Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus(DURATION - 1)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00308139
• Collaborator: (none)
• Enrollment: 303
• Locations: 25
• Arms: 2
• Duration (Months): 100
• Patients Per Site: 12.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release (LAR) on Glucose Control (HbA1c) and Safety in Subjects with Type 2 Diabetes Mellitus Managed with Diet Modification and Exercise and/or Oral Antidiabetic Medications.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: exenatide, long acting release; Drug: exenatide	Phase 3

Detailed Description

This trial is designed to examine the effect of exenatide once weekly compared to exenatide twice daily on glucose control and safety in subjects for at least 30 weeks. The study is also designed to examine glucose control during the transition from exenatide twice daily for 30 weeks to exenatide once weekly. Long-term safety and efficacy will be monitored during the open-ended assessment periods. This study will be conducted in approximately 300 subjects with type 2 diabetes treated with diet modification and exercise alone or in combination with a stable regimen of metformin, SU, thiazolidinedione (TZD), a combination of metformin and SU, a combination of metformin and TZD, or a combination of SU and TZD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 303 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release on Glucose Control (HbA1c) and Safety in Subjects With Type 2 Diabetes Mellitus Managed With Diet Modification and Exercise and/or Oral Antidiabetic Medications
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exenatide Once Weekly Subcutaneous injection (SC), once a week of long acting release (LAR) exenatide.	Drug: exenatide, long acting release; Other Names: BYDUREON
Active Comparator: Exenatide Twice Daily subcutaneous injection (SC), twice a day for the first 30 weeks, followed by exenatide LAR SC injection weekly for the remainder of the study. Sub-study: Exenatide 2 mg subcutaneous injection, Administered Using the Exenatide Once Weekly Single-Dose Tray , once a week for 11 visits, switch to Exenatide 2 mg subcutaneous injection, Administered Using the Dual chamber pen device. Exenatide 2mg SC injection administered using the Dual chamber pen device.	Drug: exenatide; Other Names: Byetta

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Baseline to Week 30 [Day -3, Week 30]

   Absolute change in HbA1c from Baseline (Day -3) to Week 30 [Week 30 - Baseline]

2. Sub-study Relative Bioavailability of Exenatide When Administered Using the Exenatide Once Weekly Dual Chambered Pen and the Exenatide Once Weekly Single Dose Tray (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose) [Week 22]

   Measure by Geometric mean ratio (GMR) of plasma exenatide average steady state concentration Css,avg at Visit 11-14 to Visit 24-27 with 90% confidence interval

Secondary Outcome Measures

1. Change in HbA1c From Baseline to Week 364 [Day -3, Week 364]

   Absolute change in HbA1c from Baseline (Day -3) to Week 364

2. Percentage of Subjects Achieving HbA1c Target of <7% [Week 30]

   Percentage of subjects achieving HbA1c target value of <7% at Week 30.

3. Percentage of Subjects Achieving HbA1c Target of <7% [Week 364]

   Percentages of subjects achieving HbA1c target value of <7% at Week 364

4. Percentage of Subjects Achieving HbA1c Target of <=6.5% [Week 30]

   Percentages of subjects achieving HbA1c target values of <=6.5% at Week 30.

5. Percentage of Subjects Achieving HbA1c Target of <=6.5% [Week 364]

   Percentages of subjects achieving HbA1c target values of <=6.5% at Week 364

6. Percentage of Subjects Achieving HbA1c Target of <=6.0% [Week 30]

   Percentage of subjects achieving HbA1c target values of <=6.0% at Week 30.

7. Exenatide LAR Steady State Concentration From Week 29 to Week 30 [Week 29 to Week 30]

   Steady-state plasma exenatide concentration over the dosing interval of Week 29 to Week 30 (0-168 hours) was evaluated. Geometric mean for the average steady-state concentration and its 10th and 90th percentiles were reported.

8. Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14 [Day -3, Week 14]

   Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14

9. Sub-study Safety and Tolerability of Exenatide When Administered Using the Once Weekly Single Dose Tray and the Once Weekly Dual (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose) [Week 22]

   Measure by geometric mean ratio of the maximum steady state plasma exenatide concentration Css, max at Visit 11-14 to Visit 24-27 with 90% confidence interval and incidence of treatment-emergent injection site adverse events.

10. Change in Body Weight From Baseline to Week 30 [Day -3, Week 30]

    Change in body weight from baseline (Day -3) to Week 30

11. Change in Body Weight From Baseline to Week 364 [Day -3, Week 364]

    Change in body weight from baseline (Day -3) to Week 364

12. Change in Fasting Plasma Glucose From Baseline to Week 30 [Day -3, Week 30]

    Change in fasting plasma glucose from baseline (Day -3) to Week 30.

13. Change in Fasting Plasma Glucose From Baseline to Week 364 [Day -3, Week 364]

    Change in fasting plasma glucose from baseline (Day -3) to Week 364.

14. Change in Blood Pressure From Baseline to Week 30 [Day -3, Week 30]

    Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 30

15. Change in Blood Pressure From Baseline to Week 364 [Day -3, Week 364]

    Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 364

16. Change in Total Cholesterol From Baseline to Week 30 [Day -3, Week 30]

    Change in total cholesterol from baseline (Day -3) to Week 30.

17. Change in Total Cholesterol From Baseline to Week 364 [Day -3, Week 364]

    Change in total cholesterol from baseline (Day -3) to Week 364.

18. Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30 [Day -3, Week 30]

    Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 30.

19. Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364 [Day -3, Week 364]

    Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 364.

20. Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364 [Day -3, Week 364]

    Change in low-density lipoprotein cholesterol (LDL-C) from baseline (Day -3) to Week 364.

21. Ratio of Triglycerides at Week 30 to Baseline [Day -3, Week 30]

    Ratio of triglycerides (measured in mg/dL) at Week 30 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.

22. Ratio of Triglycerides at Week 364 to Baseline [Day -3, Week 364]

    Ratio of triglycerides (measured in mg/dL) at Week 364 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.

23. Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening [Day 1 to Week 364]

    The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.

24. Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening [Day 1 to Week 364]

    The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has type 2 diabetes mellitus treated with diet modification and exercise alone or in combination with a stable regimen of a combination of metformin, sulphonylureas, and thiazolidinediones for a minimum of 2 months at screening.

• Hemoglobin A1c (HbA1c) of 7.1% to 11.0%, inclusive, at screening.

• Body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive, at screening.

• (For sub-study) Currently participating in open ended assessment period of main study 2993 LAR105

Exclusion Criteria:

• Has been previously exposed to exenatide (Byetta®), exenatide LAR, or any glucagon-like peptide-1 (GLP-1) analog.

• Received any investigational drug or has participated in any type of clinical trial within 30 days prior to screening.

• Has been treated, is currently treated, or is expected to require or undergo treatment with any of the following excluded medications:

• Alpha glucosidase inhibitor or meglitinide within 30 days of screening;

• Insulin within 2 weeks prior to screening or insulin for longer than 1 week within 3 months of screening;

• Regular use (> 14 days) of drugs that directly affect gastrointestinal motility;

• Regular use (> 14 days) of systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary steroids known to have a high rate of systemic absorption;

• Regular use (> 14 days) of medications with addictive potential such as opiates and opioids;

• Prescription or over-the-counter weight loss medications within 6 months of screening.

• (For sub-study) Subjects will be terminated from study who do not participate in the dual chamber pen substudy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site 182	Encino	California	United States	91436
2	Research Site 171	La Jolla	California	United States	92037
3	Research Site 518	San Diego	California	United States	92161
4	Research Site 024	Walnut Creek	California	United States	94598
5	Research Site	Colorado Springs	Colorado	United States
6	Research Site 057	Miami	Florida	United States	33156
7	Research Site	Chicago	Illinois	United States
8	Research Site 149	Indianapolis	Indiana	United States	46254
9	Research Site 099	Lexington	Kentucky	United States	40503
10	Research Site 017	Detroit	Michigan	United States	48202
11	Research Site 224	Minneapolis	Minnesota	United States	55416
12	Research Site 312	St. Louis	Missouri	United States	63141
13	Research Site 023	Butte	Montana	United States	59701
14	Research Site 053	Rochester	New York	United States	14609
15	Research Site 002	Durham	North Carolina	United States	27713
16	Research Site 123	Winston-Salem	North Carolina	United States	27103
17	Research Site 405	Cincinnati	Ohio	United States	45219
18	Research Site 557	Marion	Ohio	United States	43302
19	Research Site 231	Portland	Oregon	United States	97239
20	Research Site 152	Philadelphia	Pennsylvania	United States	19146
21	Research Site 587	Greer	South Carolina	United States	29651
22	Research Site 015	Dallas	Texas	United States	75230
23	Research Site 009	San Antonio	Texas	United States	78229
24	Research Site 108	Olympia	Washington	United States	98502
25	Research Site	Toronto	Ontario	Canada

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Lisa Porter, MD, Amylin Pharmaceuticals, LLC.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00308139
• Other Study ID Numbers: 2993LAR-105 (DURATION - 1); MB001-010
• First Posted: Mar 29, 2006
• Last Update Posted: Aug 26, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by AstraZeneca: diabetes; exenatide; long acting release; LAR; Amylin; Lilly
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide

Study Results

Participant Flow

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Period Title: Overall Study
STARTED	152	151
Intent to Treat (ITT)	148	147
ITT in the 30-Week Assessment	148	145
Pharmacokinetics Population	129	0
Evaluable Meal Tolerance Cohort	27	24
30-Week Completed	128	130
COMPLETED	58	64
NOT COMPLETED	94	87

Baseline Characteristics

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	Total
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.	Total of all reporting groups
Overall Participants	148	147	295
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	122 82.4%	123 83.7%	245 83.1%
>=65 years	26 17.6%	24 16.3%	50 16.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (9.72)	54.9 (9.63)	55.0 (9.66)
Sex: Female, Male (Count of Participants)
Female	66 44.6%	72 49%	138 46.8%
Male	82 55.4%	75 51%	157 53.2%
Glycosylated hemoglobin (HbA1c) (percentage of total hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of total hemoglobin]	8.3 (0.99)	8.3 (1.00)	8.3 (0.99)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	101.7 (18.76)	101.9 (21.05)	101.8 (19.90)
Background Oral Antidiabetic Agent (participants) [Number]
Diet and Exercise	21 14.2%	22 15%	43 14.6%
Metformin (MET)	56 37.8%	50 34%	106 35.9%
Sulfonylurea (SU)	6 4.1%	10 6.8%	16 5.4%
Thiazolidinediones (TZD)	2 1.4%	7 4.8%	9 3.1%
MET+SU	43 29.1%	39 26.5%	82 27.8%
MET+TZD	14 9.5%	14 9.5%	28 9.5%
SU+TZD	5 3.4%	5 3.4%	10 3.4%
SU+MET+TZD	1 0.7%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 30
Description	Absolute change in HbA1c from Baseline (Day -3) to Week 30 [Week 30 - Baseline]
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

The ITT Population consisted of all randomized subjects who received at least one injection of study medication. Missing data up to Week 30 were imputed using the last observation carried forward (LOCF) approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	148	147
Least Squares Mean (Standard Error) [percentage of total hemoglobin]	-1.87 (0.082)	-1.54 (0.082)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Superiority of exenatide long-acting release (LAR) once weekly to BYETTA if the upper limit of the 2-sided 95% confidence interval (CI) for treatment difference (LAR minus BYETTA) is less than 0; non-inferiority if this upper limit is less than 0.4%. Power:Assuming 20% dropout rate with 246 subjects will complete the study. This sample size would provide 90% power for non-inferiority test with assumption of greater reduction (0.1%) in LAR and a common standard deviation of 1.2%.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The choice of a 0.4% noninferiority margin was resulted from the considerations of expected clinical benefit of BYETTA in this study based on clinical data evaluating exenatide LAR and BYETTA, regulatory guidance, published literature, and statistical considerations.
Statistical Test of Hypothesis	p-Value	0.0023
	Comments
	Method	ANOVA
	Comments	Analysis of variance (ANOVA) model includes treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.107
	Estimation Comments

2. Secondary Outcome

Title	Change in HbA1c From Baseline to Week 364
Description	Absolute change in HbA1c from Baseline (Day -3) to Week 364
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the last observation carried forward (LOCF) approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [percentage of total hemoglobin]	-1.49 (0.155)	-1.57 (0.144)	-1.53 (0.115)

3. Primary Outcome

Title	Sub-study Relative Bioavailability of Exenatide When Administered Using the Exenatide Once Weekly Dual Chambered Pen and the Exenatide Once Weekly Single Dose Tray (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)
Description	Measure by Geometric mean ratio (GMR) of plasma exenatide average steady state concentration Css,avg at Visit 11-14 to Visit 24-27 with 90% confidence interval
Time Frame	Week 22

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Percentage of Subjects Achieving HbA1c Target of <7%
Description	Percentage of subjects achieving HbA1c target value of <7% at Week 30.
Time Frame	Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	148	147
Number [percentage of subjects]	70.9	51.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Percentages of subjects achieving HbA1c target value of <7% at Week 30 were compared between treatments using a Cochran-Mantel-Haenszel (CMH) test, in which baseline HbA1c stratum (<9% or >=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Percentage of Subjects Achieving HbA1c Target of <7%
Description	Percentages of subjects achieving HbA1c target value of <7% at Week 364
Time Frame	Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Number [percentage of subjects]	41.4	50.0	45.9

6. Secondary Outcome

Title	Percentage of Subjects Achieving HbA1c Target of <=6.5%
Description	Percentages of subjects achieving HbA1c target values of <=6.5% at Week 30.
Time Frame	Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	148	147
Number [percentage of subjects]	3.0	16.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Percentage of subjects achieving HbA1c target value of <=6.5% at Week 30 were compared between treatments using CMH test, in which baseline HbA1c stratum (<9% or >=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2042
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Percentage of Subjects Achieving HbA1c Target of <=6.5%
Description	Percentages of subjects achieving HbA1c target values of <=6.5% at Week 364
Time Frame	Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatmeat
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Number [percentage of subjects]	22.4	37.5	30.3

8. Secondary Outcome

Title	Percentage of Subjects Achieving HbA1c Target of <=6.0%
Description	Percentage of subjects achieving HbA1c target values of <=6.0% at Week 30.
Time Frame	Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	148	147
Number [percentage of subjects]	23.0	16.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Percentages of subjects achieving HbA1c target values of <=6.0% at Week 30 were compared between treatments using CMH test, in which baseline HbA1c stratum (<9% or >=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1513
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

9. Secondary Outcome

Title	Exenatide LAR Steady State Concentration From Week 29 to Week 30
Description	Steady-state plasma exenatide concentration over the dosing interval of Week 29 to Week 30 (0-168 hours) was evaluated. Geometric mean for the average steady-state concentration and its 10th and 90th percentiles were reported.
Time Frame	Week 29 to Week 30

Outcome Measure Data

Analysis Population Description

The Pharmacokinetics Population consisted of subjects who received exenatide LAR treatment, and had adequate plasma exenatide concentration-time data to allow for reliable evaluation of exenatide LAR pharmacokinetics.

Arm/Group Title	Exenatide Once Weekly
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.
Measure Participants	114
Geometric Mean (Inter-Quartile Range) [pg/mL]	300.23

10. Secondary Outcome

Title	Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14
Description	Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14
Time Frame	Day -3, Week 14

Outcome Measure Data

Analysis Population Description

Evaluable Meal Tolerance Cohort consisted of ITT subjects who participated in the meal tolerance test and had adequate data to allow the reliable assessment of pharmacodynamics. Only subjects with non-missing baseline and Week 14 values were included in analysis.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	22	21
Least Squares Mean (Standard Error) [mg/dL]	-95.88 (8.420)	-125.96 (8.292)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Change in 2h postprandial glucose from baseline (Day -3) to Week 14 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the 2h postprandial glucose as a covariate. Null hypothesis: no difference between treatments in change from baseline 2h postprandial glucose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	30.08
	Confidence Interval	(2-Sided) 95%; 6.88 to 53.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.458
	Estimation Comments

11. Secondary Outcome

Title	Sub-study Safety and Tolerability of Exenatide When Administered Using the Once Weekly Single Dose Tray and the Once Weekly Dual (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)
Description	Measure by geometric mean ratio of the maximum steady state plasma exenatide concentration Css, max at Visit 11-14 to Visit 24-27 with 90% confidence interval and incidence of treatment-emergent injection site adverse events.
Time Frame	Week 22

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 30
Description	Change in body weight from baseline (Day -3) to Week 30
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 week).
Measure Participants	148	147
Least Squares Mean (Standard Error) [kg]	-3.67 (0.468)	-3.59 (0.468)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Change in body weight from baseline (Day -3) to Week 30 was analyzed using an analysis of covariance (ANCOVA) model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the body weight as a covariate. Null hypothesis: no difference between treatments in change from baseline body weight. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8916
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -1.29 to 1.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.612
	Estimation Comments

13. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 364
Description	Change in body weight from baseline (Day -3) to Week 364
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [kg]	-5.25 (0.468)	-2.71 (0.468)	-3.87

14. Secondary Outcome

Title	Change in Fasting Plasma Glucose From Baseline to Week 30
Description	Change in fasting plasma glucose from baseline (Day -3) to Week 30.
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	148	147
Least Squares Mean (Standard Error) [mg/dL]	-41.5 (2.97)	-24.6 (2.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Change in fasting plasma glucose from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the fasting plasma glucose as a covariate. Null hypothesis: no difference between treatments in change from baseline fasting plasma glucose. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-16.9
	Confidence Interval	(2-Sided) 95%; -24.4 to -9.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.80
	Estimation Comments

15. Secondary Outcome

Title	Change in Fasting Plasma Glucose From Baseline to Week 364
Description	Change in fasting plasma glucose from baseline (Day -3) to Week 364.
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [mg/dL]	-18.3 (2.97)	-27.7 (2.90)	-23.6

16. Secondary Outcome

Title	Change in Blood Pressure From Baseline to Week 30
Description	Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 30
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population using observed data.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	126	130
Sitting Systolic Blood Pressure	-4.4 (1.04)	-3.8 (1.28)
Sitting Diastolic Blood Pressure	-1.1 (0.76)	-2.3 (0.83)

17. Secondary Outcome

Title	Change in Blood Pressure From Baseline to Week 364
Description	Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 364
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population using observed data.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once WeeklyEdit	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Sitting Systolic Blood Pressure	1.3 (16.21)	1.0 (17.32)	1.2 (16.73)
Sitting Diastolic Blood Pressure	-1.7 (8.87)	-3.6 (9.59)	-2.7 (9.26)

18. Secondary Outcome

Title	Change in Total Cholesterol From Baseline to Week 30
Description	Change in total cholesterol from baseline (Day -3) to Week 30.
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	139	137
Least Squares Mean (Standard Error) [mg/dL]	-11.9 (2.29)	-3.8 (2.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Change in total cholesterol from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the total cholesterol as a covariate. Null hypothesis: no difference between treatments in change from baseline total cholesterol. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-8.2
	Confidence Interval	(2-Sided) 95%; -14.1 to -2.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.04
	Estimation Comments

19. Secondary Outcome

Title	Change in Total Cholesterol From Baseline to Week 364
Description	Change in total cholesterol from baseline (Day -3) to Week 364.
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [mg/dL]	-15.0 (2.29)	-4.8 (2.35)	-9.6

20. Secondary Outcome

Title	Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30
Description	Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 30.
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	139	137
Least Squares Mean (Standard Error) [mg/dL]	-0.9 (0.56)	-1.3 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Change in HDL-C from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the HDL as a covariate. Null hypothesis: no difference between treatments in change from baseline HDL. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5613
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 1.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.74
	Estimation Comments

21. Secondary Outcome

Title	Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364
Description	Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 364.
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [mg/dL]	2.2 (0.56)	3.4 (0.57)	2.8

22. Secondary Outcome

Title	Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364
Description	Change in low-density lipoprotein cholesterol (LDL-C) from baseline (Day -3) to Week 364.
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [mg/dL]	-13.6 (0.56)	-7.5 (0.57)	-10.4

23. Secondary Outcome

Title	Ratio of Triglycerides at Week 30 to Baseline
Description	Ratio of triglycerides (measured in mg/dL) at Week 30 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time Frame	Day -3, Week 30

Outcome Measure Data

Analysis Population Description

ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly	Exenatide Twice Daily
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).
Measure Participants	139	137
Least Squares Mean (Standard Error) [ratio]	0.85 (0.029)	0.89 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide Once Weekly, Exenatide Twice Daily
	Comments	Analysis: Triglycerides data were logarithm-transformed and the change at Week 30 to baseline (Day -3), expressed as the ratio, was analyzed by an ANCOVA model including treatment, baseline HbA1c stratum (<9% or >=9%), and concomitant SU use at screening as factors, and baseline value of the triglycerides as a covariate. Null hypothesis: no difference between treatments in change from baseline triglycerides. Power: based on the primary measurement.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2915
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Geometic Least Squares Mean Ratio
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.042
	Estimation Comments

24. Secondary Outcome

Title	Ratio of Triglycerides at Week 364 to Baseline
Description	Ratio of triglycerides (measured in mg/dL) at Week 364 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time Frame	Day -3, Week 364

Outcome Measure Data

Analysis Population Description

7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.

Arm/Group Title	Exenatide Once Weekly -> Exenatide Once Weekly	Exenatide Twice Daily -> Exenatide Once Weekly	All Treatment
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.	Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.
Measure Participants	58	64	122
Least Squares Mean (95% Confidence Interval) [ratio]	0.91 (0.029)	0.94 (0.031)	0.93

25. Secondary Outcome

Title	Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening
Description	The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.
Time Frame	Day 1 to Week 364

Outcome Measure Data

Analysis Population Description

ITT Population who participated in the 30-week assessment period and using SU at screening.

Arm/Group Title	Exenatide Once Weekly With SU	Exenatide Twice Daily With SU	Exenatide Once Weekly -> Exenatide Once Weekly With SU	Exenatide Twice Daily -> Exenatide Once Weekly With SU	Exenatide Once Weekly With SU
Arm/Group Description	Subjects subcutaneous injection of 2 mg exenatide, once a week using concomitant SU at screening. Week 0 to week 30.	Subjects with subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) using concomitant SU at screening. Week 0 to week 30.	Subjects subcutaneous injection of 2 mg exenatide, once a week using concomitant SU at screening. Week 31 to week 364	Subjects with subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week using concomitant SU at screening. Week 31 to week 364.	Subcutaneous injection of 2 mg exenatide, once a week using concomitant SU at screening. Pooling unique subjects from exenatide once weekly (WK 0-30), exenatide once weekly -> exenatide once weekly (WK 31-364), and exenatide twice daily -> exenatide once weekly (WK 31-364).
Measure Participants	55	52	49	50	105
Major hypoglycemic events	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)
Minor hypoglycemic events	0.57 (0.139)	0.38 (0.113)	0.49 (0.046)	0.22 (0.029)	0.36 (0.026)

26. Secondary Outcome

Title	Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening
Description	The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.
Time Frame	Day 1 to Week 364

Outcome Measure Data

Analysis Population Description

ITT Population who participated in the 30-week assessment period and not using SU at screening.

Arm/Group Title	Exenatide Once Weekly With Non-SU	Exenatide Twice Daily With Non-SU	Exenatide Once Weekly -> Exenatide Once Weekly With Non-SU	Exenatide Twice Daily -> Exenatide Once Weekly With Non-SU	Exenatide Once Weekly With Non-SU
Arm/Group Description	Subjects subcutaneous injection of 2 mg exenatide, once a week not using concomitant SU at screening. Week 0 to week 30.	Subjects with subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) not using concomitant SU at screening. Week 0 to week 30.	Subjects subcutaneous injection of 2 mg exenatide, once a week not using concomitant SU at screening. Week 31 to week 364	Subjects with subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week not using concomitant SU at screening. Week 31 to week 364.	Subcutaneous injection of 2 mg exenatide, once a week not using concomitant SU at screening. Pooling unique subjects from exenatide once weekly (WK 0-30), exenatide once weekly -> exenatide once weekly (WK 31-364), and exenatide twice daily -> exenatide once weekly (WK 31-364).
Measure Participants	93	93	79	80	173
Major hypoglycemic events	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)
Minor hypoglycemic events	0.00 (0.000)	0.02 (0.020)	0.03 (0.009)	0.06 (0.013)	0.04 (0.007)

Adverse Events

Arm/Group Title	Exenatide Once Weekly (WK 0-30)		Exenatide Twice Daily (WK 0-30)		Exenatide Once Weekly -> Exenatide Once Weekly (WK 31-364)		Exenatide Twice Daily -> Exenatide Once Weekly (WK 31-364)		Exenatide Once Weekly
Arm/Group Description	Subcutaneous injection of 2 mg exenatide, once a week.		Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks).		Subcutaneous injection of 2 mg exenatide, once a week.		Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week.		Subcutaneous injection of 2 mg exenatide, once a week. Pooling unique subjects from exenatide once weekly (WK 0-30), exenatide once weekly -> exenatide once weekly (WK 31-364), and exenatide twice daily -> exenatide once weekly (WK 31-364).
All Cause Mortality
	Exenatide Once Weekly (WK 0-30)		Exenatide Twice Daily (WK 0-30)		Exenatide Once Weekly -> Exenatide Once Weekly (WK 31-364)		Exenatide Twice Daily -> Exenatide Once Weekly (WK 31-364)		Exenatide Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Exenatide Once Weekly (WK 0-30)		Exenatide Twice Daily (WK 0-30)		Exenatide Once Weekly -> Exenatide Once Weekly (WK 31-364)		Exenatide Twice Daily -> Exenatide Once Weekly (WK 31-364)		Exenatide Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/148 (5.4%)		5/145 (3.4%)		36/128 (28.1%)		29/130 (22.3%)		71/278 (25.5%)
Cardiac disorders
Myocardial infarction	1/148 (0.7%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		3/278 (1.1%)
Arteriosclerosis coronary artery	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Cardiac arrest	0/148 (0%)		1/145 (0.7%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Acute myocardial infarction	0/148 (0%)		0/145 (0%)		3/128 (2.3%)		0/130 (0%)		3/278 (1.1%)
Angina unstable	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Arrhythmia	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		0/130 (0%)		2/278 (0.7%)
Atrial fibrillation	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		1/130 (0.8%)		3/278 (1.1%)
Atrioventricular block complete	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Cardiac failure congestive	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		1/130 (0.8%)		3/278 (1.1%)
Coronary artery disease	0/148 (0%)		0/145 (0%)		4/128 (3.1%)		0/130 (0%)		4/278 (1.4%)
Coronary artery occlusion	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Palpitations	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Ventricular extrasystoles	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Ventricular tachycardia	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Eye disorders
Macular oedema	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Retinal detachment	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Gastrointestinal disorders
Tooth impacted	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		0/130 (0%)		1/278 (0.4%)
Abdominal pain	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Diarrhoea	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		0/130 (0%)		2/278 (0.7%)
Gastrointestinal haemorrhage	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Ileus	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Pancreatitis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
General disorders
Chest discomfort	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Chest pain	0/148 (0%)		0/145 (0%)		0/128 (0%)		2/130 (1.5%)		2/278 (0.7%)
Device dislocation	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Non-cardiac chest pain	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		0/130 (0%)		2/278 (0.7%)
Pyrexia	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Hepatobiliary disorders
Cholecystitis acute	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		2/278 (0.7%)
Bile duct stenosis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Cholecystitis	0/148 (0%)		0/145 (0%)		3/128 (2.3%)		0/130 (0%)		3/278 (1.1%)
Cholelithiasis	0/148 (0%)		0/145 (0%)		0/128 (0%)		2/130 (1.5%)		2/278 (0.7%)
Hepatitis cholestatic	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Infections and infestations
Bacteraemia	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		0/130 (0%)		1/278 (0.4%)
Diverticulitis	1/148 (0.7%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Appendicitis	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Bronchitis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Cellulitis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Clostridium difficile infection	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Escherichia urinary tract infection	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Herpes zoster oticus	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Infected bites	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Perirectal abscess	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		2/278 (0.7%)
Pneumonia	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Postoperative wound infection	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Pyelonephritis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		2/278 (0.7%)
Urinary tract infection	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		2/278 (0.7%)
Urosepsis	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Injury, poisoning and procedural complications
Multiple fractures	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Subdural haemorrhage	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Craniocerebral injury	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Limb crushing injury	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Procedural pain	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Tendon rupture	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Metabolism and nutrition disorders
Dehydration	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Hyperlactacidaemia	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Hypophosphataemia	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Metabolic acidosis	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/148 (0%)		1/145 (0.7%)		1/128 (0.8%)		1/130 (0.8%)		2/278 (0.7%)
Osteoarthritis	0/148 (0%)		1/145 (0.7%)		4/128 (3.1%)		2/130 (1.5%)		6/278 (2.2%)
Arthralgia	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		1/130 (0.8%)		3/278 (1.1%)
Arthritis	0/148 (0%)		0/145 (0%)		2/128 (1.6%)		0/130 (0%)		2/278 (0.7%)
Lumbar spinal stenosis	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/148 (0.7%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		3/278 (1.1%)
Prostate cancer	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		0/130 (0%)		1/278 (0.4%)
Adenocarcinoma of colon	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Basal cell carcinoma	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Breast cancer metastatic	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Endometrial adenocarcinoma	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Invasive ductal breast carcinoma	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Lung neoplasm malignant	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Pancreatic carcinoma	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Nervous system disorders
Cerebral artery occlusion	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		0/130 (0%)		1/278 (0.4%)
Convulsion	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Cerebrovascular accident	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Dizziness	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Ischaemic stroke	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Presyncope	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Subarachnoid haemorrhage	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Syncope	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Transient ischaemic attack	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Renal and urinary disorders
Nephrolithiasis	0/148 (0%)		1/145 (0.7%)		0/128 (0%)		0/130 (0%)		0/278 (0%)
Renal failure acute	0/148 (0%)		1/145 (0.7%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Reproductive system and breast disorders
Female genital tract fistula	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/148 (0.7%)		0/145 (0%)		0/128 (0%)		2/130 (1.5%)		3/278 (1.1%)
Acute respiratory failure	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Pulmonary embolism	0/148 (0%)		0/145 (0%)		0/128 (0%)		1/130 (0.8%)		1/278 (0.4%)
Vascular disorders
Hypertension	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		1/130 (0.8%)		2/278 (0.7%)
Hypotension	0/148 (0%)		0/145 (0%)		1/128 (0.8%)		0/130 (0%)		1/278 (0.4%)
Other (Not Including Serious) Adverse Events
	Exenatide Once Weekly (WK 0-30)		Exenatide Twice Daily (WK 0-30)		Exenatide Once Weekly -> Exenatide Once Weekly (WK 31-364)		Exenatide Twice Daily -> Exenatide Once Weekly (WK 31-364)		Exenatide Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	124/148 (83.8%)		106/145 (73.1%)		121/128 (94.5%)		122/130 (93.8%)		265/278 (95.3%)
Blood and lymphatic system disorders
