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Study of the Safety and Efficacy of MK-8521 Compared to Placebo and a Diabetes Drug in Participants With Type 2 Diabetes Mellitus (MK-8521-003)

Primary Purpose

Diabetes Mellitus

Status

Completed

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

MK-8521

Liraglutide

Placebo

About this trial

This is an interventional treatment trial for Diabetes Mellitus

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Male, or female of non-childbearing potential with Type 2 diabetes mellitus (Parts 1 and 2) or non-diabetic (Part 2)
Body mass index (BMI) between: ≥27 and ≤40 kg/m^2
A1C (average blood sugar for the past 2 to 3 months) value ≥7.0 and ≤11.0 % (Part 1) or ≥ 6.5 and ≤11.0 % (Part 2) at the time of screening (T2DM participants)
A1C value <5.7 at the time of screening (non-diabetic subjects in Part 2 only)
On a stable dose of metformin (≥1000 mg total daily dose) for at least 12 weeks at the time of screening (T2DM participants)

Exclusion Criteria:

Mentally or legally incapacitated
History of clinically significant psychiatric disorder of the last 5 years. Participants with situational depression may be enrolled in the trial at the discretion of the Investigator
History of Type 1 diabetes mellitus or a history of ketoacidosis
History of clinically significant gastrointestinal, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases
History of cardiovascular disease or cardiac conduction disorder
History of cancer (malignancy). Exceptions may include adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated ≥10 years prior to the pre-screening visit
History of proliferative diabetic retinopathy or maculopathy
Clinically significant diabetic autonomic neuropathy
QTc interval ≥470 msec (for males) or ≥480 msec (for females)
Clinical significant electrocardiogram (ECG) abnormality
Positive for hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus (HIV)
On a weight loss program and is not weight-stable (weight stable is defined history of <5% change in body weight in the last 3 months
On a weight loss medication or has undergone bariatric surgery
Major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit
Participated in another investigational trial within 4 weeks prior to the pretrial (screening) visit
History of acute or chronic pancreatitis of any etiology
Mean value for triplicate semi-recumbent systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg (after at least a 10-minute seated rest) and blood pressure is considered unlikely to be below these limits by Day-1 (Randomization) with initiation or adjustment of antihypertensive medication
Event of severe hypoglycemia with seizure or loss of consciousness in the past 12 months
Treated with anti-hyperglycemic agents other than metformin within the last 12 weeks
Previous exposure to any glucagon-like peptide-1 (GLP-1) receptor agonist (e.g. Byetta™, Victoza™ or investigational agents)

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Active Comparator

Placebo Comparator

Experimental

Active Comparator

Placebo Comparator

Experimental

Arm Label

Part 1: MK-8521 64/120 μg/day

Part 1: MK-8521 34/72 μg/day

Part 1: Liraglutide 0.6/1.2/1.8 mg/day

Part 1: Placebo for MK-8521

Part 2: MK-8521 64/120/180/240/300 µg/day-T2DM

Part 2: Liraglutide 0.6/1.2/1.8 mg/day-T2DM

Part 2: Placebo for MK-8521-T2DM

Part 2: MK-8521 64/120 µg/day-Non-Diabetic Overweight/Obese

Arm Description

Type 2 diabetes mellitus (T2DM) participants received once daily subcutaneous MK-8521 starting at 64 μg on Days 1 to 7 and escalated to 120 μg on Days 8 to 14.

T2DM participants received once daily subcutaneous MK-8521 starting at 34 μg on Days 1 to 7 and escalated to 72 μg on Days 8 to 14.

T2DM participants received once daily subcutaneous liraglutide starting at 0.6 mg on Day 1 and 2, escalated to 1.2 mg on Days 3 to 7, and escalated to 1.8 mg on Days 8 to 14.

T2DM participants received once daily subcutaneous placebo for MK-8521 for 14 days.

T2DM participants received once daily subcutaneous MK-8521 titrated to 300 µg starting at 64 µg and increasing to 120 µg on Day 8, 180 µg on Day 15, 240 µg on Day 20, and 300 µg on Day 25. The total number of dosing days was 29.

T2DM participants received once daily subcutaneous liraglutide titrated to 1.8 mg starting at 0.6 mg and increasing to 1.2 mg on Day 8, and 1.8 mg on Day 15. The total number of dosing days was 29.

T2DM participants received once daily subcutaneous placebo for MK-8521 for 29 days.

