Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Non-alcoholic Fatty Liver Disease
Interventions Drug: MK-4074 200 mg
Drug: Placebo for MK-4074
Drug: Pioglitazone hydrochloride 30 mg
Drug: Placebo for pioglitazone hydrochloride
Enrollment 31
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.
Pre-assignment Details  
Arm/Group Title MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone
Hide Arm/Group 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.
Period Title: Overall Study
Started 10 5 11 5
Treated 10 5 10 5
Completed 10 5 10 5
Not Completed 0 0 1 0
Reason Not Completed
Withdrawal by Subject             0             0             1             0
Arm/Group Title MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone Total
Hide Arm/Group 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. Total of all reporting groups
Overall Number of Baseline Participants 10 5 11 5 31
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 10 participants 5 participants 11 participants 5 participants 31 participants
35.1  (5.8) 48.0  (7.6) 43.7  (12.1) 47.8  (10.6) 42.3  (10.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 5 participants 11 participants 5 participants 31 participants
Female
0
   0.0%
1
  20.0%
2
  18.2%
4
  80.0%
7
  22.6%
Male
10
 100.0%
4
  80.0%
9
  81.8%
1
  20.0%
24
  77.4%
1.Primary Outcome
Title Percent Change From Baseline in Hepatic Fat
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title MK-4074 Pioglitazone Placebo
Hide Arm/Group 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 pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
Participants will receive oral doses of placebo to match MK-4074 or pioglitazone hydrochloride once daily for 4 weeks.
Overall Number of Participants Analyzed 10 10 10
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent change
-35.73
(-44.53 to -26.93)
-18.04
(-26.84 to -9.24)
8.63
(-0.17 to 17.43)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-4074, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Linear mixed effects model
Comments Treatment as fixed factor and predose Day 1 value, as a fixed covariate
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -44.37
Confidence Interval (2-Sided) 95%
-54.67 to -34.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Linear mixed effects model
Comments Treatment as fixed factor and predose Day 1 value, as a fixed covariate
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -26.67
Confidence Interval (2-Sided) 95%
-36.97 to -16.37
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MK-4074, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments [Not Specified]
Method Linear mixed effects model
Comments Treatment as fixed factor and predose Day 1 value, as a fixed covariate
Method of Estimation Estimation Parameter least squares mean difference
Estimated Value -17.69
Confidence Interval (2-Sided) 95%
-36.97 to -7.39
Estimation Comments [Not Specified]
2.Primary Outcome
Title Number of Participants Experiencing One or More Adverse Events (AE)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All Subjects as Treated (AST) Population consists of all participants who received at least one dose of the study drug.
Arm/Group Title MK-4074 Pioglitazone Placebo
Hide Arm/Group 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 pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
Participants will receive oral doses of placebo to match MK-4074 or pioglitazone hydrochloride once daily for 4 weeks.
Overall Number of Participants Analyzed 10 10 10
Measure Type: Number
Unit of Measure: Participants
4 4 5
3.Primary Outcome
Title Number of Participants Who Discontinued Study Drug Due to an AE
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The AST Population consists of all participants who received at least one dose of the study drug.
Arm/Group Title MK-4074 Pioglitazone Placebo
Hide Arm/Group 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 pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
Participants will receive oral doses of placebo to match MK-4074 or pioglitazone hydrochloride once daily for 4 weeks.
Overall Number of Participants Analyzed 10 10 10
Measure Type: Number
Unit of Measure: Participants
0 0 0
4.Secondary Outcome
Title Percent Change From Baseline in Alanine Transaminase (ALT)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title MK-4074 Pioglitazone Placebo
Hide Arm/Group 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 pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
Participants will receive oral doses of placebo to match MK-4074 or pioglitazone hydrochloride once daily for 4 weeks.
Overall Number of Participants Analyzed 10 10 9
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent change
-9.82
(-21.13 to 1.49)
-20.21
(-31.52 to -8.90)
-3.47
(-15.08 to 8.13)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-4074, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.200
Comments [Not Specified]
Method Linear mixed effect model
Comments Containing fixed effects for treatment, and predose Day 1 (baseline) as a fixed covariate
Method of Estimation Estimation Parameter Least square mean difference
Estimated Value -6.35
Confidence Interval (2-Sided) 95%
-18.69 to 6.00
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.028
Comments [Not Specified]
Method Linear mixed effects model
Comments Containing fixed effects for treatment, and predose Day 1 (baseline) as a fixed covariate
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -16.74
Confidence Interval (2-Sided) 95%
-29.08 to -4.40
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percent Change From Baseline Aspartate Transaminase (AST)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title MK-4074 Pioglitazone Placebo
Hide Arm/Group 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 pioglitazone hydrochloride 30 mg (1 x 30-mg tablet) once daily for 4 weeks.
