Variable Bolus Regimen 1-2-3 for Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to show the non-inferiority of insulin glulisine administered with 1 meal versus 2 meals versus 3 daily meals, as measured by the change in hemoglobin A1c (HbA1c), from baseline to study week 24.

Official Title
-----------------
One Versus Two Versus Three Daily Rapid-acting Insulin Injections of APIDRA (Insulin Glulisine) as add-on to Lantus® and Oral Sensitizer Basal Therapy in Type 2 Diabetes: a Multicenter, Randomized, Parallel, Open-label Clinical Study

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: insulin glulisine


Participation Criteria
=================
Eligibility Criteria
-----------------
Subjects with type 2 diabetes mellitus who have been using a stable combination oral antidiabetic therapy of 2 or 3 agents in different therapeutic classes for on at least 3 months will be enrolled in this study. Inclusion Criteria: Male and female subjects 18 to 79 years of age with a diagnosis of type 2 diabetes mellitus for at least 6 months Current treatment with a stable dose of 2 oral antidiabetic agents. The oral agents must be in 2 or 3 of the following 3 different classes: Sulfonylurea: dosage greater than or equal to, one-half the maximum recommended dosage (eg, glimepiride >/= 4 mg; glipizide, including gastrointestinal therapeutic system [GITS], >/= 10 mg; glyburide >/= 10 mg; Glynase® >/=3 mg). The dosage must have been stable for at least 3 months prior to screening. Biguanide: metformin dosage ≥ 1000 mg daily, including Glucophage XR®. The dosage must have been stable for at least 3 months prior to screening. Thiazolidinedione (TZD): pioglitazone >/= 15 mg or rosiglitazone >/= 24 mg. The subject must have been using the same thiazolidinedione for at least 6 months,and the dosage must have been stable for at least 3 months prior to screening. HbA1c >/= 8.0% Fasting C-peptide concentration > 0.27 nmol/L Able and willing to perform self-monitoring of blood glucose (SMBG) up to 4 times a day Able and willing to adhere to, and be compliant with, the study protocol Able to read English or Spanish at the sixth-grade level in order to complete the subject reported outcomes component of the study Signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization Exclusion Criteria: Insulin use within the previous year History of hypoglycemia unawareness Acute or chronic, or history of, metabolic acidosis, including diabetic ketoacidosis Impaired renal function as shown by, but not limited to, serum creatinine ≥ 3mg/dL. For subjects taking metformin, serum creatinine >/= 1.5 mg/dL for males, or >/= 1.4 mg/dL for females. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of normal (ULN) Clinically significant peripheral edema if subject is using a TZD History of stroke, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or angina pectoris, within the past 12 months History of, or current, congestive heart failure (New York Heart Association [NYHA] III-IV) requiring pharmacologic treatment Acute infection Any malignancy within the past 5 years, with the exception of adequately treated basal or squamous cell carcinoma or adequately treated cervical carcinoma in situ Current substance addiction or alcohol abuse or history of substance or alcohol abuse, within the past 2 years Any clinically significant renal disease (other than proteinuria) or hepatic disease Pregnant or lactating females Dementia or mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study Impaired dexterity or vision rendering the subject unable to administer injections Known hypersensitivity to insulin glargine or insulin glulisine or any of the components of Lantus or Apidra Any disease or condition (including abuse of illicit drugs, prescription medications, or alcohol) that, in the opinion of the investigator or sponsor, may interfere with the completion of the study Unlikely to comply with the protocol, eg, uncooperative attitude, inability to return for follow-up visits, or unlikely to complete the study 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 No subject will be allowed to enroll in this study more than once.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Once daily: Insulin glulisine Dosing: Supper, Lunch, Breakfast Monitoring Needed at: Bedtime,Pre-Supper, Pre-Lunch | Drug: insulin glulisine<br>* Once Daily Insulin: Subjects will receive insulin glulisine administered once daily 0-15 minutes before the greatest glycemic impact meal of the day starting at one-tenth the total dose of insulin glargine with maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Twice Daily: Subjects will receive insulin glulisine administered twice daily 0-15 minutes before the 2 greatest glycemic impact meals of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Three Times Daily: Subjects will receive insulin glulisine administered 3 times daily 0-15 minutes before each meal of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units for each meal and additional monitoring as shown in the table below.<br>|
| Experimental: 2<br>Twice daily: Insulin glulisine Dosing: Supper & Lunch, Lunch & Breakfast, Breakfast & Supper Monitoring Needed at: Bedtime & Pre-Supper, Pre-Supper & Pre-Lunch, Pre-Lunch & Bedtime | Drug: insulin glulisine<br>* Once Daily Insulin: Subjects will receive insulin glulisine administered once daily 0-15 minutes before the greatest glycemic impact meal of the day starting at one-tenth the total dose of insulin glargine with maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Twice Daily: Subjects will receive insulin glulisine administered twice daily 0-15 minutes before the 2 greatest glycemic impact meals of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Three Times Daily: Subjects will receive insulin glulisine administered 3 times daily 0-15 minutes before each meal of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units for each meal and additional monitoring as shown in the table below.<br>|
| Experimental: 3<br>Twice daily: Insulin glulisine Dosing: Supper, Lunch, Breakfast Monitoring Needed at: Bedtime, Pre-Supper, Pre-Lunch | Drug: insulin glulisine<br>* Once Daily Insulin: Subjects will receive insulin glulisine administered once daily 0-15 minutes before the greatest glycemic impact meal of the day starting at one-tenth the total dose of insulin glargine with maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Twice Daily: Subjects will receive insulin glulisine administered twice daily 0-15 minutes before the 2 greatest glycemic impact meals of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units, and with additional monitoring as shown in the table below. Three Times Daily: Subjects will receive insulin glulisine administered 3 times daily 0-15 minutes before each meal of the day starting at one-tenth the total dose of insulin glargine with a maximum starting dose of 10 Units for each meal and additional monitoring as shown in the table below.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To show non-inferiority between treatment groups (insulin glargine plus insulin glulisine administered once a day, twice a day, or 3 times a day) in the change in glycemic control as measured by hemoglobin A1C. |  | From baseline to study week 24. |