Non-diabetic overweight/obese participants received once daily subcutaneous MK-8521 titrated to 120 µg starting at 64 µg and increasing to 120 µg on Day 8. The total number of dosing days was 14.

Outcomes

Primary Outcome Measures

Number of Participants Experiencing Adverse Events (AEs) in Part 1

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. AEs are presented by individual dose received by participants during titration in an assigned study treatment sequence.

Number of Participants Experiencing Adverse Events (AEs) in Part 2

Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 1

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.

Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 2

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Semi-recumbent heart rate was assessed at baseline on Day 1; Day 7 at predose, 2, 4, 6, 8, 12, 13, 14, 15, 16, 22 hours postdose; and prior to dosing on Day 8. Heart rate was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr was calculated as the area under the measurement-time curve (AUC) divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 7 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 7: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 8. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 7 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, 13, 14, 15, 16, 22 hours postdose and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 14 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, 16, hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 14 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 19 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 19: predose, 2, 4, 6, 8, 12, 16, hours post dose; and prior to dosing on Day 20. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 19 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 24 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 24: predose, 2, 4, 6, 8, 12, 16, hours postdose; and prior to dosing on Day 25. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 24 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 29 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; and Day 29: predose, 2, 4, 6, 8, 12, 16 and 24 hours postdose. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 29 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Peak Heart Rate (PHR) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 7: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 8. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 7 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Peak Heart Rate (PHR) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 14 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Peak Heart Rate (PHR) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 19: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 20. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 19 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Peak Heart Rate (PHR) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 24: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 25. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 24 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Peak Heart Rate (PHR) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; and Day 29: predose 2, 4, 6, 8, 12, 16, and 24 hours post dose. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 29 minus baseline where baseline was defined as predose on Day 1.

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 7 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 7 dose (predose Day 8) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 14 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 14 dose (predose Day 15) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 19 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 19 dose (predose Day 20) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 24 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 24 dose (predose Day 25) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 29 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 29 dose minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

AUC0-24hr was the area under the concentration-time curve of MK-8521 from time zero to 24 hours after administration. Plasma samples were collected from predose to 24 hours postdose for determination of AUC0-24hr. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. AUC0-24hr is presented as geometric mean and percent coefficient of variation of geometric mean.

Maximum Concentration (Cmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Cmax was the maximum observed concentration of MK-8521 in plasma after administration. Plasma samples were collected from predose to 24 hours postdose for determination of Cmax. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.

Maximum Concentration (Cmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Cmax was the maximum observed concentration of MK-8521 in plasma after administration on Day 14. Plasma samples were collected from predose to 120 hours postdose for determination of Cmax. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.

Trough Concentration (Ctrough) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Ctrough was the lowest observed concentration of MK-8521 in plasma. Plasma samples were collected predose on Day 2 (sampled after the Day 1 dose and prior to Day 2 dose), 7, and 14 for determination of Ctrough. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Ctrough is presented as geometric mean and percent coefficient of variation of geometric mean.

Time to Maximum Concentration (Tmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 24 hours postdose for determination of Tmax. Tmax is presented as median with a full range.

Time to Maximum Concentration (Tmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 120 hours postdose for determination of Tmax. Tmax is presented as median with a full range.

Apparent Terminal Half Life (t1/2) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 120 hours postdose for determination of t1/2. t1/2 was measured on Day 14 which is the longest time point for sampling for T2DM participants in Part 1. t1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.

Accumulation Ratio of the Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Plasma samples were collected from predose to 24 hours postdose for determination of the accumulation ratio of AUC0-24hr. The geometric mean accumulation ratio was calculated as Day 7 AUC0-24hr/Day 1 AUC0-24hr and presented as geometric mean ratio with a full range.

Accumulation Ratio of the Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Plasma samples were collected from predose to 24 hours postdose for determination of the accumulation ratio of Cmax. The geometric mean accumulation ratio was calculated as Day 7 Cmax/Day 1 Cmax and presented as geometric mean ratio with a full range.

Accumulation Ratio of the Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Plasma samples were collected predose on Days 2 (sampled after the Day 1 dose and prior to Day 2 dose) and 7 for determination of the accumulation ratio of Ctrough. The geometric mean accumulation ratio was calculated as Day 7 Ctrough/Day 1 Ctrough (sampled after the Day 1 dose and prior to Day 2 dose) and presented as geometric mean ratio with a full range.

Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Accumulation Ratio of the Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Secondary Outcome Measures

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

FPG was measured predose on Days 1 and 7. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 7. FPG is presented as mean change from baseline with a standard error.