Participants will receive oral doses of placebo to match MK-4074 or pioglitazone hydrochloride once daily for 4 weeks.
Overall Number of Participants Analyzed 10 10 9
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent change
-6.74
(-19.73 to 6.24)
-13.95
(-26.93 to -0.97)
-3.28
(-16.64 to 10.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-4074, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.200
Comments [Not Specified]
Method Linear mixed effects model
Comments Containing fixed effects for treatment, and predose Day 1 (baseline) as a fixed covariate
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -3.47
Confidence Interval (2-Sided) 95%
-17.85 to 10.92
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pioglitazone, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.200
Comments [Not Specified]
Method Linear mixed effects model
Comments Containing fixed effects for treatment, and predose Day 1 (baseline) as a fixed covariate
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -10.67
Confidence Interval (2-Sided) 95%
-25.06 to 3.71
Estimation Comments [Not Specified]
Time Frame Up to 10 weeks
Adverse Event Reporting Description The AST Population (Safety Population) consists of all participants who received at least one dose of the study drug.
 
Arm/Group Title MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone
Hide Arm/Group 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 matching MK-4074 twice daily for 4 weeks. Participants will receive oral doses of pioglitazone hydrochloride 30 mg once daily for 4 weeks. Participants will receive oral doses of placebo to match pioglitazone hydrochloride once daily for 4 weeks.
All-Cause Mortality
MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/10 (0.00%)      0/5 (0.00%)      0/10 (0.00%)      0/5 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MK-4074 Placebo for MK-4074 Pioglitazone Placebo for Pioglitazone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/10 (40.00%)      1/5 (20.00%)      4/10 (40.00%)      4/5 (80.00%)    
Blood and lymphatic system disorders         
Iron deficiency anaemia  1  0/10 (0.00%)  0 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Eye disorders         
Eyelids pruritus  1  0/10 (0.00%)  0 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Gastrointestinal disorders         
Vomiting  1  0/10 (0.00%)  0 0/5 (0.00%)  0 2/10 (20.00%)  2 0/5 (0.00%)  0
General disorders         
Thirst  1  1/10 (10.00%)  1 0/5 (0.00%)  0 0/10 (0.00%)  0 0/5 (0.00%)  0
Infections and infestations         
Upper respiratory tract infection  1  2/10 (20.00%)  2 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Sinusitis  1  0/10 (0.00%)  0 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Tooth infection  1  1/10 (10.00%)  1 0/5 (0.00%)  0 0/10 (0.00%)  0 0/5 (0.00%)  0
Injury, poisoning and procedural complications         
Accidental overdose  1  0/10 (0.00%)  0 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Burns first degree  1  1/10 (10.00%)  1 0/5 (0.00%)  0 0/10 (0.00%)  0 0/5 (0.00%)  0
Metabolism and nutrition disorders         
Dehydration  1  0/10 (0.00%)  0 0/5 (0.00%)  0 1/10 (10.00%)  1 0/5 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Back pain  1  0/10 (0.00%)  0 1/5 (20.00%)  1 1/10 (10.00%)  1 0/5 (0.00%)  0
Nervous system disorders         
Dizziness  1  0/10 (0.00%)  0 0/5 (0.00%)  0 1/10 (10.00%)  2 1/5 (20.00%)  1
Dysgeusia  1  0/10 (0.00%)  0 0/5 (0.00%)  0 1/10 (10.00%)  1 0/5 (0.00%)  0
Headache  1  1/10 (10.00%)  1 0/5 (0.00%)  0 2/10 (20.00%)  4 1/5 (20.00%)  3
Migraine  1  0/10 (0.00%)  0 1/5 (20.00%)  1 0/10 (0.00%)  0 0/5 (0.00%)  0
Psychiatric disorders         
Anxiety  1  0/10 (0.00%)  0 0/5 (0.00%)  0 0/10 (0.00%)  0 1/5 (20.00%)  1
Respiratory, thoracic and mediastinal disorders         
Oropharyngeal pain  1  0/10 (0.00%)  0 0/5 (0.00%)  0 1/10 (10.00%)  1 0/5 (0.00%)  0
Skin and subcutaneous tissue disorders         
Pruritus  1  0/10 (0.00%)  0 1/5 (20.00%)  1 0/10 (0.00%)  0 0/5 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/ presentation. Any information identified by the sponsor as confidential must be deleted prior to submission.
Results Point of Contact
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01431521     History of Changes
Other Study ID Numbers: 4074-008
First Submitted: September 7, 2011
First Posted: September 9, 2011
Results First Submitted: February 24, 2016
Results First Posted: March 25, 2016
Last Update Posted: September 10, 2018