Clinical trial NCT01982630: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-11-13
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Number of Participants Experiencing Adverse Events (AEs) in Part 1
timeFrame: Up to approximately 42 days
measure: Number of Participants Experiencing Adverse Events (AEs) in Part 2
timeFrame: Up to approximately 57 days
measure: Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 1
timeFrame: Up to approximately 14 days
measure: Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 2
timeFrame: Up to approximately 29 days
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 7 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 7 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 14 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 14 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 19 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 24 dose
measure: 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
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 29 dose
measure: Change From Baseline in Peak Heart Rate (PHR) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 7 dose
measure: Change From Baseline in Peak Heart Rate (PHR) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 14 dose
measure: Change From Baseline in Peak Heart Rate (PHR) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 19 dose
measure: Change From Baseline in Peak Heart Rate (PHR) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 24 dose
measure: Change From Baseline in Peak Heart Rate (PHR) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and up to 24 hours post Day 29 dose
measure: Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 7 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and Day 8 (24 hours after Day 7)
measure: Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 14 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and Day 15 (24 hours after Day 14)
measure: Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 19 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and Day 20 (24 hours after Day 19)
measure: Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 24 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and Day 25 (24 hours after Day 24)
measure: Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 29 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose Day 1) and Day 30 (24 hours after Day 29)
measure: 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
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1, 7, and 14
measure: Maximum Concentration (Cmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7
measure: Maximum Concentration (Cmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14
measure: Trough Concentration (Ctrough) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose on Days 2, 7, and 14
measure: Time to Maximum Concentration (Tmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7
measure: Time to Maximum Concentration (Tmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14
measure: Apparent Terminal Half Life (t1/2) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7
measure: Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, 24, 72, 96, and 120 hours post-dose on Day 14
measure: 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
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7
measure: Accumulation Ratio of the Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose and 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours post-dose on Days 1 and 7
measure: Accumulation Ratio of the Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose on Days 2 and 7
measure: 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
timeFrame: Predose and 1, 2, 6, 10, 16, and 24 hours postdose on Days 1, 7, and 14
measure: 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
timeFrame: Predose and 1, 2, 6, 10, 16, and 24 hours post-dose on Days 1 and 7
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose on Days 1 (baseline) and 7
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Predose on Days 1 (baseline) and 14
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 7 dose
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 14 dose
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Predose on Days 1 (baseline) and 14
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Predose on Days 1 (baseline) and 19
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Predose on Days 1 (baseline) and 24
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Predose on Days 1 (baseline) and 29
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 14 dose
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 19 dose
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 24 dose
measure: Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Baseline (predose and before food on Day 1) and up to 24 hours post Day 29 dose
measure: Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
timeFrame: 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).
measure: Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
timeFrame: Predose on Days 2 (sampled 24 hours after Day 1 dose) and 7, 14, 19, 24, and 29
measure: Time to Maximum Concentration (Tmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
timeFrame: 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).
measure: Apparent Terminal Half Life (t1/2) of MK-8521 on Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
timeFrame: Predose and 1, 2, 6, 10, 16, 24, 72, 96 and 120 hours post dose on Day 29
measure: Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Non-Diabetic Overweight/Obese Participants in Part 2
timeFrame: Predose and 1, 2, 6, 10, 16, and 24 hours post dose on Day 14
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: