Treatment + Time + Treatment\*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured. |
Countries
Belgium, France, Israel, Italy, Japan, Mexico, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Tirzepatide Participants received 5 mg tirzepatide administered SC QW for 52 weeks \[initially 2.5 mg tirzepatide SC QW for 4 weeks, then 5 mg tirzepatide SC QW from weeks 5-52\]. | 47 |
| 10 mg Tirzepatide Participants received 10 mg tirzepatide administered SC QW for 52 weeks \[initially 2.5 mg tirzepatide SC QW for 4 weeks, then dose escalated to 5 mg, 7.5 mg, and 10 mg every 4 weeks until target dose (10 mg) was reached\]. | 47 |
| 15 mg Tirzepatide Participants received 15 mg tirzepatide administered SC QW for 52 weeks \[initially 2.5 mg tirzepatide SC QW for 4 weeks, then dose escalated to 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg every 4 weeks until target dose (15 mg) was reached\]. | 48 |
| Placebo Participants received placebo administered SC QW for 52 weeks. | 48 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 4 | 2 | 1 | 3 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 5 |
Baseline characteristics
| Characteristic | 10 mg Tirzepatide | 15 mg Tirzepatide | Placebo | 5 mg Tirzepatide | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.30 years STANDARD_DEVIATION 12.08 | 54.90 years STANDARD_DEVIATION 10.02 | 53.50 years STANDARD_DEVIATION 11.6 | 55.00 years STANDARD_DEVIATION 11.62 | 54.40 years STANDARD_DEVIATION 11.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 17 Participants | 18 Participants | 19 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 27 Participants | 24 Participants | 21 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 4 Participants | 6 Participants | 7 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 41 Participants | 43 Participants | 41 Participants | 164 Participants |
| Region of Enrollment Belgium | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment France | 7 Participants | 2 Participants | 6 Participants | 7 Participants | 22 Participants |
| Region of Enrollment Israel | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Italy | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Region of Enrollment Japan | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Region of Enrollment Mexico | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 10 Participants |
| Region of Enrollment Poland | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 0 Participants | 6 Participants | 1 Participants | 1 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 4 Participants | 4 Participants | 1 Participants | 14 Participants |
| Region of Enrollment United States | 26 Participants | 26 Participants | 27 Participants | 28 Participants | 107 Participants |
| Sex: Female, Male Female | 26 Participants | 29 Participants | 27 Participants | 27 Participants | 109 Participants |
| Sex: Female, Male Male | 21 Participants | 19 Participants | 21 Participants | 20 Participants | 81 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 / 47 | 0 / 47 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 43 / 47 | 43 / 47 | 44 / 48 | 40 / 48 |
| serious Total, serious adverse events | 5 / 47 | 4 / 47 | 0 / 48 | 3 / 48 |
Outcome results
Primary
Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology
NASH resolution is defined as the absence of fatty liver disease or simple steatosis without steatohepatitis; the absence of hepatocellular ballooning (nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) 0 for ballooning); with or without mild lobular inflammation (NAS 0 or 1 for inflammation); and any value for steatosis. No worsening of fibrosis is defined as no increase in fibrosis stage from baseline to Week 52.
Time frame: Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology | 51.84 Percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology | 63.13 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology | 73.92 Percentage of participants |
| Placebo | Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology | 12.62 Percentage of participants |
p-value: <0.00195% CI: [2.27, 24.44]Regression, Logistic
p-value: <0.00195% CI: [3.59, 39.11]Regression, Logistic
p-value: <0.00195% CI: [5.73, 67.25]Regression, Logistic
Secondary
Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)
MRI-PDFF is an established method that enables quantification of fat content in the liver. The value of whole liver fat as assessed by MRI-PDFF is expressed in percentage (%) and ranges from 0 to 100% with higher values representing higher liver fat level. Least square (LS) mean was calculated using mixed model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Diabetes Flag (DIABFL) + REGION1 + Treatment + Time + Treatment\*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured.
Time frame: Baseline to Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -10.12 absolute percentage of liver fat | Standard Error 1.165 |
| 10 mg Tirzepatide | Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -10.15 absolute percentage of liver fat | Standard Error 1.071 |
| 15 mg Tirzepatide | Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -11.34 absolute percentage of liver fat | Standard Error 1.107 |
| Placebo | Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | -1.31 absolute percentage of liver fat | Standard Error 1.142 |
p-value: <0.00195% CI: [-12.04, -5.58]Mixed Models Analysis
p-value: <0.00195% CI: [-11.93, -5.73]Mixed Models Analysis
p-value: <0.00195% CI: [-13.17, -6.87]Mixed Models Analysis
Secondary
Mean Change From Baseline in Body Weight
Change in body weight at the end of 52 weeks measured in kilogram (kg) using a calibrated scale. LS mean was calculated using MMRM model for post-baseline measures: Variable = Baseline + DIABFL + REGION1 + Treatment + Time + Treatment\*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured.
Time frame: Baseline to Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Mean Change From Baseline in Body Weight | -11.46 Kilogram (kg) | Standard Error 1.404 |
| 10 mg Tirzepatide | Mean Change From Baseline in Body Weight | -14.22 Kilogram (kg) | Standard Error 1.38 |
| 15 mg Tirzepatide | Mean Change From Baseline in Body Weight | -17.88 Kilogram (kg) | Standard Error 1.376 |
| Placebo | Mean Change From Baseline in Body Weight | -1.04 Kilogram (kg) | Standard Error 1.392 |
p-value: <0.00195% CI: [-14.32, -6.52]Mixed Models Analysis
p-value: <0.00195% CI: [-17.05, -9.32]Mixed Models Analysis
p-value: <0.00195% CI: [-20.71, -12.98]Mixed Models Analysis
Secondary
Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components
Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in at least 2 NAS components (lobular inflammation, hepatocellular ballooning or steatosis). The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8, with the higher score indicating more aggressive disease.
Time frame: Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components | 81.02 Percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components | 86.55 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components | 88.77 Percentage of participants |
| Placebo | Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components | 38.09 Percentage of participants |
p-value: <0.00195% CI: [2.41, 20]Regression, Logistic
p-value: <0.00195% CI: [3.36, 32.61]Regression, Logistic
p-value: <0.00195% CI: [3.87, 42.65]Regression, Logistic
Secondary
Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology
NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Participants were evaluated with the NASH CRN scoring system with ≥1-point reduction without worsening of NASH (defined as no increase in the NAS score).
Time frame: Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology | 59.21 Percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology | 53.35 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology | 54.3 Percentage of participants |
| Placebo | Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology | 32.51 Percentage of participants |
p-value: 0.02595% CI: [1.15, 7.9]Regression, Logistic
p-value: 0.07495% CI: [0.92, 6.13]Regression, Logistic
p-value: 0.06395% CI: [0.95, 6.4]Regression, Logistic
Secondary
Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology
Participants were evaluated with the NASH CRN scoring system with ≥1 stage increase in fibrosis.
Time frame: Week 52
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline values and had evaluable data for this outcome prior to treatment discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology | 12.04 Percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology | 9.81 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology | 5.53 Percentage of participants |
| Placebo | Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology | 13.03 Percentage of participants |
p-value: 0.89395% CI: [0.25, 3.4]Regression, Logistic
p-value: 0.64795% CI: [0.18, 2.87]Regression, Logistic
p-value: 0.24695% CI: [0.08, 1.91]Regression, Logistic