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

Primary Purpose

Non-alcoholic Fatty Liver Disease

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
MK-4074 200 mg
Placebo for MK-4074
Pioglitazone hydrochloride 30 mg
Placebo for pioglitazone hydrochloride
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-alcoholic Fatty Liver Disease

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Arm Label

    MK-4074

    Placebo for MK-4074

    Pioglitazone

    Placebo for pioglitazone

    Arm Description

    Participants will receive oral doses of MK-4074 200 mg (2 x 100-mg capsules) twice daily for 4 weeks.

    Participants will receive oral doses of placebo to match MK-4074 twice daily for 4 weeks.

    Participants will receive oral doses of pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.

    Participants will receive oral doses of placebo to match pioglitazone hydrochloride once daily for 4 weeks.

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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.

    Secondary Outcome Measures

    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.
    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.

    Full Information

    First Posted
    September 7, 2011
    Last Updated
    August 10, 2018
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01431521
    Brief Title
    Study of Changes in Hepatic Fat Following Administration of MK-4074 and Pioglitazone Hydrochloride (MK-4074-008)
    Official Title
    An Exploratory Study to Evaluate Changes in Hepatic Fat Following Multiple-Dose Administration of MK-4074 and Pioglitazone Hydrochloride
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    October 26, 2011 (Actual)
    Primary Completion Date
    September 18, 2012 (Actual)
    Study Completion Date
    October 1, 2012 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. 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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Non-alcoholic Fatty Liver Disease

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    31 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    MK-4074
    Arm Type
    Experimental
    Arm Description
    Participants will receive oral doses of MK-4074 200 mg (2 x 100-mg capsules) twice daily for 4 weeks.
    Arm Title
    Placebo for MK-4074
    Arm Type
    Placebo Comparator
    Arm Description
    Participants will receive oral doses of placebo to match MK-4074 twice daily for 4 weeks.
    Arm Title
    Pioglitazone
    Arm Type
    Experimental
    Arm Description
    Participants will receive oral doses of pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
    Arm Title
    Placebo for pioglitazone
    Arm Type
    Placebo Comparator
    Arm Description
    Participants will receive oral doses of placebo to match pioglitazone hydrochloride once daily for 4 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    MK-4074 200 mg
    Intervention Description
    2 x 100-mg capsules, orally, twice-daily (BID) for 4 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo for MK-4074
    Intervention Description
    2 x 100-mg capsules, orally, BID for 4 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    Pioglitazone hydrochloride 30 mg
    Intervention Description
    1 x 30-mg tablet, orally, once daily for 4 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo for pioglitazone hydrochloride
    Intervention Description
    1 x 30-mg tablet, orally, once daily for 4 weeks
    Primary Outcome Measure Information:
    Title
    Percent Change From Baseline in Hepatic Fat
    Description
    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
    Title
    Number of Participants Experiencing One or More Adverse Events (AE)
    Description
    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
    Title
    Number of Participants Who Discontinued Study Drug Due to an AE
    Description
    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
    Secondary Outcome Measure Information:
    Title
    Percent Change From Baseline in Alanine Transaminase (ALT)
    Description
    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
    Title
    Percent Change From Baseline Aspartate Transaminase (AST)
    Description
    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

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    60 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Available IPD and Supporting Information:
    Available IPD/Information Type
    CSR Synopsis
    Available IPD/Information URL
    http://www.merck.com/clinical-trials/study.html?id=4074-008&kw=4074-008&tab=access

    Learn more about this trial

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

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