Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Participants With Type 2 Diabetes Mellitus (MK-8666-003)
Primary Purpose
Type 2 Diabetes Mellitus
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
MK-8666
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Type 2 Diabetes Mellitus
Eligibility Criteria
Inclusion Criteria:
- If female, must be either postmenopausal or surgically sterile
- A Body Mass Index (BMI) ≥18 kg/m^2 to ≤40 kg/m^2, inclusive.
- A diagnosis of T2DM
- Drug naïve or is being treated with no more than 2 oral antihyperglycemic agents (thiazolidenediones are excluded)
- Judged to be in good health except for T2DM
- Willing to follow a standard weight maintaining diet throughout the study
- A nonsmoker or has not used nicotine or nicotine-containing products for at least 3 months
Exclusion Criteria:
- A history of clinically significant endocrine (except T2DM), gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases
- A history of myositis or complaints including diffuse myalgias, muscle tenderness, or weakness.
- A history of cancer (malignancy) excepting adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix
- Has clinically unstable diabetic retinopathy, neuropathy, and/or clinical evidence of gastroparesis (frequent nausea, bloating or vomiting, severe gastroesophageal reflux, early satiety)
- A history of type 1 diabetes mellitus and/or history of ketoacidosis
- Taking a medication for a co-morbid condition that is not permitted during the study
- A history of significant multiple and/or severe allergies
- Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus
- Had major surgery, donated or lost 1 unit of blood within 4 weeks prior to study participation
- Participated in another investigational trial within 4 weeks prior to study participation
- Consumes excessive amounts of alcoholic or caffeine-containing beverages
- A regular user of illicit drugs or a history of drug or alcohol abuse within the past year
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
MK-8666 50 mg
MK-8666 150 mg
MK-8666 500 mg
Placebo
Arm Description
MK-8666, 50 mg, oral, once a day (QD) for Days 1 to 14.
MK-8666, 150 mg, oral, QD, for Days 1 to 14
MK-8666, 500 mg, oral, QD for Days 1 to 14
Placebo, oral, QD for Days 1 to 14
Outcomes
Primary Outcome Measures
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15
Blood glucose was measured on a fasting basis (collected after an 8-hour fast). Blood was collected on Day -1 (pre-planned dose), predose on Days 1, 3, 7, and 14, and 24h postdose Day 14 (Day 15). The baseline measurement was computed as the average of the Day -1 and predose Day 1 measurements. FPG is expressed as mg/dL. This change from baseline reflects values for Day 15 FPG minus Day 0 FPG values.
Number of Participants Who Experienced at Least Once Adverse Event
An adverse event (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 adverse event (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
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
AUC0-last is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for AUC0-24h was geometric mean coefficient of variation percentage.
Maximum Plasma Drug Concentration After Dosing (Cmax)
Cmax is a measure of the maximum amount of drug in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for Cmax was geometric mean coefficient of variation percentage.
Time to Reach Cmax (Tmax)
Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group.
Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15
The 24h-WMG was considered to provide an integrated assessment of the glycemic exposure over the 24-hour period, and was derived from 18 blood samples collected immediately prior to, and after each meal, and overnight and fasting one hour pre-dose. A "weighted" rather than a "simple" mean is used to avoid overrepresentation of post-meal glucose values. On each day (Day -1 and Day 14), the WMG was computed as a time-weighted average of the 18 individual measurements.
Full Information
NCT ID
NCT01971554
First Posted
October 14, 2013
Last Updated
August 10, 2018
Sponsor
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT01971554
Brief Title
Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Participants With Type 2 Diabetes Mellitus (MK-8666-003)
Official Title
A Multiple Dose Clinical Trial to Study the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Type 2 Diabetes Mellitus Patients
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
October 14, 2013 (Actual)
Primary Completion Date
April 26, 2014 (Actual)
Study Completion Date
April 26, 2014 (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 is a study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-8666 in participants with type 2 diabetes mellitus (T2DM). Participants enrolled in this trial would be either treatment-naive or have washed off of oral anti-hyperglycemic agents. MK-8666 is planned to be administered orally for up to 2 weeks. The primary hypothesis for this study is that after 14 days of once daily treatment with MK-8666, at a dose that is safe and well tolerated, the placebo-corrected fasting plasma glucose reduction from baseline is ≥34 mg/dL.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
63 (Actual)
8. Arms, Groups, and Interventions
Arm Title
MK-8666 50 mg
Arm Type
Experimental
Arm Description
MK-8666, 50 mg, oral, once a day (QD) for Days 1 to 14.
Arm Title
MK-8666 150 mg
Arm Type
Experimental
Arm Description
MK-8666, 150 mg, oral, QD, for Days 1 to 14
Arm Title
MK-8666 500 mg
Arm Type
Experimental
Arm Description
MK-8666, 500 mg, oral, QD for Days 1 to 14
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo, oral, QD for Days 1 to 14
Intervention Type
Drug
Intervention Name(s)
MK-8666
Intervention Description
MK-8666, capsules, oral, QD, Days 1 to 14
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo, capsules, oral, QD, Days 1 to 14
Primary Outcome Measure Information:
Title
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15
Description
Blood glucose was measured on a fasting basis (collected after an 8-hour fast). Blood was collected on Day -1 (pre-planned dose), predose on Days 1, 3, 7, and 14, and 24h postdose Day 14 (Day 15). The baseline measurement was computed as the average of the Day -1 and predose Day 1 measurements. FPG is expressed as mg/dL. This change from baseline reflects values for Day 15 FPG minus Day 0 FPG values.
Time Frame
Predose (Baseline) and 24 h postdose Day 14 (Day 15)
Title
Number of Participants Who Experienced at Least Once Adverse Event
Description
An adverse event (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 28 days
Title
Number of Participants Who Discontinued Study Drug Due to an AE
Description
An adverse event (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 14 days
Secondary Outcome Measure Information:
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
Description
AUC0-last is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for AUC0-24h was geometric mean coefficient of variation percentage.
Time Frame
Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose
Title
Maximum Plasma Drug Concentration After Dosing (Cmax)
Description
Cmax is a measure of the maximum amount of drug in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for Cmax was geometric mean coefficient of variation percentage.
Time Frame
Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose
Title
Time to Reach Cmax (Tmax)
Description
Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group.
Time Frame
Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose
Title
Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15
Description
The 24h-WMG was considered to provide an integrated assessment of the glycemic exposure over the 24-hour period, and was derived from 18 blood samples collected immediately prior to, and after each meal, and overnight and fasting one hour pre-dose. A "weighted" rather than a "simple" mean is used to avoid overrepresentation of post-meal glucose values. On each day (Day -1 and Day 14), the WMG was computed as a time-weighted average of the 18 individual measurements.
Time Frame
Baseline and Day 15
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
If female, must be either postmenopausal or surgically sterile
A Body Mass Index (BMI) ≥18 kg/m^2 to ≤40 kg/m^2, inclusive.
A diagnosis of T2DM
Drug naïve or is being treated with no more than 2 oral antihyperglycemic agents (thiazolidenediones are excluded)
Judged to be in good health except for T2DM
Willing to follow a standard weight maintaining diet throughout the study
A nonsmoker or has not used nicotine or nicotine-containing products for at least 3 months
Exclusion Criteria:
A history of clinically significant endocrine (except T2DM), gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases
A history of myositis or complaints including diffuse myalgias, muscle tenderness, or weakness.
A history of cancer (malignancy) excepting adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix
Has clinically unstable diabetic retinopathy, neuropathy, and/or clinical evidence of gastroparesis (frequent nausea, bloating or vomiting, severe gastroesophageal reflux, early satiety)
A history of type 1 diabetes mellitus and/or history of ketoacidosis
Taking a medication for a co-morbid condition that is not permitted during the study
A history of significant multiple and/or severe allergies
Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus
Had major surgery, donated or lost 1 unit of blood within 4 weeks prior to study participation
Participated in another investigational trial within 4 weeks prior to study participation
Consumes excessive amounts of alcoholic or caffeine-containing beverages
A regular user of illicit drugs or a history of drug or alcohol abuse within the past year
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
Citations:
PubMed Identifier
28727908
Citation
Krug AW, Vaddady P, Railkar RA, Musser BJ, Cote J, Ederveen A, Krefetz DG, DeNoia E, Free AL, Morrow L, Chakravarthy MV, Kauh E, Tatosian DA, Kothare PA. Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection. Clin Transl Sci. 2017 Sep;10(5):404-411. doi: 10.1111/cts.12479. Epub 2017 Jul 20.
Results Reference
result
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Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Participants With Type 2 Diabetes Mellitus (MK-8666-003)
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