Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Brief summary
The principal goal of this study is to determine the efficacy of efinopegdutide in liver fat reduction in participants with NAFLD. The primary hypotheses are that efinopegdutide is superior to semaglutide, or that efinopegdutide is superior to semaglutide by at least 10% with respect to mean relative reduction from baseline in liver fat content (LFC) after 24 weeks.
Interventions
DRUGEfinopegdutide 20 mg/mL
Subcutaneous injection in a dose-escalation administration of 2.4 mg, 5.0 mg, and 10.0 mg
Subcutaneous injection in a dose-escalation administration of 0.25 mg, 0.5 mg, and 1.0 mg
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* LFC ≥10% as assessed by MRI-PDFF at time of screening. * Body Mass Index (BMI) ≥25 kg/m² and ≤50 kg/m² at time of screening. * Stable weight (based on self-reporting) defined as ≤5% gain or loss of body weight for at least 3 months before screening visit. * No history of Type 2 Diabetes Mellitus (T2DM) OR history of T2DM with an Glycated Hemoglobin (A1C) ≤8.5% at screening AND controlled by diet or a stable dose of metformin for the 3 months before screening. * A female participant is eligible to participate if she is not pregnant or breastfeeding, is not a woman of childbearing potential (WOCBP), or is a WOCBP and agrees to follow contraceptive guidance during the study intervention period and for at least 5 weeks after the last dose of study intervention. * Participants in Taiwan are eligible between the ages of 20 to 70 years of age (inclusive). * Participants in South Korea are eligible between the ages of 19 to 70 years of age (inclusive).
Exclusion criteria
* History of Type 1 Diabetes Mellitus (T1DM), diabetic ketoacidosis, or diabetes secondary to pancreatitis or pancreatectomy. * Ongoing, inadequately controlled hypothyroidism or hyperthyroidism. * Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasm type-2 syndrome. * Recent event (within 6 months prior to screening) of congestive heart failure, unstable angina, myocardial infarction, arterial revascularization, stroke, or transient ischemic attack. * History or evidence of chronic liver disease other than NAFLD or Non-Alcoholic SteatoHepatitis (NASH). * Known history of cirrhosis. * History of acute or chronic pancreatitis. * History of a bariatric surgical procedure or a known clinically significant gastric emptying abnormality. * History of malignancy ≤5 years prior to screening, except for skin cancer or cervical cancer. * Clinically active hematologic disorder. * Diagnosis of human immunodeficiency virus (HIV). * Surgery requiring general anesthesia within 3 months before screening visit. * History of organ transplantation, except for corneal transplant. * Active diabetic proliferative retinopathy or a history of maculopathy. * Untreated obstructive sleep apnea. * History of treatment with any glucagon-like peptide-1 (GLP-1) receptor agonist within 6 months before screening. * History of treatment with thiazolidinediones (ie, pioglitazone, rosiglitazone) within 6 months before screening. * Previous use (within 3 months before screening) or current use of prescription weight-management medications or over-the-counter weight-loss medications or therapies. * Treatment with systemic corticosteroid medication within 3 months before screening. * Current treatment with anticoagulants (eg, warfarin, heparin). * Inability to have an MRI-PDFF performed due to either severe claustrophobia, metallic implant that prevents MRI-PDFF examination, or any other contraindication to MRI-PDFF examination. * Previous or current history of significant alcohol consumption (average of 7 standard drinks per week in females or 14 standard drinks per week in males) for a period of more than 3 consecutive months in the 24 months before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Relative Reduction From Baseline in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF), Evaluated by Blinded Independent Central Review (BICR) After 24 Weeks | Baseline and up to ~24 Weeks | LFC was measured with liver images taken by MRI-PDFF and analyzed by BICR. Relative Reduction from Baseline to Week 24 = (Baseline - Week 24) / Baseline x 100%. Mean relative reduction from baseline in liver fat content is presented. |
| Percentage of Participants Who Experienced an Adverse Event (AE) | Up to ~29 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an adverse event is presented. |
