Study of Changes in Hepatic Fat Following Administration of MK-4074 and Pioglitazone Hydrochloride (MK-4074-008)

An Exploratory Study to Evaluate Changes in Hepatic Fat Following Multiple-Dose Administration of MK-4074 and Pioglitazone Hydrochloride

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).

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: MK-4074 200 mg; Drug: Placebo for MK-4074; Drug: Pioglitazone hydrochloride 30 mg; Drug: Placebo for pioglitazone hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: MK-4074; Participants will receive oral doses of MK-4074 200 mg (2 x 100-mg capsules) twice daily for 4 weeks.	Drug: MK-4074 200 mg; 2 x 100-mg capsules, orally, twice-daily (BID) for 4 weeks
PLACEBO_COMPARATOR: Placebo for MK-4074; Participants will receive oral doses of placebo to match MK-4074 twice daily for 4 weeks.	Drug: Placebo for MK-4074; 2 x 100-mg capsules, orally, BID for 4 weeks.
EXPERIMENTAL: Pioglitazone; Participants will receive oral doses of pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.	Drug: Pioglitazone hydrochloride 30 mg; 1 x 30-mg tablet, orally, once daily for 4 weeks
PLACEBO_COMPARATOR: Placebo for pioglitazone; Participants will receive oral doses of placebo to match pioglitazone hydrochloride once daily for 4 weeks.	Drug: Placebo for pioglitazone hydrochloride; 1 x 30-mg tablet, orally, once daily for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and Week 4
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.	Up to 10 weeks
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.	Up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and Week 4
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.	Baseline and Week 4

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 26, 2011
• Primary Completion (ACTUAL): September 18, 2012
• Study Completion (ACTUAL): October 1, 2012

Study Registration Dates

• First Submitted: September 7, 2011
• First Submitted That Met QC Criteria: September 7, 2011
• First Posted (ESTIMATE): September 9, 2011

Study Record Updates

• Last Update Posted (ACTUAL): September 10, 2018
• Last Update Submitted That Met QC Criteria: August 10, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 4074-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis