Non-alcoholic Fatty Liver Disease
Conditions
Brief summary
This study will evaluate changes in liver fat content following multiple oral doses of MK-4074 and Pioglitazone Hydrochloride in adult males and females with fatty liver disease. The primary hypothesis of the study is that a multiple-dose administration of MK-4074 200 mg twice daily for 4 weeks results in a decrease in hepatic fat content with respect to placebo in adult male and female participants with hepatic steatosis (i.e., on order of 50% reduction in hepatic fat with respect to placebo is expected).
Interventions
DRUGMK-4074 200 mg
2 x 100-mg capsules, orally, twice-daily (BID) for 4 weeks
DRUGPlacebo for MK-4074
2 x 100-mg capsules, orally, BID for 4 weeks.
DRUGPioglitazone hydrochloride 30 mg
1 x 30-mg tablet, orally, once daily for 4 weeks
DRUGPlacebo for pioglitazone hydrochloride
1 x 30-mg tablet, orally, once daily for 4 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Females must be of non-childbearing potential * Body mass index (BMI) ≥32.0 kg/m\^2 * In good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests * No clinically significant abnormality on electrocardiogram * Has documented hepatic fat content ≥10% within 6 months of enrollment * Maintained stable weight (by history) for at least 4 weeks * Agrees not to initiate a weight loss program and agrees to maintain consistent dietary habits and exercise routines for the duration of the study * Has a rating of 'moderate' or 'severe' steatosis on ultrasound at the prestudy (screening) visit
Exclusion criteria
* Change in weight greater than 4% between prestudy visit and randomization into the study * History of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the participant * Liver disease other than fatty liver or non-alcoholic steatohepatitis (NASH) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x the upper limit of normal range * Serum triglyceride level \>600 mg/dL * History of stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal, cardiovascular (including congestive heart failure), hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * Had abdominal surgery, gastric bypass, bowel resection, recent liver biopsy, or any other procedure within a minimum of 4 weeks * History of neoplastic disease * Claustrophobia or other contraindication to magnetic resonance imaging (MRI) * Have not washed off agents associated with changes in hepatic fat or used for treatment of Non-alcoholic fatty liver disease (NAFLD) or NASH for a minimum of 3 months prior * Consumes excessive amounts of alcohol, coffee, tea, cola, or other caffeinated beverages * Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks * Significant multiple and/or severe allergies * Intolerance or hypersensitivity to pioglitazone hydrochloride or any inactive ingredients * Regular user of any illicit drugs or has a history of drug (including alcohol) abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Hepatic Fat | Baseline and Week 4 | Hepatic fat content was assessed via magnetic resonance imaging (MRI) prior to first dose administration and following 4 weeks of treatment. Percent change in hepatic fat fraction from baseline was calculated for each of the 9 liver regions separately and then these were averaged to calculate overall percent change from baseline for each participant. |
| Number of Participants Experiencing One or More Adverse Events (AE) | Up to 10 weeks | An AE is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to 4 weeks | An AE is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Alanine Transaminase (ALT) | Baseline and Week 4 | Hepatic steatosis is not uncommonly associated with mild elevations in serum transaminases, specifically ALT, and these elevations may be a marker of more advanced hepatic disease. Serum transaminases were monitored at baseline and once weekly for the duration of the study to permit a better understanding of the time course of potential improvement in hepatic inflammation during the course of this short study. |
| Percent Change From Baseline Aspartate Transaminase (AST) | Baseline and Week 4 | Hepatic steatosis is not uncommonly associated with mild elevations in serum transaminases, including AST, and these elevations may be a marker of more advanced hepatic disease. Serum transaminases were monitored at baseline and once weekly for the duration of the study to permit a better understanding of the time course of potential improvement in hepatic inflammation during the course of this short study. |
Participant flow
Recruitment details
Thirty-one male or female participants (non-childbearing potential) between the ages of 18 and 60, inclusive, with body mass index (BMI) ≥ 32 kg/m\^2 were enrolled in the study. Participants were pre-screened by means of ultrasound, and only those participants with a rating of moderate or severe steatosis were further evaluated by means of MRI.
