Nonalcoholic Steatohepatitis
Conditions
Keywords
Non-alcoholic fatty liver disease
Brief summary
This study will evaluate the effect of each dose of MK-3655 versus placebo on the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks. The primary hypothesis of the study is that at least 1 dose of MK-3655 is superior to placebo with respect to the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks.
Interventions
DRUGMK-3655
MK-3655 50, 100 or 300 dose for injection
DRUGPlacebo
Matching placebo to MK-3655
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Has histological confirmation of NASH * Is a male or female aged 18 years to 80 years (in Japan and Taiwan aged 20 to 80 years) * Has a body mass index (BMI) ≥25 kg/m\^2 and ≤50 kg/m\^2 and stable weight for the past 3 months * Has no history of Type 2 diabetes mellitus (T2DM) OR a history of T2DM controlled by diet or stable doses of antihyperglycemic agents (AHAs) * Contraceptive use by male participants should be consistent with local regulations. * A female participant is eligible to participate if she is not pregnant or breastfeeding, and she is not a woman of child-bearing potential (WOCBP) OR she is a WOCBP and uses a contraceptive method that is highly effective during the intervention period and for at least 16 weeks after the last dose of study intervention.
Exclusion criteria
* Has presence of cirrhosis on liver biopsy * Has Type 1 diabetes * Has a history of malignancy, unless cancer free ≥5 years, or is under evaluation for active or suspected malignancy except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer * Has a history of bariatric surgery ≤5 years before study participation * Has undergone a major surgical procedure ≤3 months before study participation or has major surgery planned during the study * Has a history or evidence of chronic liver disease other than NASH. Individuals with a history of Hepatitis B or C may be eligible for participation. * Has significant systemic or major illnesses other than liver disease, including recent events (≤6 months before study entry) of congestive heart failure, unstable coronary artery disease, arterial revascularization, pulmonary disease, renal failure, stroke, transient ischemic attack, or organ transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks | Week 52 | The NASH Clinical Research Network (CRN) scoring system evaluated by Blinded Independent Central Review (BICR) was used to assess treatment response. The NASH CRN scoring scales were: lobular inflammation score (0-3); hepatocyte ballooning score (0-2); steatosis score (0-3); and fibrosis score (0-4). NASH resolution was defined as a score of 0-1 for inflammation, 0 for ballooning, and any grade of steatosis. |
| Percentage of Participants Who Experienced an Adverse Event (AE) | Up to 64 weeks | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. |
| Percentage of Participants Discontinuing Study Medication Due to an AE | Up to 52 weeks | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks | Baseline and Week 24 | LFC % was measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF) and evaluated by BICR. MRI-PDFF is a highly accurate noninvasive measure of the proportion of fat content of a tissue. |
| Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks | Week 52 | Participants were evaluated with the NASH CRN scoring system with BICR with ≥1 stage improvement in fibrosis without worsening of steatohepatitis defined as no increase in the ballooning, inflammation, or steatosis scores. |
| Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks | Week 52 | Participants with ≥2 point improvement in the NAS with ≥1 point improvement in inflammation or ballooning without worsening of fibrosis were assessed with the NASH CRN scoring system (evaluated by BICR). The NAS was calculated as the unweighted sum of the scores and ranges from 0-8 (highest activity). |
Countries
Argentina, Australia, Canada, Chile, China, Colombia, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Malaysia, Mexico, New Zealand, Puerto Rico, Russia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
Males and females with pre-cirrhotic Nonalcoholic Steatohepatitis (NASH) aged 18 to 80 years (in Japan and Taiwan, aged 20 to 80 years were randomized in this study
Participants by arm
| Arm | Count |
|---|---|
| MK-3655 50 mg Following a 2-week placebo run-in, participants received MK-3655 50 mg by SC injection Q4W for 52 weeks. | 45 |
| MK-3655 100 mg Following a 2-week placebo run-in, participants received MK-3655 100 mg by SC injection Q4W for 52 weeks. | 48 |
| MK-3655 300 mg Following a 2-week placebo run-in, participants received MK-3655 300 mg by SC injection Q4W for 52 weeks. | 46 |
| Placebo Following a 2-week placebo run-in, participants received placebo by SC injection Q4W for 52 weeks. | 44 |
| Total | 183 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 32 | 35 | 36 | 33 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | MK-3655 100 mg | MK-3655 300 mg | MK-3655 50 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.3 Years STANDARD_DEVIATION 12.3 | 56.6 Years STANDARD_DEVIATION 11.3 | 59.6 Years STANDARD_DEVIATION 8.9 | 55.8 Years STANDARD_DEVIATION 10.1 | 56.5 Years STANDARD_DEVIATION 10.8 |
| Baseline Fibrosis Stage Stage 2 | 22 Participants | 21 Participants | 21 Participants | 21 Participants | 85 Participants |
| Baseline Fibrosis Stage Stage 3 | 26 Participants | 25 Participants | 24 Participants | 23 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 17 Participants | 12 Participants | 18 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 28 Participants | 33 Participants | 25 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Percent Liver Fat Content <20% | 23 Participants | 30 Participants | 30 Participants | 31 Participants | 114 Participants |
| Percent Liver Fat Content ≥ 20% | 25 Participants | 16 Participants | 15 Participants | 13 Participants | 69 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 16 Participants | 15 Participants | 16 Participants | 65 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 27 Participants | 26 Participants | 26 Participants | 107 Participants |
| Region East Asia excluding Japan | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 21 Participants |
| Region Japan | 12 Participants | 11 Participants | 11 Participants | 11 Participants | 45 Participants |
| Region Other | 31 Participants | 30 Participants | 28 Participants | 28 Participants | 117 Participants |
| Sex: Female, Male Female | 20 Participants | 23 Participants | 25 Participants | 19 Participants | 87 Participants |
| Sex: Female, Male Male | 28 Participants | 23 Participants | 20 Participants | 25 Participants | 96 Participants |
| Type 2 Diabetes Mellitus (T2DM) No | 23 Participants | 21 Participants | 23 Participants | 20 Participants | 87 Participants |
| Type 2 Diabetes Mellitus (T2DM) Yes | 25 Participants | 25 Participants | 22 Participants | 24 Participants | 96 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 / 45 | 0 / 48 | 0 / 46 | 0 / 44 |
| other Total, other adverse events | 19 / 45 | 26 / 47 | 27 / 46 | 21 / 44 |
| serious Total, serious adverse events | 1 / 45 | 1 / 47 | 1 / 46 | 8 / 44 |
Outcome results
Primary
Percentage of Participants Discontinuing Study Medication Due to an AE
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Time frame: Up to 52 weeks
Population: APaT population, which included all randomized participants who received at least 1 injection of study intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3655 50 mg | Percentage of Participants Discontinuing Study Medication Due to an AE | 2.2 Percentage of Participants |
| MK-3655 100 mg | Percentage of Participants Discontinuing Study Medication Due to an AE | 0 Percentage of Participants |
| MK-3655 300 mg | Percentage of Participants Discontinuing Study Medication Due to an AE | 0 Percentage of Participants |
| Placebo | Percentage of Participants Discontinuing Study Medication Due to an AE | 0 Percentage of Participants |
Primary
Percentage of Participants Who Experienced an Adverse Event (AE)
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Time frame: Up to 64 weeks
Population: All Participants as Treated (APaT) population, which included all randomized participants who received at least 1 injection of study intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3655 50 mg | Percentage of Participants Who Experienced an Adverse Event (AE) | 73.3 Percentage of Participants |
| MK-3655 100 mg | Percentage of Participants Who Experienced an Adverse Event (AE) | 70.2 Percentage of Participants |
| MK-3655 300 mg | Percentage of Participants Who Experienced an Adverse Event (AE) | 76.1 Percentage of Participants |
| Placebo | Percentage of Participants Who Experienced an Adverse Event (AE) | 77.3 Percentage of Participants |
Primary
Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks
The NASH Clinical Research Network (CRN) scoring system evaluated by Blinded Independent Central Review (BICR) was used to assess treatment response. The NASH CRN scoring scales were: lobular inflammation score (0-3); hepatocyte ballooning score (0-2); steatosis score (0-3); and fibrosis score (0-4). NASH resolution was defined as a score of 0-1 for inflammation, 0 for ballooning, and any grade of steatosis.
Time frame: Week 52
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3655 50 mg | Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks | 16.7 Percentage of Participants |
| MK-3655 100 mg | Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks | 14.3 Percentage of Participants |
| MK-3655 300 mg | Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks | 17.6 Percentage of Participants |
| Placebo | Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks | 5.9 Percentage of Participants |
p-value: 0.350495% CI: [-13.4, 35.1]Miettinen and Nurminen's method
p-value: 0.37395% CI: [-15.6, 32.1]Miettinen and Nurminen's method
p-value: 0.142895% CI: [-8.5, 42.3]Miettinen and Nurminen's method
Secondary
Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks
LFC % was measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF) and evaluated by BICR. MRI-PDFF is a highly accurate noninvasive measure of the proportion of fat content of a tissue.
Time frame: Baseline and Week 24
Population: FAS population, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-3655 50 mg | Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks | 30.1 Percent Change |
| MK-3655 100 mg | Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks | 30.0 Percent Change |
| MK-3655 300 mg | Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks | 37.2 Percent Change |
| Placebo | Mean Percent Relative Reduction From Baseline in Liver Fat Content (LFC) After 24 Weeks | 11.0 Percent Change |
95% CI: [1.7, 36.4]
95% CI: [2.2, 35.8]
95% CI: [9.5, 42.8]
Secondary
Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks
Participants were evaluated with the NASH CRN scoring system with BICR with ≥1 stage improvement in fibrosis without worsening of steatohepatitis defined as no increase in the ballooning, inflammation, or steatosis scores.
Time frame: Week 52
Population: FAS population, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3655 50 mg | Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks | 22.2 Percentage of Participants |
| MK-3655 100 mg | Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks | 38.1 Percentage of Participants |
| MK-3655 300 mg | Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks | 29.4 Percentage of Participants |
| Placebo | Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks | 17.6 Percentage of Participants |
p-value: 0.897895% CI: [-26.5, 30.3]Miettinen and Nurminen's method
p-value: 0.186995% CI: [-10.6, 46.4]Miettinen and Nurminen's method
p-value: 0.563695% CI: [-22.1, 38.5]Miettinen and Nurminen's method
Secondary
Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks
Participants with ≥2 point improvement in the NAS with ≥1 point improvement in inflammation or ballooning without worsening of fibrosis were assessed with the NASH CRN scoring system (evaluated by BICR). The NAS was calculated as the unweighted sum of the scores and ranges from 0-8 (highest activity).
Time frame: Week 52
Population: FAS population, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3655 50 mg | Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks | 33.3 Percentage of Participants |
| MK-3655 100 mg | Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks | 47.6 Percentage of Participants |
| MK-3655 300 mg | Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks | 35.3 Percentage of Participants |
| Placebo | Percentage of Participants With ≥2 Point Improvement in NAS With ≥1 Point Improvement in Inflammation or Ballooning Without Worsening of Fbrosis by Histology (Evaluated by BICR) After 52 Weeks | 29.4 Percentage of Participants |
p-value: 0.917495% CI: [-28.6, 32.6]Miettinen and Nurminen's method
p-value: 0.27295% CI: [-14.5, 47.1]Miettinen and Nurminen's method
p-value: 0.758695% CI: [-26.7, 37.3]Miettinen and Nurminen's method