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

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00283049
• Collaborator: (none)
• Enrollment: 390
• Location: 1
• Arms: 3
• Duration (Months): 33
• Patients Per Site Per Month: 11.8

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Insulin Glargine; Drug: Insulin Glulisine	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 390 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulins + Sulfonylurea (SU) + Thiazolidinedione (TZD) 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; Insulin glargine administered subcutaneously once daily.; Drug: Insulin Glulisine; Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Experimental: Insulins + Metformin (MET) + Thiazolidinedione (TZD) 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; Insulin glargine administered subcutaneously once daily.; Drug: Insulin Glulisine; Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Experimental: Insulins + Metformin (MET) + Sulfonylurea (SU) 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; Insulin glargine administered subcutaneously once daily.; Drug: Insulin Glulisine; Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)

Outcome Measures

Primary Outcome Measures

1. Change in Hemoglobin A1c (HbA1c) From Baseline to Week 12 [12 weeks from Baseline]

Secondary Outcome Measures

1. Change From Baseline to Individual Time Points in HbA1c, Insulin Doses, and Total Insulin Dosage [60 weeks from Baseline]

2. Percentage of Subjects Achieving an HbA1C Less Than (<) 7.0% and Less Than (<) 6.5% [60 weeks from Baseline]

3. 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]

4. 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]

5. Occurrences of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia, and Serious Hypoglycemia [60 weeks from Baseline]

   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.

6. Rate of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia and Serious Hypoglycemia [60 Weeks from Baseline]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects meeting all of the following criteria will be considered for enrollment into the study:

1. 18 to 79 years of age, inclusive

2. Diagnosis of type 2 diabetes mellitus

3. Continuous treatment with therapeutic dosages of a thiazolidinedione (rosiglitazone or pioglitazone), metformin, and a sulfonylurea daily prior to entering the study

4. Screening HbA1c ≥ 7.0%

5. Fasting C-peptide concentration ≥ 0.27 ng/ml

6. Negative glutamic acid decarboxylase (GAD) antibodies

7. Demonstrated ability and willingness to perform self-monitoring blood glucose (SMBG) using a plasma-referenced glucose meter and to maintain an electronic diary

8. Demonstrated ability and willingness to use an electronic diary to record SMBG results, insulin doses, and hypoglycemic events.

9. Signed, informed consent and Health Insurance Portability and Accountability Act (HIPAA) documentation

Exclusion Criteria:

1. Stroke, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or angina pectoris, within the last 12 months

2. Cardiac status New York Heart Association (NYHA) III-IV

3. 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

4. Chronic use of insulin: (more than 3 weeks of continuous use) in the past 12 months

5. Acute infection

6. Clinically significant peripheral edema

7. Acute or chronic history of metabolic acidosis, including diabetic ketoacidosis

8. 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

9. History of hypoglycemia unawareness

10. Pregnancy or lactation

11. Known hypersensitivity to insulin glargine or any of the components of Lantus®

12. Known hypersensitivity to insulin glulisine or any of the components of Apidra®

13. 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

14. Current addiction or current alcohol abuse, or history of substance or alcohol abuse within the last 2 years

15. Diagnosis of dementia

16. 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

17. 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

18. 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)

19. Any disease or condition that in the opinion of the investigator and/or sponsor may interfere with the completion of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	sanofi-aventis, US	Bridgewater	New Jersey	United States	08807

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Lisa Jean-Louis, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00283049
• Other Study ID Numbers: HOE901_4052
• First Posted: Jan 27, 2006
• Last Update Posted: Jan 13, 2011
• Last Verified: Jan 1, 2011

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin glulisine

Study Results

Participant Flow

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Period Title: Overall Study
STARTED	128	128	130
COMPLETED	70	83	76
NOT COMPLETED	58	45	54

Baseline Characteristics

Arm/Group Title	SU + TZD + IG	MET + TZD + IG	MET+SU + IG	Total
Arm/Group Description	Arm 1: Insulin glargine(IG) administered subcutaneously once daily plus a sulfonylurea and a thiazolidinedione(TZD). Insulin glulisine will be added after Week 12 or later for those subjects needing additional prandial insulin therapy (HbA1c >6.5%)	Arm 2: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a thiazolidinedione (TZD). Insulin glulisine will be added after Week 12 or later for those subjects needing additional prandial insulin therapy (HbA1c >6.5%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing additional prandial insulin therapy (HbA1c >6.5%)	Total of all reporting groups
Overall Participants	128	128	130	386
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.1 (9.57)	54.7 (10.14)	54.6 (9.41)	55.2 (9.71)
Sex: Female, Male (Count of Participants)
Female	51 39.8%	54 42.2%	52 40%	157 40.7%
Male	77 60.2%	74 57.8%	78 60%	229 59.3%
Region of Enrollment (participants) [Number]
USA	128 100%	128 100%	130 100%	386 100%
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	33.2 (6.41)	34.3 (6.57)	34.5 (7.04)	34.0 (6.69)
Duration of diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.5 (6.95)	9.7 (5.68)	10.5 (6.00)	10.2 (6.23)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	98.1 (21.46)	99.6 (20.22)	101.2 (24.98)	99.6 (22.31)

Outcome Measures

1. Primary Outcome

Title	Change in Hemoglobin A1c (HbA1c) From Baseline to Week 12
Time Frame	12 weeks from Baseline

Outcome Measure Data

Analysis Population Description

Safety Population (excluding patients from Good Clinical Practice [GCP] non-compliant sites)

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	116	111	120
Mean (Standard Deviation) [Percentage]	-1.2 (1.72)	-1.2 (1.35)	-1.2 (1.31)

2. Secondary Outcome

Title	Change From Baseline to Individual Time Points in HbA1c, Insulin Doses, and Total Insulin Dosage
Time Frame	60 weeks from Baseline

Outcome Measure Data

Analysis Population Description

The study was terminated prematurely due to technical issues with electronic diary data. Consequently, some of the initially planned efficacy analyses, based directly or indirectly on the e-diary data, were not performed.

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	0	0	0

3. Secondary Outcome

Title	Percentage of Subjects Achieving an HbA1C Less Than (<) 7.0% and Less Than (<) 6.5%
Time Frame	60 weeks from Baseline

Outcome Measure Data

Analysis Population Description

The study was terminated prematurely due to technical issues with electronic diary data. Consequently, some of the initially planned efficacy analyses, based directly or indirectly on the e-diary data, were not performed.

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	0	0	0

4. Secondary Outcome

Title	Change From Baseline to Study Time Points in 7-point Blood Glucose (BG) Profile (Before Meals, 2 Hours After Meals, at Bedtime)
Time Frame	60 weeks from Baseline

Outcome Measure Data

Analysis Population Description

The study was terminated prematurely due to technical issues with electronic diary data. Consequently, some of the initially planned efficacy analyses, based directly or indirectly on the e-diary data, were not performed.

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	0	0	0

5. Secondary Outcome

Title	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)
Time Frame	60 weeks from Baseline

Outcome Measure Data

Analysis Population Description

The study was terminated prematurely due to technical issues with electronic diary data. Consequently, some of the initially planned efficacy analyses, based directly or indirectly on the e-diary data, were not performed.

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	0	0	0

6. Secondary Outcome

Title	Occurrences of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia, and Serious Hypoglycemia
Description	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.
Time Frame	60 weeks from Baseline

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	128	128	130
Any reported symptomatic Hypoglycemic event	110 85.9%	107 83.6%	112 86.2%
Symptomatic events with Self-monitored BG (SMBG)	109 85.2%	106 82.8%	112 86.2%
SMBG <70 mg/dL with symptom	107 83.6%	102 79.7%	112 86.2%
SMBG <50mg/dL with symptom	74 57.8%	71 55.5%	85 65.4%
SMBG <36 mg/dL with symptom	23 18%	24 18.8%	35 26.9%
Severe Hypoglycemias	8 6.3%	10 7.8%	5 3.8%
Severe only due to SMBG <36mg/dL	1 0.8%	1 0.8%	0 0%
Severe: Prompt response to CHO countermeasure	4 3.1%	5 3.9%	4 3.1%
Severe:SMBG<36mg/dL, prompt response to CHO	3 2.3%	4 3.1%	2 1.5%
Serious hypoglycemia	3 2.3%	1 0.8%	0 0%
Coma/Loss of Consciousness	3 2.3%	1 0.8%	0 0%

7. Secondary Outcome

Title	Rate of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia and Serious Hypoglycemia
Description	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.
Time Frame	60 Weeks from Baseline

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)	Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)	Arm 2: Insulin glargine (IG) 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%)	Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
Measure Participants	128	128	130
Exposure (Patient-years)	0.941 (0.3285)	0.943 (0.3692)	0.967 (0.3118)
Hypoglycemic (HE) event with SMBG <70mg/dL	30.1 (35.54)	16.5 (20.35)	25.3 (26.81)
HE with SMBG <50mg/dL	4.9 (7.48)	3.3 (5.74)	5.6 (8.17)
HE with SMBG <36mg/dL	0.3 (0.87)	0.3 (0.76)	0.6 (1.55)
Severe HE (BG<36mg/dL or prompt response to CHO	0.1 (0.31)	0.1 (0.53)	0.1 (0.30)
Serious HE (coma/loss of consciousness,seizure)	0.0 (0.14)	0.0 (0.09)	0.0 (0.00)

Adverse Events

Arm/Group Title	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
Arm/Group Description	Arm 1: Insulin glargine (IG) 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%)		Arm 2: Insulin glargine (IG) 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%)		Arm 3: Insulin glargine (IG) administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
All Cause Mortality
	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/128 (17.2%)		20/128 (15.6%)		13/130 (10%)
Blood and lymphatic system disorders
Anaemia	1/128 (0.8%)		0/128 (0%)		1/130 (0.8%)
Cardiac disorders
Acute myocardial infarction	0/128 (0%)		0/128 (0%)		2/130 (1.5%)
Angina pectoris	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Angina unstable	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Aortic valve stenosis	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Cardiac failure congestive	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Cardio-respiratory arrest	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Coronary artery disease	3/128 (2.3%)		2/128 (1.6%)		1/130 (0.8%)
Coronary artery occlusion	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Myocardial infarction	0/128 (0%)		1/128 (0.8%)		1/130 (0.8%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Pancreatitis	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
General disorders
Chest Discomfort	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Non-cardiac chest pain	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Immune system disorders
Drug hypersensitivity	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Infections and infestations
Appendicitis	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Bronchitis	2/128 (1.6%)		0/128 (0%)		0/130 (0%)
Bronchopneumonia	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Cellulitis	1/128 (0.8%)		1/128 (0.8%)		0/130 (0%)
Gastroenteritis	1/128 (0.8%)		1/128 (0.8%)		0/130 (0%)
Pneumonia	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Scrotal abscess	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Injury, poisoning and procedural complications
Burns second degree	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Injury	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Overdose	2/128 (1.6%)		5/128 (3.9%)		0/130 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/128 (0.8%)		2/128 (1.6%)		0/130 (0%)
Hypoglycaemic unconsciousness	1/128 (0.8%)		1/128 (0.8%)		0/130 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Intervertebral disc protrusion	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Musculoskeletal pain	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer recurrent	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Bladder transitional cell carcinoma	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Bone cancer metastatic	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Breast cancer	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Prostate cancer	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Squamous cell carcinoma	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Nervous system disorders
Convulsion	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Hypoglycaemic coma	2/128 (1.6%)		0/128 (0%)		0/130 (0%)
Myelitis transverse	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Transient ischaemic attack	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Renal and urinary disorders
Nephrolithiasis	1/128 (0.8%)		1/128 (0.8%)		0/130 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Dyspnoea exertional	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Pulmonary embolism	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Pulmonary oedema	1/128 (0.8%)		0/128 (0%)		0/130 (0%)
Vascular disorders
Aortic stenosis	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Arterial stenosis	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Arteriosclerosis	0/128 (0%)		0/128 (0%)		1/130 (0.8%)
Deep vein thrombosis	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Hypertensive crisis	0/128 (0%)		1/128 (0.8%)		0/130 (0%)
Other (Not Including Serious) Adverse Events
	Insulin Glargine + Sulfonylurea (SU) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Thiazolidinedione (TZD)		Insulin Glargine + Metformin (MET) + Sulfonylurea (SU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/128 (77.3%)		84/128 (65.6%)		84/130 (64.6%)
General disorders
Edema Peripheral	16/128 (12.5%)		6/128 (4.7%)		11/130 (8.5%)
Infections and infestations
Nasopharyngitis	11/128 (8.6%)		12/128 (9.4%)		14/130 (10.8%)
Upper respiratory tract infection	9/128 (7%)		17/128 (13.3%)		9/130 (6.9%)
Bronchitis	11/128 (8.6%)		7/128 (5.5%)		6/130 (4.6%)
Influenza	6/128 (4.7%)		7/128 (5.5%)		7/130 (5.4%)
Sinusitis	7/128 (5.5%)		7/128 (5.5%)		6/130 (4.6%)
Investigations
Weight increased	8/128 (6.3%)		3/128 (2.3%)		1/130 (0.8%)
Metabolism and nutrition disorders
Hypoglycemia	6/128 (4.7%)		7/128 (5.5%)		5/130 (3.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/128 (7%)		6/128 (4.7%)		7/130 (5.4%)
Pain in extremity	10/128 (7.8%)		4/128 (3.1%)		4/130 (3.1%)
Back pain	4/128 (3.1%)		6/128 (4.7%)		7/130 (5.4%)
Vascular disorders
Hypertension	4/128 (3.1%)		2/128 (1.6%)		7/130 (5.4%)

Limitations/Caveats

The study was terminated prematurely due to technical issues with electronic diary data. Consequently, some of the initially planned efficacy analyses, based directly or indirectly on the e-diary data, were not performed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.