12-Week Study of DS-8500a in Subjects With Type 2 Diabetes Mellitus on Metformin

Study Overview
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Brief Summary
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The hypothesis of this Phase 2, 12-week study, is that DS-8500a will improve glycemic control relative to placebo, based on changes in HbA1c, with acceptable safety and tolerability, in patients with Type 2 Diabetes Mellitus (T2DM) who are treated with metformin.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled With Active Comparator, 12-Week Study of DS-8500a in Subjects With Type 2 Diabetes Mellitus on Metformin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin 100 mg
* Drug: DS-8500a 25mg
* Drug: Placebo Tablet
* Drug: Placebo Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written informed consent and adhere to the study visit schedule and treatment Diagnosed with Type 2 diabetes mellitus as defined in the American Diabetes Association Standards of Medical Care in Diabetes 2015 Male or female ≥ 18 and ≤ 70 years of age Screening fasting C-peptide > 0.5 ng/mL Women of child bearing potential (WOCBP) must be willing to use double-barrier contraception for the entire study WOCBP must have a negative pregnancy test (human chorionic gonadotropin, beta subunit [βhCG]) before entering the Lead-in Period Body mass index ≥ 25 kg/m2 and ≤ 45 kg/m2 at the Screening Visit On stable (≥ 8 weeks) metformin monotherapy ≥ 1000 mg/day Screening HbA1c ≥ 7.0% and ≤ 10% Taking ≥ 80% and ≤ 120% of both dispensed DS-8500a placebo tablets and sitagliptin placebo capsules during the Lead-in Period Exclusion Criteria: History of type 1 diabetes and/or history of ketoacidosis History of insulin use for > 2 weeks within 2 months prior to the Screening Visit Two or more readings of fasting Self-monitoring of Blood Glucose (SMBG) > 240 mg/dL or worsening symptoms of hyperglycemia with one SMBG level of > 240 mg/dL during the second week of Lead-in Period, confirmed by laboratory measurement Screening hemoglobin <12 g/dL for males and <11 g/dL for females Blood donation within 2 months prior to the Screening Visit or plans to donate blood or blood products during the study Subjects after bariatric surgery or any gastric bypass Screening thyroid stimulating hormone (TSH) levels not within normal range (based on reference laboratory values ) Screening Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) > 2.0 x upper limit of normal (ULN), and/or total bilirubin > 1.5 x ULN. If a subject has total bilirubin > 1.5 ULN, unconjugated and conjugated bilirubin fractions should be analyzed and only subjects documented to have Gilbert's syndrome may be enrolled Screening Serum creatinine ≥ 1.5 mg/dL for males and ≥ 1.4 mg/dL for females, or creatinine clearance (CrCl) < 50 mL/min for both males and females Screening Creatine kinase (CK) > 3.0 × ULN History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, peripheral arterial event or any revascularization procedure during the 6 months prior to the Screening Visit or planned vascular procedures or surgery during study period History of congestive heart failure (CHF) Exclusionary concomitant medications: a. Eight weeks prior to screening and throughout the duration of the study: Any diabetes medication other than metformin; any prescription or over the counter medication for weight-loss. Systemic corticosteroids (including nasal and inhaled), with the exception of use of topical and ophthalmic corticosteroids. Rosuvastatin > 20 mg daily. b. During treatment periods, additional medications will be prohibited based on potential drug-drug interaction (DDI) (see Section 5.6) Subjects with anticipated interruption in metformin or study drug use during the course of the clinical trial (e.g., due to an imaging procedure involving iodinated contrast media) Subjects in whom treatment with sitagliptin 100 mg is contraindicated ( e.g., known hypersensitivity or intolerance to sitagliptin) or may not be medically advisable (e.g., history of pancreatitis) Abuse of or dependence on prescription medications, illicit drugs, or alcohol within the last 1 year Any history of a malignancy other than basal cell carcinoma within the past 5 years Pregnancy or breast-feeding, or intent to become pregnant during the study period Known (or evidence of) infection with human immunodeficiency virus Any condition, laboratory abnormality, or concomitant therapy which, in the opinion of the Investigator, might pose a risk to the subject or make participation not in the subject's best interest Subject is currently enrolled in or has not yet completed at least 30 days since ending another investigational device or drug study or is receiving other investigational agents A direct or familial relationship with the Sponsor, Investigator, or site personnel affiliated with the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-8500a 25mg<br>One DS-8500a 25 mg tablet, 2 placebo tablets, and one placebo capsule in a once-daily oral dose | Drug: DS-8500a 25mg<br>* DS-8500a 25mg tablet for oral administration<br>* Other names: Investigational product;Drug: Placebo Tablet<br>* Placebo matching DS-8500a tablet for oral administration<br>* Other names: Placebo;Drug: Placebo Capsule<br>* Placebo matching sitagliptin over-capsule for oral administration<br>* Other names: Placebo;|
| Experimental: DS-8500a 50 mg<br>Two DS-8500a 25 mg tablets, 1 placebo tablet, and one placebo capsule in a once-daily oral dose | Drug: DS-8500a 25mg<br>* DS-8500a 25mg tablet for oral administration<br>* Other names: Investigational product;Drug: Placebo Tablet<br>* Placebo matching DS-8500a tablet for oral administration<br>* Other names: Placebo;Drug: Placebo Capsule<br>* Placebo matching sitagliptin over-capsule for oral administration<br>* Other names: Placebo;|
