Addition Of Exenatide To Insulin Glargine In Type 2 Diabetes Mellitus

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00765817
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 261
• Locations: 59
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will compare the efficacy and safety of exenatide versus placebo in adults whose diabetes is not fully controlled by insulin glargine with or without metformin and/or pioglitazone.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: placebo; Drug: exenatide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 261 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial Comparing Exenatide With Placebo in Subjects With Type 2 Diabetes on Insulin Glargine With or Without Oral Antihyperglycemic Medications
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1	Drug: placebo; subcutaneous injection, twice a day
Experimental: 2	Drug: exenatide; subcutaneous injection, twice a day, 10mcg

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Hemoglobin (HbA1c) [baseline and 30 weeks]

   Change in HbA1c from baseline following 30 weeks of therapy (i.e., HbA1c at week 30 minus HbA1c at baseline). Unit of measure is percent of hemoglobin that is glycosylated.

Secondary Outcome Measures

1. Percentage of Patients Achieving HbA1c <=7% [baseline and 30 weeks]

   Percentage of patients in each arm who had HbA1c >7% at baseline and had HbA1c <=7% at week 30 (percentage = [number of subjects with HbA1c <=7% at week 30 divided by number of subjects with HbA1c >7% at baseline] * 100%).

2. Percentage of Patients Achieving HbA1c <=6.5% [baseline and 30 weeks]

   Percentage of patients in each arm who had HbA1c >6.5% at baseline and had HbA1c <=6.5% at week 30 (percentage = [number of subjects with HbA1c <=6.5% at week 30 divided by number of subjects with HbA1c >6.5% at baseline] * 100%).

3. Change in Fasting Serum Glucose [baseline and 30 weeks]

   Change in fasting serum glucose following 30 weeks of therapy (i.e., fasting serum glucose at week 30 minus fasting serum glucose at baseline)

4. Change in 7-point Self-monitored Blood Glucose (SMBG) Profile [baseline and 30 weeks]

   Change in 7-point (pre-breakfast, 2 hour post-breakfast, pre-lunch, 2 hour post-lunch, pre-dinner, 2 hour post-dinner, 0300 hours) SMBG profile from baseline to week 30 (change = blood glucose value at week 30 minus blood glucose value at baseline)

5. Change in Total Cholesterol [baseline and 30 weeks]

   Change in total cholesterol following 30 weeks of therapy (i.e., total cholesterol at week 30 minus total cholesterol at baseline)

6. Change in Low Density Lipoprotein (LDL) Cholesterol [baseline and 30 weeks]

   Change in LDL cholesterol following 30 weeks of therapy (i.e., LDL cholesterol at week 30 minus LDL cholesterol at baseline)

7. Change in High Density Lipoprotein (HDL) Cholesterol [baseline and 30 weeks]

   Change in HDL cholesterol following 30 weeks of therapy (i.e., HDL cholesterol at week 30 minus HDL cholesterol at baseline)

8. Change in Triglycerides [baseline and 30 weeks]

   Change in triglycerides following 30 weeks of therapy (i.e., triglycerides at week 30 minus triglycerides at baseline)

9. Change in Body Weight [baseline and 30 weeks]

   Change in body weight following 30 weeks of therapy (i.e., body weight at week 30 minus body weight at baseline)

10. Change in Waist Circumference [baseline and 30 weeks]

    Change in waist circumference following 30 weeks of therapy (i.e., waist circumference at week 30 minus waist circumference at baseline)

11. Change in Daily Insulin Dose [baseline and 30 weeks]

    Change in daily insulin dose following 30 weeks of therapy (i.e., daily insulin dose at week 30 minus daily insulin dose at baseline)

12. Change in Daily Insulin Dose (on a Per Body Weight Basis) [baseline and 30 weeks]

    Change in daily insulin dose per kilogram (kg) following 30 weeks of therapy (i.e., daily insulin dose per kg at week 30 minus daily insulin dose per kg at baseline)

13. Change in Systolic Blood Pressure (SBP) [baseline and 30 weeks]

    Change in SBP following 30 weeks of therapy (i.e., SBP at week 30 minus SBP at baseline)

14. Change in Diastolic Blood Pressure (DBP) [baseline and 30 weeks]

    Change in DBP following 30 weeks of therapy (i.e., DBP at week 30 minus DBP at baseline)

15. Minor Hypoglycemia Rate Per Year [baseline and weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 30]

    Number of minor hypoglycemia events experienced per subject per year. Minor hypoglycemia was defined as any time a subject felt he or she was experiencing a sign or symptom associated with hypoglycemia that was either self-treated by the subject or resolved on its own and had a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL).

16. Percentage of Subjects Experiencing Minor Hypoglycemia [baseline and weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 30]

    Percentage of subjects in each arm experiencing at least one episode of minor hypoglycemia at any point during the study. Minor hypoglycemia was defined as any time a subject felt he or she was experiencing a sign or symptom associated with hypoglycemia that was either self-treated by the subject or resolved on its own and had a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have type 2 diabetes.

• Have been taking insulin glargine at a dose of ≥20 units/day for at least 3 months before entering the study.

Have been taking insulin glargine alone or in combination with one of the following for at least 3 months before entering the study:

1. metformin (stable dose for 6 weeks)

2. pioglitazone (stable dose for 6 weeks)

3. a combination of metformin and pioglitazone (stable dose for 6 weeks)

• Have HbA1C between 7.1% and 10.5%, inclusive.

• Have a body mass index (BMI) ≤45 kg/m2.

• Have a history of stable body weight (not varying by >5% for at least 3 months prior to screening).

Exclusion Criteria:

• Have taken medications to lower blood sugar other than insulin glargine, pioglitazone, or metformin in the 3 months before entering the study for more than a 1-week period, or within 1 week of entering the study.

• Have had more than one episode of major (severe) hypoglycemia in the 6 months before entering the study.

• Are pregnant or intend to become pregnant during the study or are sexually active women not actively practicing birth control.

• Women who are breastfeeding.

• Have any significant diseases of the blood, heart, kidney, gastrointestinal system, or other significant diseases such as cancer.

• Have had a kidney transplant or are currently on kidney dialysis.

• Have a cancer that's never been treated, that's currently being treated, or that was diagnosed within the last 5 years.

• Have had a bad reaction to exenatide in the past or have a condition that is not recommended to be exposed to exenatide or any of exenatide's other ingredients.

• Have used a drug for weight loss in the 3 months before entering the study for more than a 1-week period, or within 1 month of entering the study.

• Are currently on a weight-loss program or have been on one within 3 months of entering the study.

• Have had a blood transfusion or severe blood loss within 3 months of entering the study.

• Are taking systemic glucocorticoids or have received systemic glucocorticoids within 8 weeks of entering the study.

• Have an irregular sleep cycle (for example, sleeping during the day and working during the night).

• Have a history of pancreatitis.

• Have received treatment with an experimental drug within 30 days of entering the study.

• If on metformin, have a condition that is not recommended to be exposed to metformin, or any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.

• If on metformin, have had a radiologic contrast study performed within 48 hours of entering the study.

• If on pioglitazone, have a condition that is not recommended to be exposed to pioglitazone, including congestive heart failure, or are taking pioglitazone at a dose that is not approved for use with insulin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Peoria	Arizona	United States
2	Research Site	Phoenix	Arizona	United States
3	Research Site	Buena Park	California	United States
4	Research Site	Concord	California	United States
5	Research Site	Fresno	California	United States
6	Research Site	Greenbrae	California	United States
7	Research Site	La Mesa	California	United States
8	Research Site	Lancaster	California	United States
9	Research Site	Northridge	California	United States
10	Research Site	Palm Springs	California	United States
11	Research Site	Salinas	California	United States
12	Research Site	Hollywood	Florida	United States
13	Research Site	Jacksonville	Florida	United States
14	Research Site	Atlanta	Georgia	United States
15	Research Site	Honolulu	Hawaii	United States
16	Research Site	Idaho Falls	Idaho	United States
17	Research Site	Des Moines	Iowa	United States
18	Research Site	Wichita	Kansas	United States
19	Research Site	Baton Rouge	Louisiana	United States
20	Research Site	Lafayette	Louisiana	United States
21	Research Site	Matairie	Louisiana	United States
22	Research Site	Boston	Massachusetts	United States
23	Research Site	Minneapolis	Minnesota	United States
24	Research Site	Chesterfield	Missouri	United States
25	Research Site	St Louis	Missouri	United States
26	Research Site	Omaha	Nebraska	United States
27	Research Site	Las Vegas	Nevada	United States
28	Research Site	Berkeley Heights	New Jersey	United States
29	Research SIte	Teaneck	New Jersey	United States
30	Research Site	Alburquerque	New Mexico	United States
31	Research SIte	New York	New York	United States
32	Research Site	Durham	North Carolina	United States
33	Research Site	Bend	Oregon	United States
34	Research Site	Dallas	Texas	United States
35	Research Site	El Paso	Texas	United States
36	Research Site	Georgetown	Texas	United States
37	Research Site	San Antonio	Texas	United States
38	Research Site	Richmond	Virginia	United States
39	Research Site	Vancouver	Washington	United States
40	Research Site	Kenosha	Wisconsin	United States
41	Research Site	Athens		Greece
42	Research Site	Thessaloniki		Greece
43	Research Site	Holon		Israel
44	Research Site	Kfar Sava		Israel
45	Research Site	Tel Hashomer		Israel
46	Research Site	Coatzacoalcos		Mexico
47	Research Site	Mexico		Mexico
48	Research Site	Monterrey		Mexico
49	Research Site	Carolina		Puerto Rico
50	Research Site	Hato Rey		Puerto Rico
51	Research Site	Ponce		Puerto Rico
52	Research Site	San Juan		Puerto Rico
53	Research Site	Birmingham		United Kingdom
54	Research Site	Guildford		United Kingdom
55	Research Site	Leicester		United Kingdom
56	Research Site	Livingston		United Kingdom
57	Research Site	Middlesbrough		United Kingdom
58	Research Site	Swansea		United Kingdom
59	Research Site	Torquay		United Kingdom

Sponsors and Collaborators

• AstraZeneca
• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00765817
• Other Study ID Numbers: H8O-US-GWCO
• First Posted: Oct 3, 2008
• Last Update Posted: Oct 24, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by AstraZeneca: diabetes; exenatide; Amylin; Lilly; metformin; pioglitazone; insulin glargine
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide

Study Results

Participant Flow

Pre-assignment Detail	Two subjects who started the study, subsequently withdrew prior to receiving study medication and are not part of the full analysis set

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Period Title: Overall Study
STARTED	138	123
COMPLETED	112	101
NOT COMPLETED	26	22

Baseline Characteristics

Arm/Group Title	Exenatide Arm	Placebo Arm	Total
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)	Total of all reporting groups
Overall Participants	137	122	259
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	100 73%	84 68.9%	184 71%
>=65 years	37 27%	38 31.1%	75 29%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.67 (8.91)	59.40 (9.96)	59.01 (9.41)
Sex: Female, Male (Count of Participants)
Female	67 48.9%	44 36.1%	111 42.9%
Male	70 51.1%	78 63.9%	148 57.1%

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Hemoglobin (HbA1c)
Description	Change in HbA1c from baseline following 30 weeks of therapy (i.e., HbA1c at week 30 minus HbA1c at baseline). Unit of measure is percent of hemoglobin that is glycosylated.
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	112	100
Least Squares Mean (Standard Error) [percentage of hemoglobin]	-1.71 (0.09)	-1.00 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Percentage of Patients Achieving HbA1c <=7%
Description	Percentage of patients in each arm who had HbA1c >7% at baseline and had HbA1c <=7% at week 30 (percentage = [number of subjects with HbA1c <=7% at week 30 divided by number of subjects with HbA1c >7% at baseline] * 100%).
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set. Last observation carried forward. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. Only patients with baseline HbA1c > target were included in calculation.

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	127	106
Number [percentage]	58.3	31.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Percentage of Patients Achieving HbA1c <=6.5%
Description	Percentage of patients in each arm who had HbA1c >6.5% at baseline and had HbA1c <=6.5% at week 30 (percentage = [number of subjects with HbA1c <=6.5% at week 30 divided by number of subjects with HbA1c >6.5% at baseline] * 100%).
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set. Last observation carried forward. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. Only patients with baseline HbA1c > target were included in calculation.

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	131	113
Number [percentage]	42.0	13.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Change in Fasting Serum Glucose
Description	Change in fasting serum glucose following 30 weeks of therapy (i.e., fasting serum glucose at week 30 minus fasting serum glucose at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	111	98
Least Squares Mean (Standard Error) [mmol/L]	-1.28 (0.2)	-0.87 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.174
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change in 7-point Self-monitored Blood Glucose (SMBG) Profile
Description	Change in 7-point (pre-breakfast, 2 hour post-breakfast, pre-lunch, 2 hour post-lunch, pre-dinner, 2 hour post-dinner, 0300 hours) SMBG profile from baseline to week 30 (change = blood glucose value at week 30 minus blood glucose value at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	108	89
Pre-breakfast: baseline	7.89 (0.2)	8.27 (0.2)
Pre-breakfast: change at week 30	-1.58 (0.1)	-1.48 (0.1)
2 hour post-breakfast: baseline	10.89 (0.2)	11.82 (0.2)
2 hour post-breakfast: change at week 30	-3.56 (0.2)	-1.72 (0.2)
Pre-lunch: baseline	8.95 (0.2)	9.77 (0.2)
Pre-lunch: change at week 30	-2.23 (0.2)	-1.15 (0.2)
2 hour post-lunch: baseline	11.35 (0.2)	11.70 (0.2)
2 hour post-lunch: change at week 30	-2.74 (0.2)	-1.38 (0.2)
Pre-dinner: baseline	9.85 (0.2)	9.99 (0.2)
Pre-dinner: change at week 30	-2.25 (0.2)	-1.33 (0.2)
2 hour post-dinner: baseline	12.03 (0.3)	11.86 (0.3)
2 hour post-dinner: change at week 30	-3.87 (0.2)	-1.34 (0.3)
0300: baseline	8.95 (0.2)	9.20 (0.2)
0300: change at week 30	-2.27 (0.2)	-1.48 (0.2)

6. Secondary Outcome

Title	Change in Total Cholesterol
Description	Change in total cholesterol following 30 weeks of therapy (i.e., total cholesterol at week 30 minus total cholesterol at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	110	98
Least Squares Mean (Standard Error) [mmol/L]	-0.16 (0.08)	-0.02 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.203
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Change in Low Density Lipoprotein (LDL) Cholesterol
Description	Change in LDL cholesterol following 30 weeks of therapy (i.e., LDL cholesterol at week 30 minus LDL cholesterol at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	102	97
Least Squares Mean (Standard Error) [mmol/L]	-0.19 (0.07)	-0.00 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.063
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Change in High Density Lipoprotein (HDL) Cholesterol
Description	Change in HDL cholesterol following 30 weeks of therapy (i.e., HDL cholesterol at week 30 minus HDL cholesterol at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	110	98
Least Squares Mean (Standard Error) [mmol/L]	0.01 (0.02)	0.00 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Change in Triglycerides
Description	Change in triglycerides following 30 weeks of therapy (i.e., triglycerides at week 30 minus triglycerides at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	110	98
Least Squares Mean (Standard Error) [mmol/L]	-0.02 (0.09)	-0.03 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.933
	Comments
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	Change in Body Weight
Description	Change in body weight following 30 weeks of therapy (i.e., body weight at week 30 minus body weight at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	112	101
Least Squares Mean (Standard Error) [kg]	-1.78 (0.3)	0.96 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

11. Secondary Outcome

Title	Change in Waist Circumference
Description	Change in waist circumference following 30 weeks of therapy (i.e., waist circumference at week 30 minus waist circumference at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	137	120
Least Squares Mean (Standard Error) [cm]	-1.08 (0.52)	-0.25 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.226
	Comments
	Method	ANCOVA
	Comments

12. Secondary Outcome

Title	Change in Daily Insulin Dose
Description	Change in daily insulin dose following 30 weeks of therapy (i.e., daily insulin dose at week 30 minus daily insulin dose at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	110	100
Least Squares Mean (Standard Error) [insulin units (U)]	13.19 (2.02)	19.71 (2.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	ANCOVA
	Comments

13. Secondary Outcome

Title	Change in Daily Insulin Dose (on a Per Body Weight Basis)
Description	Change in daily insulin dose per kilogram (kg) following 30 weeks of therapy (i.e., daily insulin dose per kg at week 30 minus daily insulin dose per kg at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	110	100
Least Squares Mean (Standard Error) [insulin units per kg (U/kg)]	0.15 (0.02)	0.20 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments
	Method	ANCOVA
	Comments

14. Secondary Outcome

Title	Change in Systolic Blood Pressure (SBP)
Description	Change in SBP following 30 weeks of therapy (i.e., SBP at week 30 minus SBP at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	112	101
Least Squares Mean (Standard Error) [mmHg]	-2.74 (1.2)	1.71 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	ANCOVA
	Comments

15. Secondary Outcome

Title	Change in Diastolic Blood Pressure (DBP)
Description	Change in DBP following 30 weeks of therapy (i.e., DBP at week 30 minus DBP at baseline)
Time Frame	baseline and 30 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set, Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	112	101
Least Squares Mean (Standard Error) [mmHg]	-1.73 (0.6)	1.69 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

16. Secondary Outcome

Title	Minor Hypoglycemia Rate Per Year
Description	Number of minor hypoglycemia events experienced per subject per year. Minor hypoglycemia was defined as any time a subject felt he or she was experiencing a sign or symptom associated with hypoglycemia that was either self-treated by the subject or resolved on its own and had a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL).
Time Frame	baseline and weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 30

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	137	122
Mean (Standard Deviation) [events per subject per year]	1.61 (5.94)	1.55 (4.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.666
	Comments
	Method	Negative binomial regression model
	Comments

17. Secondary Outcome

Title	Percentage of Subjects Experiencing Minor Hypoglycemia
Description	Percentage of subjects in each arm experiencing at least one episode of minor hypoglycemia at any point during the study. Minor hypoglycemia was defined as any time a subject felt he or she was experiencing a sign or symptom associated with hypoglycemia that was either self-treated by the subject or resolved on its own and had a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL).
Time Frame	baseline and weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 30

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Exenatide Arm	Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)	Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
Measure Participants	137	122
Number [percentage]	24.8	28.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Arm/Group Title	Exenatide Arm		Placebo Arm
Arm/Group Description	Exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 26 weeks (with a background of titrated insulin glargine and other oral antidiabetic agents)		Placebo volume equivalent to the active volume injected in the exenatide arm (with a background of titrated insulin glargine and other oral antidiabetic agents)
All Cause Mortality
	Exenatide Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Exenatide Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/137 (5.8%)		11/122 (9%)
Cardiac disorders
Angina unstable	0/137 (0%)		1/122 (0.8%)
Coronary artery occlusion	1/137 (0.7%)		0/122 (0%)
Myocardial infarction	0/137 (0%)		1/122 (0.8%)
Palpitations	0/137 (0%)		1/122 (0.8%)
Transient ischemic attack	0/137 (0%)		1/122 (0.8%)
Gastrointestinal disorders
Small intestine obstruction	0/137 (0%)		1/122 (0.8%)
General disorders
Chest pain	1/137 (0.7%)		1/122 (0.8%)
Infections and infestations
Herpes zoster	1/137 (0.7%)		0/122 (0%)
Sepsis	0/137 (0%)		1/122 (0.8%)
Staphylococcal infection	1/137 (0.7%)		0/122 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/137 (0.7%)		0/122 (0%)
Ankle fracture	0/137 (0%)		1/122 (0.8%)
Eye penetration	1/137 (0.7%)		0/122 (0%)
Fall	1/137 (0.7%)		0/122 (0%)
Metabolism and nutrition disorders
Hypoglycemia	0/137 (0%)		1/122 (0.8%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	2/137 (1.5%)		0/122 (0%)
Psychiatric disorders
Suicide attempt	0/137 (0%)		1/122 (0.8%)
Renal and urinary disorders
Cystitis	0/137 (0%)		1/122 (0.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/137 (0.7%)		0/122 (0%)
Pulmonary embolism	0/137 (0%)		1/122 (0.8%)
Skin and subcutaneous tissue disorders
Uticaria	0/137 (0%)		1/122 (0.8%)
Other (Not Including Serious) Adverse Events
	Exenatide Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	109/138 (79%)		66/123 (53.7%)
Gastrointestinal disorders
Nausea	56/138 (40.6%)		10/123 (8.1%)
Diarrhea	25/138 (18.1%)		10/123 (8.1%)
Vomiting	25/138 (18.1%)		5/123 (4.1%)
Constipation	14/138 (10.1%)		2/123 (1.6%)
Dyspepsia	9/138 (6.5%)		2/123 (1.6%)
General disorders
Asthenia	7/138 (5.1%)		1/123 (0.8%)
Infections and infestations
Nasopharyngitis	8/138 (5.8%)		6/123 (4.9%)
Musculoskeletal and connective tissue disorders
Back Pain	9/138 (6.5%)		2/123 (1.6%)
Nervous system disorders
Headache	19/138 (13.8%)		5/123 (4.1%)
Dizziness	6/138 (4.3%)		7/123 (5.7%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Tract Infection	11/138 (8%)		9/123 (7.3%)
Cough	7/138 (5.1%)		7/123 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.