Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Participants With Type 2 Diabetes Mellitus (MK-8666-003)

Study Overview
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Brief Summary
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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.

Official Title
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A Multiple Dose Clinical Trial to Study the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of MK-8666 in Type 2 Diabetes Mellitus Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: MK-8666
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8666 50 mg<br>MK-8666, 50 mg, oral, once a day (QD) for Days 1 to 14. | Drug: MK-8666<br>* MK-8666, capsules, oral, QD, Days 1 to 14<br>Drug: Placebo<br>* Placebo, capsules, oral, QD, Days 1 to 14<br>|
| Experimental: MK-8666 150 mg<br>MK-8666, 150 mg, oral, QD, for Days 1 to 14 | Drug: MK-8666<br>* MK-8666, capsules, oral, QD, Days 1 to 14<br>Drug: Placebo<br>* Placebo, capsules, oral, QD, Days 1 to 14<br>|
| Experimental: MK-8666 500 mg<br>MK-8666, 500 mg, oral, QD for Days 1 to 14 | Drug: MK-8666<br>* MK-8666, capsules, oral, QD, Days 1 to 14<br>Drug: Placebo<br>* Placebo, capsules, oral, QD, Days 1 to 14<br>|
| Placebo Comparator: Placebo<br>Placebo, oral, QD for Days 1 to 14 | Drug: Placebo<br>* Placebo, capsules, oral, QD, Days 1 to 14<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Predose (Baseline) and 24 h postdose Day 14 (Day 15) | 
| 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. | Up to 28 days | 
| 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. | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Baseline and Day 15 |