Type 2 Diabetes Mellitus
Conditions
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.
Interventions
DRUGMK-8666
MK-8666, capsules, oral, QD, Days 1 to 14
DRUGPlacebo
Placebo, capsules, oral, QD, Days 1 to 14
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | Predose (Baseline) and 24 h postdose Day 14 (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 | Up to 28 days | 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 | Up to 14 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 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 | 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. |
| Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | Baseline and 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. |
| Maximum Plasma Drug Concentration After Dosing (Cmax) | 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 | 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) | 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 | 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. |
Participant flow
Recruitment details
Sixty-three participants were recruited at 4 clinical sites in the United States.
Pre-assignment details
Male and female participants with Type 2 diabetes mellitus between the ages of 18 and 65 years inclusive were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| MK-8666 50 mg MK-8666 50 mg once daily for 14 consecutive days | 9 |
| MK-8666 150 mg MK-8666 150 mg once daily for 14 consecutive days | 18 |
| MK-8666 500 mg MK-8666 500 mg once daily for 14 consecutive days | 18 |
| Placebo Placebo once daily for 14 consecutive days | 18 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MK-8666 50 mg | MK-8666 150 mg | MK-8666 500 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.9 Years FULL_RANGE 10 | 55.6 Years FULL_RANGE 6.2 | 55.2 Years FULL_RANGE 6.9 | 54.7 Years FULL_RANGE 8.3 | 55.0 Years |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 7 Participants | 8 Participants | 25 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 11 Participants | 10 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 9 | 9 / 18 | 10 / 18 | 5 / 18 |
| serious Total, serious adverse events | 0 / 9 | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
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.
Time frame: Predose (Baseline) and 24 h postdose Day 14 (Day 15)
Population: The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-8666 50 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | 32.8 mg/dL | Standard Error 9.7 |
| MK-8666 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | 37.9 mg/dL | Standard Error 7 |
| MK-8666 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | 56.0 mg/dL | Standard Error 7 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | 2.0 mg/dL | Standard Error 7 |
90% CI: [11.3, 50.3]
90% CI: [20, 51.9]
90% CI: [38.1, 70]
Primary
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.
Time frame: Up to 14 days
Population: The Safety population consisted of all participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8666 50 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| MK-8666 150 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| MK-8666 500 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
Primary
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.
Time frame: Up to 28 days
Population: The Safety population consisted of all participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8666 50 mg | Number of Participants Who Experienced at Least Once Adverse Event | 3 Participants |
| MK-8666 150 mg | Number of Participants Who Experienced at Least Once Adverse Event | 9 Participants |
| MK-8666 500 mg | Number of Participants Who Experienced at Least Once Adverse Event | 10 Participants |
| Placebo | Number of Participants Who Experienced at Least Once Adverse Event | 5 Participants |
Secondary
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.
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
Population: The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8666 50 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 14 | 15.3 μM·hr | Geometric Coefficient of Variation 88 |
| MK-8666 50 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 1 | 6.11 μM·hr | Geometric Coefficient of Variation 88 |
| MK-8666 150 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 1 | 37.2 μM·hr | Geometric Coefficient of Variation 44 |
| MK-8666 150 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 14 | 66.9 μM·hr | Geometric Coefficient of Variation 32 |
| MK-8666 500 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 1 | 143 μM·hr | Geometric Coefficient of Variation 33 |
| MK-8666 500 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Day 14 | 172 μM·hr | Geometric Coefficient of Variation 37 |
Secondary
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.
Time frame: Baseline and Day 15
Population: The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Data from 1 participant at Day 14 (Placebo group) was missing as the participant had to leave the study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-8666 50 mg | Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | 19.0 mg/dL | Standard Error 7.9 |
| MK-8666 150 mg | Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | 27.3 mg/dL | Standard Error 5.7 |
| MK-8666 500 mg | Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | 45.4 mg/dL | Standard Error 5.7 |
| Placebo | Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | -3.3 mg/dL | Standard Error 5.8 |
90% CI: [6.2, 38.4]
90% CI: [17.4, 43.8]
90% CI: [35.6, 62]
Secondary
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 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
Population: The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8666 50 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 1 | 0.906 μM | Geometric Coefficient of Variation 102 |
| MK-8666 50 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 14 | 1.50 μM | Geometric Coefficient of Variation 93 |
| MK-8666 150 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 1 | 4.49 μM | Geometric Coefficient of Variation 45 |
| MK-8666 150 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 14 | 7.16 μM | Geometric Coefficient of Variation 37 |
| MK-8666 500 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 1 | 17.1 μM | Geometric Coefficient of Variation 40 |
| MK-8666 500 mg | Maximum Plasma Drug Concentration After Dosing (Cmax) | Day 14 | 19.9 μM | Geometric Coefficient of Variation 32 |
Secondary
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.
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
Population: The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MK-8666 50 mg | Time to Reach Cmax (Tmax) | Day 1 | 2.0 hr |
| MK-8666 50 mg | Time to Reach Cmax (Tmax) | Day 14 | 2.0 hr |
| MK-8666 150 mg | Time to Reach Cmax (Tmax) | Day 1 | 2.25 hr |
| MK-8666 150 mg | Time to Reach Cmax (Tmax) | Day 14 | 2.0 hr |
| MK-8666 500 mg | Time to Reach Cmax (Tmax) | Day 1 | 2.5 hr |
| MK-8666 500 mg | Time to Reach Cmax (Tmax) | Day 14 | 2.0 hr |