| Experimental: DS-8500a 75 mg<br>Three DS-8500a 25 mg tablets and one placebo capsule in a once-daily oral dose | Drug: DS-8500a 25mg<br>* DS-8500a 25mg tablet for oral administration<br>* Other names: Investigational product;Drug: Placebo Capsule<br>* Placebo matching sitagliptin over-capsule for oral administration<br>* Other names: Placebo;|
| Placebo Comparator: Placebo<br>Three placebo tablets and one placebo capsule in a once-daily oral dose | Drug: Placebo Tablet<br>* Placebo matching DS-8500a tablet for oral administration<br>* Other names: Placebo;Drug: Placebo Capsule<br>* Placebo matching sitagliptin over-capsule for oral administration<br>* Other names: Placebo;|
| Active Comparator: Sitagliptin 100 mg<br>Three placebo tablets and one sitagliptin 100 mg over-capsule in a once-daily oral dose | Drug: Sitagliptin 100 mg<br>* Two sitagliptin 50 mg tablets, over-encapsulated to provide a once-daily dose of 100 mg, for oral administration<br>* Other names: Januvia;Drug: Placebo Tablet<br>* Placebo matching DS-8500a tablet for oral administration<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 12 | Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the three-month average glucose concentration in the blood. Target HbA1c for Type 2 diabetics was less than 7% at the time of this trial. Negative scores show improvement from baseline. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Cholesterol (TC) at Week 12 | Total cholesterol is a measure of the total amount of cholesterol in the blood, including low-density lipoprotein cholesterol (LDL-C) - the bad cholesterol, high-density lipoprotein cholesterol (HDL-C) - the good cholesterol, and triglycerides. The equation to calculate total cholesterol is: LDL + HDL + (triglycerides/5) = total cholesterol. | Baseline, Week 12 | 
| Change From Baseline in LDL-C at Week 12 | LDL-C is known as the bad cholesterol, so a lower score (negative change) means improvement. | Baseline, Week 12 | 
| Change From Baseline in HDL-C at Week 12 | HDL-C is known as the good cholesterol, so a higher score (positive change) means improvement. | Baseline, Week 12 | 
| Change From Baseline in Non-HDL-C at Week 12 | Non-HDL-C is the measure of bad cholesterol in the blood, including triglycerides and LDL-C, so a negative change means improvement. The equation for Non-HDL-C = LDL-C + (triglycerides/5). | Baseline, Week 12 | 
| Change From Baseline in Triglycerides at Week 12 | Triglycerides are a type of fat found in the blood. The body uses them for energy. Some triglycerides are needed for good health. But high triglycerides might raise the risk of heart disease. Since Type 2 diabetics tend to have high triglycerides, a negative change means improvement. | Baseline, Week 12 | 
| Change From Baseline in Area-Under-the Curve 0-3 Hours (AUC0-3h) of Plasma Glucose (PG) in Response to the Mixed Meal Tolerance Test (MMTT) at Week 4 | The MMTT requires a participant to drink a mixed meal, such as Boost or Ensure, that contains protein, carbohydrates, and fat. The goal of the test is to find out how much insulin the pancreas makes in response to food by measuring the level of glucose in the blood. The lower the level of glucose in the blood during the first three hours after the test (AUC0-3h), the more insulin the body has made in response to the test. This would mean a negative change shows improvement. | Baseline, Week 4 | 
| Change From Baseline in AUC0-3h of PG in Response to the MMTT at Week 12 | The MMTT requires a participant to drink a mixed meal, such as Boost or Ensure, that contains protein, carbohydrates, and fat. The goal of the test is to find out how much insulin the pancreas makes in response to food by measuring the level of glucose in the blood. The lower the level of glucose in the blood during the first three hours after the test (AUC0-3h), the more insulin the body has made in response to the test. This would mean a negative change shows improvement. | Baseline, Week 12 | 
| Change From Baseline in Maximum Concentration (Cmax) of PG in Response to MMTT at Week 4 | Cmax measures the highest amount of glucose in the blood, so a negative change means improvement. | Baseline, Week 4 | 
| Change From Baseline in Cmax of PG in Response to MMTT at Week 12 | Cmax measures the highest amount of glucose in the blood, so a negative change means improvement. | Baseline, Week 12 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 2 | Normal fasting plasma glucose -- or blood sugar -- is between 70 and 100 milligrams per deciliter (mg/dL) for people who do not have diabetes. People with Type 2 diabetes typically have FPG that is too high, so a negative change from baseline means improvement. | Baseline, Week 2 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 4 | Normal fasting plasma glucose -- or blood sugar -- is between 70 and 100 milligrams per deciliter (mg/dL) for people who do not have diabetes. People with Type 2 diabetes typically have FPG that is too high, so a negative change from baseline means improvement. | Baseline, Week 4 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 8 | Normal fasting plasma glucose -- or blood sugar -- is between 70 and 100 milligrams per deciliter (mg/dL) for people who do not have diabetes. People with Type 2 diabetes typically have FPG that is too high, so a negative change from baseline means improvement. | Baseline, Week 8 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | Normal fasting plasma glucose -- or blood sugar -- is between 70 and 100 milligrams per deciliter (mg/dL) for people who do not have diabetes. People with Type 2 diabetes typically have FPG that is too high, so a negative change from baseline means improvement. | Baseline, Week 12 | 
| Count of Participants With HbA1c Less Than 7.0% at Week 12 | HbA1C less than 7% is the success goal for many Type 2 diabetics. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 2 diabetes mellitus, interventional, double blind, phase 2