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

• ClinicalTrials.gov Identifier: NCT01431521
• Recruitment Status: Completed
• First Posted: September 9, 2011
• Results First Posted: March 25, 2016
• Last Update Posted: September 10, 2018
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Non-alcoholic Fatty Liver Disease	Drug: MK-4074 200 mg; Drug: Placebo for MK-4074; Drug: Pioglitazone hydrochloride 30 mg; Drug: Placebo for pioglitazone hydrochloride	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study to Evaluate Changes in Hepatic Fat Following Multiple-Dose Administration of MK-4074 and Pioglitazone Hydrochloride
• Actual Study Start Date: October 26, 2011
• Actual Primary Completion Date: September 18, 2012
• Actual Study Completion Date: October 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Hepatic Fat [ Time Frame: 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.
2. Number of Participants Experiencing One or More Adverse Events (AE) [ Time Frame: 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.
3. Number of Participants Who Discontinued Study Drug Due to an AE [ Time Frame: 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 Outcome Measures :

1. Percent Change From Baseline in Alanine Transaminase (ALT) [ Time Frame: 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.
2. Percent Change From Baseline Aspartate Transaminase (AST) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

Study Data/Documents: CSR Synopsis 

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01431521
• Other Study ID Numbers: 4074-008
• First Posted: September 9, 2011
• Results First Posted: March 25, 2016
• Last Update Posted: September 10, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs