Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control

Study Overview
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Brief Summary
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The purpose of this study is to compare the change in hemoglobin A1c (HbA1c) from baseline to Week 12 between the 3 treatment arms.

Official Title
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Safety and Efficacy of Insulin Glargine Injection [rDNA Origin] Treatment in Place of the TZD or the Sulfonylurea or Metformin in Triple Agent Therapy for T2DM Adult Subjects With Unsatisfactory Control

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin Glargine
* Drug: Insulin Glulisine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects meeting all of the following criteria will be considered for enrollment into the study: 18 to 79 years of age, inclusive Diagnosis of type 2 diabetes mellitus Continuous treatment with therapeutic dosages of a thiazolidinedione (rosiglitazone or pioglitazone), metformin, and a sulfonylurea daily prior to entering the study Screening HbA1c ≥ 7.0% Fasting C-peptide concentration ≥ 0.27 ng/ml Negative glutamic acid decarboxylase (GAD) antibodies Demonstrated ability and willingness to perform self-monitoring blood glucose (SMBG) using a plasma-referenced glucose meter and to maintain an electronic diary Demonstrated ability and willingness to use an electronic diary to record SMBG results, insulin doses, and hypoglycemic events. Signed, informed consent and Health Insurance Portability and Accountability Act (HIPAA) documentation Exclusion Criteria: Stroke, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or angina pectoris, within the last 12 months Cardiac status New York Heart Association (NYHA) III-IV Impaired renal function as shown by, but not limited to, serum creatinine ≥ 1.5 mg/dL for males, or ≥ 1.4 mg/dL for females Chronic use of insulin: (more than 3 weeks of continuous use) in the past 12 months Acute infection Clinically significant peripheral edema Acute or chronic history of metabolic acidosis, including diabetic ketoacidosis Clinical evidence of active liver disease, or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 2.5 times the upper limit of the normal range History of hypoglycemia unawareness Pregnancy or lactation Known hypersensitivity to insulin glargine or any of the components of Lantus® Known hypersensitivity to insulin glulisine or any of the components of Apidra® Any malignancy within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or adequately treated cervical carcinoma in situ Current addiction or current alcohol abuse, or history of substance or alcohol abuse within the last 2 years Diagnosis of dementia Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study subject is currently taking or was treated with the following medications 3 months prior to screening: Byetta(exenatide), Starlix(nateglinide),Prandin (repaglinide), Januvia(sitagliptin), Janumet(metformin + sitagliptin) Any disease or condition that in the opinion of the investigator and/or sponsor may interfere with the completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulins + Sulfonylurea (SU) + Thiazolidinedione (TZD)<br>Arm 1: Insulin glargine administered subcutaneously once daily plus a sulfonylurea and a TZD. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%) | Drug: Insulin Glargine<br>* Insulin glargine administered subcutaneously once daily.<br>Drug: Insulin Glulisine<br>* Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)<br>|
| Experimental: Insulins + Metformin (MET) + Thiazolidinedione (TZD)<br>Arm 2: Insulin glargine administered subcutaneously once daily plus metformin and a TZD. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%) | Drug: Insulin Glargine<br>* Insulin glargine administered subcutaneously once daily.<br>Drug: Insulin Glulisine<br>* Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)<br>|
| Experimental: Insulins + Metformin (MET) + Sulfonylurea (SU)<br>Arm 3: Insulin glargine administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added arms after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%) | Drug: Insulin Glargine<br>* Insulin glargine administered subcutaneously once daily.<br>Drug: Insulin Glulisine<br>* Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin A1c (HbA1c) From Baseline to Week 12 |  | 12 weeks from Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Individual Time Points in HbA1c, Insulin Doses, and Total Insulin Dosage |  | 60 weeks from Baseline | 
| Percentage of Subjects Achieving an HbA1C Less Than (<) 7.0% and Less Than (<) 6.5% |  | 60 weeks from Baseline | 
| Change From Baseline to Study Time Points in 7-point Blood Glucose (BG) Profile (Before Meals, 2 Hours After Meals, at Bedtime) |  | 60 weeks from Baseline | 
| Change From Baseline to End of Study and to Individual Time Points in Components of Lipid Profile (Total Cholesterol, High-density Lipoprotein Cholesterol [HDL], Low-density Lipoprotein Cholesterol [LDL], Triglycerides, LDL Subfractions) |  | 60 weeks from Baseline | 
| Occurrences of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia, and Serious Hypoglycemia | Symptomatic hypoglycemia (BG<70 mg/dL, BG<50 mg/dL): including 1 or more symptoms: headache, dizziness, general feeling of weakness, drowsiness, confusion, pallor, irritability, trembling, sweating, rapid heartbeat & a cold, clammy feeling. Mild-to-moderate hypoglycemia: SMBG ≥ 36 mg/dL but <70 mg/dL Severe hypoglycemia: assistance of another party is required & either: SMBG of <36 mg/dL, or with prompt response to treatment with oral carbohydrates, IV glucose or glucagon. Serious hypoglycemia: Hypoglycemia with coma/loss of consciousness Or Hypoglycemia seizure/convulsion. | 60 weeks from Baseline | 
| Rate of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia and Serious Hypoglycemia | Symptomatic hypoglycemia (BG<70 mg/dL, BG<50 mg/dL): including 1 or more symptoms: headache, dizziness, general feeling of weakness, drowsiness, confusion, pallor, irritability, trembling, sweating, rapid heartbeat & a cold, clammy feeling. Mild-to-moderate hypoglycemia: SMBG ≥ 36 mg/dL but <70 mg/dL Severe hypoglycemia: assistance of another party is required & either: SMBG of <36 mg/dL, or with prompt response to treatment with oral carbohydrates, IV glucose or glucagon. Serious hypoglycemia: Hypoglycemia with coma/loss of consciousness Or Hypoglycemia seizure/convulsion. | 60 Weeks from Baseline |