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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
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

    First Posted
    October 14, 2013
    Last Updated
    August 10, 2018
    Sponsor
    Merck Sharp & Dohme LLC
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    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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