A Preliminary Study of the Efficacy and Safety of MK-8521 for Type 2 Diabetes (MK-8521-004)

Study Overview
=================
Brief Summary
-----------------
This is a multicenter randomized, double-blind, placebo- and active-controlled (liraglutide; Victoza®), parallel-group, clinical trial of MK-8521 in participants with type 2 diabetes mellitus (T2DM) with inadequate glycemic control while on a stable dose of metformin (≥1000 mg/day). The trial will include a 1-week screening period; at least an 8-week antihyperglycemic agent (AHA) washout period, if required; a 14-week blinded therapy period (which includes single-blind run-in and double-blind therapy); and a 14-day post-treatment visit, 2 weeks after the last dose of investigational product. The primary hypothesis of the trial is that MK-8521 provides greater reduction in hemoglobin A1C relative to placebo after 12 weeks of once-daily administration in participants with T2DM with inadequate glycemic control on metformin monotherapy.

Official Title
-----------------
A Phase IIa, Multicenter, Placebo- and Active-controlled, Randomized, Double-Blind, Clinical Trial to Evaluate the Safety and Efficacy of MK-8521 Compared to Placebo in Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Type II Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: MK-8521
* Drug: Placebo
* Drug: Liraglutide
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have T2DM in accordance with American Diabetes Association guidelines Be on metformin monotherapy (>-1000 mg/day: metformin IR or metformin XR) for at least 12 weeks prior to study start with a hemoglobin A1C (A1C) >-7.5 and <-10.5% OR Be on dual therapy with metformin (>-1000 mg/day: dose stable for at least 4 weeks prior to study start) with an A1C of >-7.0% and <-10.0% and a second AHA and be willing to washout the second AHA. Allowable AHAs are dipeptidyl peptidase 4 (DPP-4 inhibitors), alpha-glucosidase inhibitors, sulfonylureas, and glinides. Have a body mass index (BMI) ≥23 kg/m^2 and ≤40 kg/m^2 Is a female who is not of reproductive potential, or is a female of reproductive potential who agrees to avoid becoming pregnant: while receiving study drug and for 14 days after the last dose of study drug Exclusion Criteria: Have a history of type 1 diabetes or a history of diabetic ketoacidosis Has a history of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant) Has been treated with any gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) receptor agonist (e.g. Byetta™, Victoza™ or investigational agents) within the last 6 months or has had GLP-1 receptor agonist discontinued due to gastrointestinal intolerance or lack of efficacy. Note: treatment with a GLP-1 receptor agonist that was discontinued >6 months prior to study start is not an exclusion if the GLP-1 receptor agonist was discontinued for reasons other than gastrointestinal intolerance or lack of efficacy. Has a history of clinically significant gastrointestinal disorder (including diabetic gastroparesis; irritable bowel disease; recurrent episodes of nausea, vomiting, diarrhea and abdominal pain) Has a history of clinically significant and active, immunological, respiratory, genitourinary or major neurological (including stroke, transient ischemic attack and chronic seizures) abnormalities or diseases Has a history of cardiovascular disease (including diabetic cardiomyopathy) or significant cardiac condition (including a history of myocardial infarction, stable or unstable angina, arterial revascularization, pathologic, symptomatic or sustained tachyarrhythmia [e.g. atrial fibrillation, sustained supraventricular tachycardia, symptomatic non-sustained supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, Wolf-Parkinson-White syndrome, congenital long QT syndrome, etc.]) or heart failure Has a family history of medullary carcinoma of the thyroid or multiple endocrine neoplasm type-2 syndrome Has active diabetic proliferative retinopathy or a history of maculopathy Has human immunodeficiency virus (HIV) Has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or active symptomatic gallbladder disease Is on a weight loss medication or has undergone bariatric surgery Has a history of acute or chronic pancreatitis of any etiology Had an event of severe hypoglycemia with neuroglycopenia in the past 12 months Has a positive urine pregnancy test Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of investigational product Routinely consumes >1 alcoholic drinks per day or >7 alcoholic drinks per week or engages in binge drinking Routinely consumes ≥480mg /day caffeine in caffeinated beverages (1 cup of coffee contains approximately 120 mg of caffeine Is taking a beta blocker or medications with sympathomimetic activity (e.g. pseudoephedrine, phenylpropanolamine, etc.) Is currently a user of nicotine or nicotine containing products or does not agree to refrain from using nicotine during the trial, including 14 days following the last dose of investigational product Is currently a user of any illicit drugs (including any marijuana use) or has a history of drug (including alcohol) abuse within approximately 5 years has other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or blinded investigational product administration