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

FPG was measured predose on Days 1 and 14. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 14. FPG is presented as mean change from baseline with a standard error.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Blood samples for glucose were collected immediately prior to, and after each meal. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Blood for plasma glucose concentrations was obtained at predose Day 1 at pre meal (breakfast), 0.5, 1, 2, 3, 4 (pre lunch), 4.5, 5, 6, 7, 10 (pre dinner), 10.5, 11, 12, 13, 15 and 23 hours post breakfast meal; and on Day 7 at 1 (pre breakfast), 1.5, 2, 3, 4, 5 (pre lunch), 5.5, 6, 7, 8, 11 (pre dinner), 11.5, 12, 13, 14, 16, 24 hours post dose. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with fixed effects for treatment, day and treatment by day interaction, a random effect for participant, and baseline 24-hour WMG as a covariate. WMG is presented as least squares mean with a 95% confidence interval.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Blood samples for glucose were collected immediately prior to and after each meal. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Blood for plasma glucose concentrations was obtained on Day -1 at pre meal (breakfast), 0.5, 1, 2, 3, 4 (pre lunch), 4.5, 5, 6, 7, 10 (pre dinner), 10.5, 11, 12, 13, 15 and 23 hours post breakfast meal; and on Day 14 at 1 (pre breakfast), 1.5, 2, 3, 4, 5 (pre lunch), 5.5, 6, 7, 8, 11(pre dinner), 11.5, 12, 13, 14, 16, 24 hours post dose. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with fixed effects for treatment, day and treatment by day interaction, a random effect for participant, and baseline 24-hour WMG as a covariate. WMG is presented as least squares mean with a 95% confidence interval.

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

FPG was measured predose on Days 1 and 19. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 19. FPG is presented as least squares mean change from baseline with a 95% confidence interval.

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

FPG was measured predose on Days 1 and 24. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 24. FPG is presented as least squares mean change from baseline with a 95% confidence interval.

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

FPG was measured predose on Days 1 and 29. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 29. FPG is presented as least squares mean change from baseline with a 95% confidence interval.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 14 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 14 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 19 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 19 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 24 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 24 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 29 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 29 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Cmax was the maximum observed concentration of MK-8521 in plasma after administration. Plasma samples were collected from predose to 120 hours postdose for determination of Cmax. Per protocol, Cmax in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.

Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Ctrough was the lowest observed concentration of MK-8521 in plasma. Plasma samples were collected predose on Day 2 (sampled after the Day 1 dose and prior to Day 2 dose), 7, 14, 19, 24, and 29 for determination of Ctrough. Per protocol, Ctrough in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Ctrough is presented as geometric mean and percent coefficient of variation of geometric mean.

Time to Maximum Concentration (Tmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 120 hours postdose for determination of Tmax. Per protocol, Tmax in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Tmax is presented as median with a full range.

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 120 hours postdose for determination of t1/2. Per protocol, t1/2 was measured on Day 29 which is the longest time point for sampling for T2DM participants 1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Non-Diabetic Overweight/Obese Participants in Part 2

t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 24 hours postdose for determination of t1/2. Per protocol, t1/2 was measured on Day 14 which is the longest time point for sampling for non-diabetic overweight/obese participants 1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.

Full Information

NCT ID

NCT01982630

First Posted

November 6, 2013

Last Updated

December 16, 2021

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT01982630

Brief Title

Study of the Safety and Efficacy of MK-8521 Compared to Placebo and a Diabetes Drug in Participants With Type 2 Diabetes Mellitus (MK-8521-003)

Official Title

A Phase Ib, Multicenter, Placebo and Active- Comparator-Controlled, Randomized, Double-Blind, Clinical Trial to Evaluate the Safety and Efficacy of MK-8521 Compared to Placebo and a Diabetes Drug in Subjects With Type 2 Diabetes Mellitus

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Completed

Study Start Date

November 7, 2013 (Actual)

Primary Completion Date

October 3, 2014 (Actual)

Study Completion Date

October 3, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study will evaluate the safety, efficacy, and pharmacokinetics of MK-8521 given once daily compared to placebo and another diabetes drug in participants with Type 2 diabetes mellitus (T2DM). This study was modified by a protocol amendment to a 2-part trial to further test the safety and tolerability of MK-8521 at higher doses and to compare MK-8521 pharmacokinetics between participants with T2DM and healthy participants. An additional cohort of T2DM participants and a cohort of non-diabetic obese participants has been added.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

87 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: MK-8521 64/120 μg/day

Arm Type

Experimental

Arm Description

Type 2 diabetes mellitus (T2DM) participants received once daily subcutaneous MK-8521 starting at 64 μg on Days 1 to 7 and escalated to 120 μg on Days 8 to 14.