| Percentage of Participants Who Discontinued Study Intervention Due to an AE | Up to ~24 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to adverse event is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Absolute Reduction From Baseline in LFC Measured by MRI-PDFF (Evaluated by BICR) After 24 Weeks | Baseline and up to ~24 Weeks | LFC was measured by liver images taken by MRI-PDFF and analyzed by BICR. The absolute reduction from baseline to Week 24 = Baseline - Week 24. The mean absolute reduction from baseline in LFC after 24 weeks of treatment is presented. |
| Mean Percent Change From Baseline in Body Weight After 24 Weeks | Baseline and up to ~24 weeks | Body weight in kilograms was measured using a standardized, digital scale. The mean percent change from baseline in body weight after 24 weeks is presented. |
| Mean Percent Change From Baseline in Total Cholesterol After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in total cholesterol. The mean percent change in total cholesterol is presented. |
| Mean Percent Change From Baseline in Non-High Density Lipoprotein-Cholesterol (Non-HDL-C) After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in non-HDL-C. The mean percent change in non-HDL-C is presented. |
| Mean Percent Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in HDL-C. Mean percent change in HDL-C is presented. |
| Mean Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in LDL-C. The mean percent change in LDL-C is presented. |
| Mean Percent Change From Baseline in Triglycerides (TG) After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in triglycerides. The mean percent change in triglycerides is presented. |
| Mean Percent Change From Baseline in Apolipoprotein B (apoB) After 24 Weeks | Baseline and up to ~24 weeks | Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in apoB. The mean percent change in apoB is presented. |
Countries
Argentina, Australia, Canada, France, Israel, Italy, Mexico, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This study was conducted at 51 clinical sites in 16 countries.
Pre-assignment details
Participant flow as per the database cutoff date of 19OCT2022.
Participants by arm
| Arm | Count |
|---|---|
| Efinopegdutide Efinopegdutide 20 mg/mL administered by injection once weekly for 24 weeks in a dose-escalation regimen: 2.4 mg from day 1 to week 3, 5.0 mg from week 4 to 7, and 10.0 mg from week 8 to 24. | 72 |
| Semaglutide Semaglutide 1.34 mg/mL administered by injection once weekly for 24 weeks in a dose-escalation regimen: 0.25 mg from day 1 to week 3, 0.5 mg from week 4 to 7, and 1.0 mg from week 8 to 24. | 73 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Efinopegdutide | Semaglutide | Total |
|---|---|---|---|
| Age, Continuous | 48.0 Years STANDARD_DEVIATION 11 | 50.7 Years STANDARD_DEVIATION 10.9 | 49.4 Years STANDARD_DEVIATION 11 |
| Body Mass Index (BMI) | 35.2 Kg/M^2 STANDARD_DEVIATION 5.7 | 33.5 Kg/M^2 STANDARD_DEVIATION 5 | 34.3 Kg/M^2 STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 26 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 47 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 62 Participants | 63 Participants | 125 Participants |
| Sex: Female, Male Female | 39 Participants | 41 Participants | 80 Participants |
| Sex: Female, Male Male | 33 Participants | 32 Participants | 65 Participants |
| Weight | 100.2 kg STANDARD_DEVIATION 18.9 | 94.4 kg STANDARD_DEVIATION 18.9 | 97.3 kg STANDARD_DEVIATION 19.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 0 / 73 |
| other Total, other adverse events | 57 / 72 | 44 / 73 |
| serious Total, serious adverse events | 1 / 72 | 1 / 73 |
Outcome results
Primary
Mean Relative Reduction From Baseline in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF), Evaluated by Blinded Independent Central Review (BICR) After 24 Weeks
LFC was measured with liver images taken by MRI-PDFF and analyzed by BICR. Relative Reduction from Baseline to Week 24 = (Baseline - Week 24) / Baseline x 100%. Mean relative reduction from baseline in liver fat content is presented.
Time frame: Baseline and up to ~24 Weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Relative Reduction From Baseline in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF), Evaluated by Blinded Independent Central Review (BICR) After 24 Weeks | 72.7 Percent Reduction |
| Semaglutide | Mean Relative Reduction From Baseline in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF), Evaluated by Blinded Independent Central Review (BICR) After 24 Weeks | 42.3 Percent Reduction |
p-value: <0.000190% CI: [22.1, 38.7]Mixed Models Analysis
Primary
Percentage of Participants Who Discontinued Study Intervention Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to adverse event is presented.