Participants by arm
| Arm | Count |
|---|---|
| MK-4074 Participants will receive oral doses of MK-4074 200 mg (2 x 100-mg capsules) twice daily for 4 weeks. | 10 |
| Placebo for MK-4074 Participants will receive oral doses of placebo to match MK-4074 twice daily for 4 weeks. | 5 |
| Pioglitazone Participants will receive oral doses of pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks. | 11 |
| Placebo for Pioglitazone Participants will receive oral doses of placebo to match pioglitazone hydrochloride once daily for 4 weeks. | 5 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | MK-4074 | Placebo for MK-4074 | Pioglitazone | Placebo for Pioglitazone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 35.1 Years STANDARD_DEVIATION 5.8 | 48.0 Years STANDARD_DEVIATION 7.6 | 43.7 Years STANDARD_DEVIATION 12.1 | 47.8 Years STANDARD_DEVIATION 10.6 | 42.3 Years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 9 Participants | 1 Participants | 24 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 1 / 5 | 4 / 10 | 4 / 5 |
| serious Total, serious adverse events | 0 / 10 | 0 / 5 | 0 / 10 | 0 / 5 |
Outcome results
Primary
Number of Participants Experiencing One or More Adverse Events (AE)
An AE is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 10 weeks
Population: All Subjects as Treated (AST) Population consists of all participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-4074 | Number of Participants Experiencing One or More Adverse Events (AE) | 4 Participants |
| Pioglitazone | Number of Participants Experiencing One or More Adverse Events (AE) | 4 Participants |
| Placebo | Number of Participants Experiencing One or More Adverse Events (AE) | 5 Participants |
Primary
Number of Participants Who Discontinued Study Drug Due to an AE
An AE is 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 is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 4 weeks
Population: The AST Population consists of all participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-4074 | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Pioglitazone | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
Primary
Percent Change From Baseline in Hepatic Fat
Hepatic fat content was assessed via magnetic resonance imaging (MRI) prior to first dose administration and following 4 weeks of treatment. Percent change in hepatic fat fraction from baseline was calculated for each of the 9 liver regions separately and then these were averaged to calculate overall percent change from baseline for each participant.
Time frame: Baseline and Week 4
Population: Per-Protocol (PP) Population consists of those participants who comply with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-4074 | Percent Change From Baseline in Hepatic Fat | -35.73 Percent change |
| Pioglitazone | Percent Change From Baseline in Hepatic Fat | -18.04 Percent change |
| Placebo | Percent Change From Baseline in Hepatic Fat | 8.63 Percent change |
p-value: <0.00195% CI: [-54.67, -34.07]Linear mixed effects model
p-value: <0.00195% CI: [-36.97, -16.37]Linear mixed effects model
p-value: 0.00795% CI: [-36.97, -7.39]Linear mixed effects model
Secondary
Percent Change From Baseline Aspartate Transaminase (AST)
Hepatic steatosis is not uncommonly associated with mild elevations in serum transaminases, including AST, and these elevations may be a marker of more advanced hepatic disease. Serum transaminases were monitored at baseline and once weekly for the duration of the study to permit a better understanding of the time course of potential improvement in hepatic inflammation during the course of this short study.
Time frame: Baseline and Week 4
Population: The AST Population consists of all participants who received at least one dose of the study drug. One participant in the Placebo group did not have AST data for Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-4074 | Percent Change From Baseline Aspartate Transaminase (AST) | -6.74 Percent change |
| Pioglitazone | Percent Change From Baseline Aspartate Transaminase (AST) | -13.95 Percent change |
| Placebo | Percent Change From Baseline Aspartate Transaminase (AST) | -3.28 Percent change |
p-value: >0.295% CI: [-17.85, 10.92]Linear mixed effects model
p-value: >0.295% CI: [-25.06, 3.71]Linear mixed effects model
Secondary
Percent Change From Baseline in Alanine Transaminase (ALT)
Hepatic steatosis is not uncommonly associated with mild elevations in serum transaminases, specifically ALT, and these elevations may be a marker of more advanced hepatic disease. Serum transaminases were monitored at baseline and once weekly for the duration of the study to permit a better understanding of the time course of potential improvement in hepatic inflammation during the course of this short study.
Time frame: Baseline and Week 4
Population: The AST Population consists of all participants who received at least one dose of the study drug. One participant in the Placebo group did not have ALT data for Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-4074 | Percent Change From Baseline in Alanine Transaminase (ALT) | -9.82 Percent change |
| Pioglitazone | Percent Change From Baseline in Alanine Transaminase (ALT) | -20.21 Percent change |
| Placebo | Percent Change From Baseline in Alanine Transaminase (ALT) | -3.47 Percent change |
p-value: >0.295% CI: [-18.69, 6]Linear mixed effect model
p-value: 0.02895% CI: [-29.08, -4.4]Linear mixed effects model