Arm Title

Part 1: MK-8521 34/72 μg/day

Arm Type

Experimental

Arm Description

T2DM participants received once daily subcutaneous MK-8521 starting at 34 μg on Days 1 to 7 and escalated to 72 μg on Days 8 to 14.

Arm Title

Part 1: Liraglutide 0.6/1.2/1.8 mg/day

Arm Type

Active Comparator

Arm Description

T2DM participants received once daily subcutaneous liraglutide starting at 0.6 mg on Day 1 and 2, escalated to 1.2 mg on Days 3 to 7, and escalated to 1.8 mg on Days 8 to 14.

Arm Title

Part 1: Placebo for MK-8521

Arm Type

Placebo Comparator

Arm Description

T2DM participants received once daily subcutaneous placebo for MK-8521 for 14 days.

Arm Title

Part 2: MK-8521 64/120/180/240/300 µg/day-T2DM

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Liraglutide 0.6/1.2/1.8 mg/day-T2DM

Arm Type

Active Comparator

Arm Description

T2DM participants received once daily subcutaneous liraglutide titrated to 1.8 mg starting at 0.6 mg and increasing to 1.2 mg on Day 8, and 1.8 mg on Day 15. The total number of dosing days was 29.

Arm Title

Part 2: Placebo for MK-8521-T2DM

Arm Type

Placebo Comparator

Arm Description

T2DM participants received once daily subcutaneous placebo for MK-8521 for 29 days.

Arm Title

Part 2: MK-8521 64/120 µg/day-Non-Diabetic Overweight/Obese

Arm Type

Experimental

Arm Description

Non-diabetic overweight/obese participants received once daily subcutaneous MK-8521 titrated to 120 µg starting at 64 µg and increasing to 120 µg on Day 8. The total number of dosing days was 14.

Intervention Type

Drug

Intervention Name(s)

MK-8521

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

Number of Participants Experiencing Adverse Events (AEs) in Part 1

Description

Time Frame

Up to approximately 42 days

Title

Number of Participants Experiencing Adverse Events (AEs) in Part 2

Description

Time Frame

Up to approximately 57 days

Title

Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 1

Description

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.

Time Frame

Up to approximately 14 days

Title

Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 2

Description

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.

Time Frame

Up to approximately 29 days

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 7 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 7 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 14 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, 16, hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 14 minus baseline where baseline was defined as predose on Day 1.

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 14 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 19 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 19 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 24 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 24 dose

Title

Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 29 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 29 dose

Title

Change From Baseline in Peak Heart Rate (PHR) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 7 dose

Title

Change From Baseline in Peak Heart Rate (PHR) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 14 minus baseline where baseline was defined as predose on Day 1.

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 14 dose

Title

Change From Baseline in Peak Heart Rate (PHR) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 19: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 20. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 19 minus baseline where baseline was defined as predose on Day 1.

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 19 dose

Title

Change From Baseline in Peak Heart Rate (PHR) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 24: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 25. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 24 minus baseline where baseline was defined as predose on Day 1.

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 24 dose

Title

Change From Baseline in Peak Heart Rate (PHR) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; and Day 29: predose 2, 4, 6, 8, 12, 16, and 24 hours post dose. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 29 minus baseline where baseline was defined as predose on Day 1.

Time Frame

Baseline (predose Day 1) and up to 24 hours post Day 29 dose

Title

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 7 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose Day 1) and Day 8 (24 hours after Day 7)

Title

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 14 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 14 dose (predose Day 15) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Time Frame

Baseline (predose Day 1) and Day 15 (24 hours after Day 14)

Title

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 19 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 19 dose (predose Day 20) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Time Frame

Baseline (predose Day 1) and Day 20 (24 hours after Day 19)

Title

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 24 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 24 dose (predose Day 25) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Time Frame

Baseline (predose Day 1) and Day 25 (24 hours after Day 24)

Title

Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 29 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 29 dose minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.

Time Frame

Baseline (predose Day 1) and Day 30 (24 hours after Day 29)

Title

Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1, 7, and 14

Title

Maximum Concentration (Cmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7

Title

Maximum Concentration (Cmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14

Title

Trough Concentration (Ctrough) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose on Days 2, 7, and 14

Title

Time to Maximum Concentration (Tmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7

Title

Time to Maximum Concentration (Tmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14

Title

Apparent Terminal Half Life (t1/2) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7

Title

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14

Title

Accumulation Ratio of the Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7

Title

Accumulation Ratio of the Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7

Title

Accumulation Ratio of the Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose on Days 2 and 7

Title

Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Description

Time Frame

Predose and 1, 2, 6, 10, 16, and 24 hours postdose on Days 1, 7, and 14

Title

Description

Time Frame

Predose and 1, 2, 6, 10, 16, and 24 hours post-dose on Days 1 and 7

Secondary Outcome Measure Information:

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose on Days 1 (baseline) and 7

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Predose on Days 1 (baseline) and 14

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 7 dose

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1

Description

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 14 dose

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Predose on Days 1 (baseline) and 14

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Predose on Days 1 (baseline) and 19

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Predose on Days 1 (baseline) and 24

Title

Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Predose on Days 1 (baseline) and 29

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 14 dose

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 19 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 19 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 19 dose

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 24 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 24 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 24 dose

Title

Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 29 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 29 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.

Time Frame

Baseline (predose and before food on Day 1) and up to 24 hours post Day 29 dose

Title

Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Description

Time Frame

Predose and 1, 2, 6, 10, 16, 24 hours post dose on Days 1, 7, 14, 19, 24 (T2DM) and Days 1 and 7 (Non-Diabetic Overweight/Obese); predose and 1, 2, 6, 10, 16, 24, 72, 96. and 120 hours post dose on Day 14 (Non-Diabetic Overweight/Obese) and Day 29 (T2DM).

Title

Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Description

Time Frame

Predose on Days 2 (sampled 24 hours after Day 1 dose) and 7, 14, 19, 24, and 29

Title

Time to Maximum Concentration (Tmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2

Description

Time Frame

Title

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2

Description

t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 120 hours postdose for determination of t1/2. Per protocol, t1/2 was measured on Day 29 which is the longest time point for sampling for T2DM participants 1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.

Time Frame

Predose and 1, 2, 6, 10, 16, 24, 72, 96 and 120 hours post dose on Day 29

Title

Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Non-Diabetic Overweight/Obese Participants in Part 2

Description

Time Frame

Predose and 1, 2, 6, 10, 16, and 24 hours post dose on Day 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male, or female of non-childbearing potential with Type 2 diabetes mellitus (Parts 1 and 2) or non-diabetic (Part 2) Body mass index (BMI) between: ≥27 and ≤40 kg/m^2 A1C (average blood sugar for the past 2 to 3 months) value ≥7.0 and ≤11.0 % (Part 1) or ≥ 6.5 and ≤11.0 % (Part 2) at the time of screening (T2DM participants) A1C value <5.7 at the time of screening (non-diabetic subjects in Part 2 only) On a stable dose of metformin (≥1000 mg total daily dose) for at least 12 weeks at the time of screening (T2DM participants) Exclusion Criteria: Mentally or legally incapacitated History of clinically significant psychiatric disorder of the last 5 years. Participants with situational depression may be enrolled in the trial at the discretion of the Investigator History of Type 1 diabetes mellitus or a history of ketoacidosis History of clinically significant gastrointestinal, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases History of cardiovascular disease or cardiac conduction disorder History of cancer (malignancy). Exceptions may include adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated ≥10 years prior to the pre-screening visit History of proliferative diabetic retinopathy or maculopathy Clinically significant diabetic autonomic neuropathy QTc interval ≥470 msec (for males) or ≥480 msec (for females) Clinical significant electrocardiogram (ECG) abnormality Positive for hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus (HIV) On a weight loss program and is not weight-stable (weight stable is defined history of <5% change in body weight in the last 3 months On a weight loss medication or has undergone bariatric surgery Major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit Participated in another investigational trial within 4 weeks prior to the pretrial (screening) visit History of acute or chronic pancreatitis of any etiology Mean value for triplicate semi-recumbent systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg (after at least a 10-minute seated rest) and blood pressure is considered unlikely to be below these limits by Day-1 (Randomization) with initiation or adjustment of antihypertensive medication Event of severe hypoglycemia with seizure or loss of consciousness in the past 12 months Treated with anti-hyperglycemic agents other than metformin within the last 12 weeks Previous exposure to any glucagon-like peptide-1 (GLP-1) receptor agonist (e.g. Byetta™, Victoza™ or investigational agents)

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

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Learn more about this trial

Study of the Safety and Efficacy of MK-8521 Compared to Placebo and a Diabetes Drug in Participants With Type 2 Diabetes Mellitus (MK-8521-003)

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