Time frame: Up to ~24 weeks
Population: All randomized participants who received at least 1 injection (including only partial) of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efinopegdutide | Percentage of Participants Who Discontinued Study Intervention Due to an AE | 5.6 Percentage of Participants |
| Semaglutide | Percentage of Participants Who Discontinued Study Intervention Due to an AE | 0 Percentage of Participants |
95% CI: [0.4, 13.5]
Primary
Percentage of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an adverse event is presented.
Time frame: Up to ~29 weeks
Population: All randomized participants who received at least 1 injection (including only partial) of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efinopegdutide | Percentage of Participants Who Experienced an Adverse Event (AE) | 88.9 Percentage of Participants |
| Semaglutide | Percentage of Participants Who Experienced an Adverse Event (AE) | 72.6 Percentage of Participants |
95% CI: [3.5, 29.1]
Secondary
Mean Absolute Reduction From Baseline in LFC Measured by MRI-PDFF (Evaluated by BICR) After 24 Weeks
LFC was measured by liver images taken by MRI-PDFF and analyzed by BICR. The absolute reduction from baseline to Week 24 = Baseline - Week 24. The mean absolute reduction from baseline in LFC after 24 weeks of treatment is presented.
Time frame: Baseline and up to ~24 Weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Absolute Reduction From Baseline in LFC Measured by MRI-PDFF (Evaluated by BICR) After 24 Weeks | 14.9 Percentage of liver fat |
| Semaglutide | Mean Absolute Reduction From Baseline in LFC Measured by MRI-PDFF (Evaluated by BICR) After 24 Weeks | 8.8 Percentage of liver fat |
p-value: <0.00190% CI: [4.6, 7.7]Mixed Models Analysis
Secondary
Mean Percent Change From Baseline in Apolipoprotein B (apoB) After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in apoB. The mean percent change in apoB is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Apolipoprotein B (apoB) After 24 Weeks | -14.7 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Apolipoprotein B (apoB) After 24 Weeks | -9.2 Percent Change |
90% CI: [-10.4, -0.4]
Secondary
Mean Percent Change From Baseline in Body Weight After 24 Weeks
Body weight in kilograms was measured using a standardized, digital scale. The mean percent change from baseline in body weight after 24 weeks is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Body Weight After 24 Weeks | -8.5 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Body Weight After 24 Weeks | -7.1 Percent Change |
p-value: 0.08590% CI: [-2.7, -0.1]Mixed Models Analysis
Secondary
Mean Percent Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in HDL-C. Mean percent change in HDL-C is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) After 24 Weeks | -8.1 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) After 24 Weeks | 3.6 Percent Change |
90% CI: [-15.8, -7.7]
Secondary
Mean Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in LDL-C. The mean percent change in LDL-C is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) After 24 Weeks | -13.0 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) After 24 Weeks | -6.9 Percent Change |
90% CI: [-12, -0.1]
Secondary
Mean Percent Change From Baseline in Non-High Density Lipoprotein-Cholesterol (Non-HDL-C) After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in non-HDL-C. The mean percent change in non-HDL-C is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Non-High Density Lipoprotein-Cholesterol (Non-HDL-C) After 24 Weeks | -16.8 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Non-High Density Lipoprotein-Cholesterol (Non-HDL-C) After 24 Weeks | -11.0 Percent Change |
90% CI: [-10.9, -0.6]
Secondary
Mean Percent Change From Baseline in Total Cholesterol After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in total cholesterol. The mean percent change in total cholesterol is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Total Cholesterol After 24 Weeks | -15.2 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Total Cholesterol After 24 Weeks | -8.0 Percent Change |
90% CI: [-11.2, -3.1]
Secondary
Mean Percent Change From Baseline in Triglycerides (TG) After 24 Weeks
Fasting blood samples were collected at baseline and after 24 weeks of treatment to assess mean percent change in triglycerides. The mean percent change in triglycerides is presented.
Time frame: Baseline and up to ~24 weeks
Population: All randomized participants who had received at least 1 injection (including only partial) of study intervention and had at least 1 assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Efinopegdutide | Mean Percent Change From Baseline in Triglycerides (TG) After 24 Weeks | -30.9 Percent Change |
| Semaglutide | Mean Percent Change From Baseline in Triglycerides (TG) After 24 Weeks | -23.3 Percent Change |
90% CI: [-14.3, -0.9]