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8521 300 μg<br>Participants receive double-blind MK-8521 300 μg daily (QD), subcutaneously, over 12 weeks. | Drug: MK-8521<br>* Dose strengths: 180 μg QD administered subcutaneously. A 2-step dose escalation regimen [60 μg, 120 μg] over the first 2 weeks is used to achieve the final dose up to 180 μg.); 300 μg QD administered subcutaneously (A 3-step dose escalation regimen [60 μg, 120 μg, 180 μg] over the first 3 weeks is used to achieve the final dose up to 300 μg.<br>Drug: Placebo<br>* Double dummy matching placebo for the MK-8521 and placebo arms: matching placebo for MK-8521 300 μg QD administered subcutaneously; matching placebo for MK-8521 180 μg QD administered subcutaneously. A dose escalation regimen consistent with that of the MK-8521 300 μg and 180 μg arms of the study; mock escalation will be performed over the first 2 to 3 weeks.<br>Drug: Metformin<br>* Metformin immediate release (IR) or metformin extended release (XR) administered ≥1000 mg QD as background therapy<br>|
| Experimental: MK-8521 180 μg<br>Participants receive double-blind MK-8521 180 μg QD, subcutaneously, over 12 weeks. | Drug: MK-8521<br>* Dose strengths: 180 μg QD administered subcutaneously. A 2-step dose escalation regimen [60 μg, 120 μg] over the first 2 weeks is used to achieve the final dose up to 180 μg.); 300 μg QD administered subcutaneously (A 3-step dose escalation regimen [60 μg, 120 μg, 180 μg] over the first 3 weeks is used to achieve the final dose up to 300 μg.<br>Drug: Placebo<br>* Double dummy matching placebo for the MK-8521 and placebo arms: matching placebo for MK-8521 300 μg QD administered subcutaneously; matching placebo for MK-8521 180 μg QD administered subcutaneously. A dose escalation regimen consistent with that of the MK-8521 300 μg and 180 μg arms of the study; mock escalation will be performed over the first 2 to 3 weeks.<br>Drug: Metformin<br>* Metformin immediate release (IR) or metformin extended release (XR) administered ≥1000 mg QD as background therapy<br>|
| Placebo Comparator: Placebo<br>Participants receive matching double-blind placebo, QD over 12 weeks. | Drug: Placebo<br>* Double dummy matching placebo for the MK-8521 and placebo arms: matching placebo for MK-8521 300 μg QD administered subcutaneously; matching placebo for MK-8521 180 μg QD administered subcutaneously. A dose escalation regimen consistent with that of the MK-8521 300 μg and 180 μg arms of the study; mock escalation will be performed over the first 2 to 3 weeks.<br>Drug: Metformin<br>* Metformin immediate release (IR) or metformin extended release (XR) administered ≥1000 mg QD as background therapy<br>|
| Active Comparator: Liraglutide 1.8 mg<br>Participants receive open-label 1.8 mg of liraglutide, QD, subcutaneously, over 12 weeks. | Drug: Liraglutide<br>* Dose strength: 1.8 mg QD administered subcutaneously. A 2-step dose escalation regimen (0.6 mg, 1.2 mg) over the first 2 weeks is used to achieve the final dose up to 1.8 mg.<br>* Other names: Victoza®;Drug: Metformin<br>* Metformin immediate release (IR) or metformin extended release (XR) administered ≥1000 mg QD as background therapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | A1C is the percentage of hemoglobin that has glucose bound to it and is a blood marker used to report average blood glucose levels over prolonged periods of time. A1C is reported as a percentage (%). This change from baseline reflects the Week 12 A1C minus the Week 0 A1C. | Baseline and Week 12 | 
| Number of Participants With an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Week 14 | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Week 12 | 
| Number of Participants With an AE of Symptomatic Hypoglycemia | An 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. Hypoglycemia episodes are those with glucose values ≤70 mg/dL (3.9 mmol/L). Symptomatic hypoglycemia episodes were episodes with clinical symptoms reported by the investigator as hypoglycemia and classified as adverse events. | Up to Week 14 | 
| Change From Baseline in Heart Rate at Week 12 | This change from baseline reflects the Week 12 heart rate minus the Week 0 heart rate. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Body Weight at Week 12 | This change from baseline reflects the Week 12 body weight minus the Week 0 body weight. | Baseline and Week 12 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | This change from baseline reflects the Week 12 FPG minus the Week 0 FPG. | Baseline and Week 12 | 
| Change From Baseline in Fasting Low Density Lipoprotein (LDL) Cholesterol at Week 12 | This change from baseline reflects the Week 12 fasting LDL cholesterol minus the Week 0 fasting LDL cholesterol. | Baseline and Week 12 | 
| Change From Baseline in Fasting High Density Lipoprotein (HDL) Cholesterol at Week 12 | This change from baseline reflects the Week 12 fasting HDL cholesterol minus the Week 0 fasting HDL cholesterol. | Baseline and Week 12 | 
| Change From Baseline in Fasting Triglycerides at Week 12 | This change from baseline reflects the Week 12 fasting triglycerides minus the Week 0 fasting triglycerides. | Baseline and Week 12 | 
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 | This change from baseline reflects the Week 12 SBP minus the Week 0 SBP. | Baseline and Week 12 | 
| Change From Baseline in Diastolic Blood Pressure (DBP) at Week 12 | This change from baseline reflects the Week 12 DBP minus the Week 0 DBP. | Baseline and Week 12 |