Insulin Glargine All to Target Trial

Study Overview
=================
Brief Summary
-----------------
The primary objectives were: To demonstrate the superiority of Lantus plus stepwise addition of mealtime Apidra® (Lantus/Apidra-3) versus twice-daily Premixed insulin based on the proportion of patients achieving target glycemic control (as measured by hemoglobin A1c [HbA1c] <7.0%) at Week 60 To demonstrate the noninferiority of Lantus plus addition of 1 mealtime Apidra injection (Lantus/Apidra-1) versus twice-daily Premixed insulin based on the reduction from Baseline to Week 60 in HbA1c

Official Title
-----------------
All to Target Trial Lantus® (Insulin Glargine) With Stepwise Addition of APIDRA® (Insulin Glulisine) or Lantus With One Injection of Apidra vs a Twice-Daily Premixed Insulin Regimen (Novolog® Mix 70/30) in Adult Subjects With Type 2 Diabetes Failing Dual or Triple Therapy With Oral Agents: a 64-week, Multi-center, Randomized, Parallel, Open-label Clinical Study.

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Male or female patients 30 to 80 years of age Body Mass Index <45 kg/m2 With Type 2 diabetes mellitus for at least 2 years With an HbA1c level at screening of >7.5% and >7.0% at randomization On stable dual or triple oral therapy for at least 3 months Oral agents in 2 or 3 of the following classes: SU or repaglinide, biguanide, or TZD, willing and able to perform self-monitoring of BG Females of child-bearing potentially were required to be willing and able to use adequate contraception

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 80 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: Lantus/Apidra-3<br>Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents. | Drug: Insulin Glargine<br>* Subcutaneous injection once-a-day<br>* Other names: Lantus;Drug: Insulin Glulisine<br>* Subcutaneous injection up to 3 injections per day.<br>* Other names: Apidra;|
| Experimental: Lantus/Apidra-1<br>Insulin glargine (Lantus) plus up to 1 injection of insulin glulisine (Apidra) added to oral agents. | Drug: Insulin Glulisine<br>* Subcutaneous injection up to 1 injection per day<br>* Other names: Apidra;Drug: Insulin Glargine<br>* Subcutaneous injection once-a-day<br>* Other names: Lantus;|
| Experimental: Novolog Mix 70/30<br>Premixed insulin (Novolog® Mix 70/30) added to oral agents. | Drug: Premixed Insulin<br>* Subcutaneous injection twice-a-day.<br>* Other names: Novolog Mix 70/30;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | Responders defined as patients who achieved an HbA1c value <7.0% versus nonresponders. Patients who did not achieve an HbA1c value <7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders. | At week 60 | 
| Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | Absolute Change in HbA1c from Baseline to Week 60. If the Week 60 HbA1c evaluation was missing, the patient was counted as having not completed per protocol. | At week 60 | 
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | Responders defined as patients who achieved an HbA1c value <7.0% versus nonresponders. Patients who did not achieve an HbA1c value <7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders. | At week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30) | Absolute Change in HbA1c from Baseline to Week 60. | From baseline to week 60 | 
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30) | Patients who achieved an HbA1c value <7.0% were defined as responders. Patients who did not achieve HbA1c values <7.0% and patients with missing HbA1c values were considered nonresponders. | At week 60 | 
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | Severe hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia in which the patient required assistance of another person and one of the following: the event was associated with a measured blood glucose level below 36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, iv glucose, or glucagon administration. A symptomatic hypoglycemic event was defined as a hypoglycemic episode with an associated SMBG value of <50 mg/dL with reported symptoms. | At week 60 | 
| Adjusted Incidence Rate of Hypoglycemia | Adjusted incidence rate of hypoglycemia: estimated percent of patients having at least 1 event of a given type of hypoglycemia. A severe Hypoglycemic Event (HE) is one where patient requires assistance. It is confirmed either by a prompt response to certain countermeasures or by a blood Glucose (BG) <36 mg/dL during or soon after the event. A serious HE is one where the patient has loss of consciousness, coma, seizure, or convulsion. Nocturnal = events occurring between 00:00 & 06:00 based on a 24-hour clock. An event is included if the HE start date is within the treatment period. | Week 60 | 
| Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Adjusted Hypoglycemic event rate: Total # of events for a given type of hypoglycemia divided by the total exposure to study drug (patient-years). Rates are estimated from a general linear model adjusted for baseline BMI and oral agent combination of antidiabetic medications on which the patient entered the study. An event is included if the hypoglycemic event start date is within the treatment period (i.e., from the Randomization date to & including 1 day after the date of last dose of study drug). | Week 60 |