Anaemia	2/148 (1.4%)		2/145 (1.4%)		8/128 (6.3%)		5/130 (3.8%)		15/278 (5.4%)
Eye disorders
Cataract	2/148 (1.4%)		0/145 (0%)		15/128 (11.7%)		9/130 (6.9%)		25/278 (9%)
Gastrointestinal disorders
Nausea	40/148 (27%)		49/145 (33.8%)		26/128 (20.3%)		25/130 (19.2%)		82/278 (29.5%)
Diarrhoea	24/148 (16.2%)		18/145 (12.4%)		35/128 (27.3%)		34/130 (26.2%)		79/278 (28.4%)
Constipation	15/148 (10.1%)		9/145 (6.2%)		11/128 (8.6%)		16/130 (12.3%)		40/278 (14.4%)
Vomiting	16/148 (10.8%)		27/145 (18.6%)		21/128 (16.4%)		21/130 (16.2%)		54/278 (19.4%)
Dyspepsia	11/148 (7.4%)		3/145 (2.1%)		7/128 (5.5%)		9/130 (6.9%)		26/278 (9.4%)
Gastrooesophageal reflux disease	11/148 (7.4%)		6/145 (4.1%)		15/128 (11.7%)		13/130 (10%)		39/278 (14%)
Abdominal discomfort	5/148 (3.4%)		2/145 (1.4%)		8/128 (6.3%)		8/130 (6.2%)		19/278 (6.8%)
Abdominal pain	5/148 (3.4%)		3/145 (2.1%)		8/128 (6.3%)		8/130 (6.2%)		20/278 (7.2%)
Abdominal pain upper	2/148 (1.4%)		2/145 (1.4%)		7/128 (5.5%)		8/130 (6.2%)		17/278 (6.1%)
Large intestine polyp	1/148 (0.7%)		0/145 (0%)		11/128 (8.6%)		10/130 (7.7%)		22/278 (7.9%)
Toothache	1/148 (0.7%)		3/145 (2.1%)		6/128 (4.7%)		9/130 (6.9%)		16/278 (5.8%)
General disorders
Injection site pruritus	27/148 (18.2%)		2/145 (1.4%)		5/128 (3.9%)		9/130 (6.9%)		40/278 (14.4%)
Injection site erythema	11/148 (7.4%)		0/145 (0%)		7/128 (5.5%)		6/130 (4.6%)		21/278 (7.6%)
Fatigue	9/148 (6.1%)		5/145 (3.4%)		11/128 (8.6%)		12/130 (9.2%)		31/278 (11.2%)
Injection site bruising	7/148 (4.7%)		14/145 (9.7%)		7/128 (5.5%)		10/130 (7.7%)		24/278 (8.6%)
Oedema peripheral	1/148 (0.7%)		0/145 (0%)		6/128 (4.7%)		14/130 (10.8%)		21/278 (7.6%)
Immune system disorders
Seasonal allergy	2/148 (1.4%)		2/145 (1.4%)		13/128 (10.2%)		5/130 (3.8%)		20/278 (7.2%)
Infections and infestations
Urinary tract infection	15/148 (10.1%)		11/145 (7.6%)		23/128 (18%)		30/130 (23.1%)		63/278 (22.7%)
Gastroenteritis viral	12/148 (8.1%)		8/145 (5.5%)		18/128 (14.1%)		11/130 (8.5%)		37/278 (13.3%)
Upper respiratory tract infection	12/148 (8.1%)		25/145 (17.2%)		54/128 (42.2%)		64/130 (49.2%)		124/278 (44.6%)
Nasopharyngitis	10/148 (6.8%)		8/145 (5.5%)		34/128 (26.6%)		41/130 (31.5%)		78/278 (28.1%)
Sinusitis	7/148 (4.7%)		10/145 (6.9%)		26/128 (20.3%)		35/130 (26.9%)		66/278 (23.7%)
Bronchitis	4/148 (2.7%)		6/145 (4.1%)		18/128 (14.1%)		25/130 (19.2%)		46/278 (16.5%)
Conjunctivitis	1/148 (0.7%)		2/145 (1.4%)		6/128 (4.7%)		9/130 (6.9%)		16/278 (5.8%)
Ear infection	0/148 (0%)		1/145 (0.7%)		6/128 (4.7%)		7/130 (5.4%)		13/278 (4.7%)
Gastroenteritis	0/148 (0%)		0/145 (0%)		9/128 (7%)		6/130 (4.6%)		15/278 (5.4%)
Herpes zoster	1/148 (0.7%)		1/145 (0.7%)		7/128 (5.5%)		10/130 (7.7%)		18/278 (6.5%)
Influenza	2/148 (1.4%)		3/145 (2.1%)		11/128 (8.6%)		17/130 (13.1%)		30/278 (10.8%)
Onychomycosis	0/148 (0%)		0/145 (0%)		6/128 (4.7%)		7/130 (5.4%)		13/278 (4.7%)
Tooth abscess	3/148 (2%)		1/145 (0.7%)		7/128 (5.5%)		7/130 (5.4%)		17/278 (6.1%)
Tooth infection	4/148 (2.7%)		1/145 (0.7%)		10/128 (7.8%)		7/130 (5.4%)		20/278 (7.2%)
Injury, poisoning and procedural complications
Contusion	3/148 (2%)		1/145 (0.7%)		12/128 (9.4%)		10/130 (7.7%)		25/278 (9%)
Fall	2/148 (1.4%)		2/145 (1.4%)		12/128 (9.4%)		10/130 (7.7%)		24/278 (8.6%)
Laceration	1/148 (0.7%)		1/145 (0.7%)		6/128 (4.7%)		8/130 (6.2%)		14/278 (5%)
Ligament sprain	1/148 (0.7%)		3/145 (2.1%)		6/128 (4.7%)		10/130 (7.7%)		17/278 (6.1%)
Metabolism and nutrition disorders
Diabetes mellitus	0/148 (0%)		0/145 (0%)		13/128 (10.2%)		8/130 (6.2%)		21/278 (7.6%)
Hypercholesterolaemia	0/148 (0%)		1/145 (0.7%)		7/128 (5.5%)		6/130 (4.6%)		13/278 (4.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/148 (4.7%)		6/145 (4.1%)		25/128 (19.5%)		28/130 (21.5%)		58/278 (20.9%)
Arthritis	2/148 (1.4%)		3/145 (2.1%)		7/128 (5.5%)		10/130 (7.7%)		19/278 (6.8%)
Back pain	7/148 (4.7%)		6/145 (4.1%)		27/128 (21.1%)		25/130 (19.2%)		55/278 (19.8%)
Bursitis	2/148 (1.4%)		0/145 (0%)		5/128 (3.9%)		10/130 (7.7%)		16/278 (5.8%)
Muscle spasms	3/148 (2%)		3/145 (2.1%)		12/128 (9.4%)		13/130 (10%)		28/278 (10.1%)
Musculoskeletal pain	2/148 (1.4%)		0/145 (0%)		23/128 (18%)		15/130 (11.5%)		40/278 (14.4%)
Myalgia	5/148 (3.4%)		2/145 (1.4%)		4/128 (3.1%)		11/130 (8.5%)		19/278 (6.8%)
Osteoarthritis	1/148 (0.7%)		2/145 (1.4%)		15/128 (11.7%)		10/130 (7.7%)		26/278 (9.4%)
Pain in extremity	1/148 (0.7%)		2/145 (1.4%)		21/128 (16.4%)		22/130 (16.9%)		44/278 (15.8%)
Tendonitis	1/148 (0.7%)		0/145 (0%)		5/128 (3.9%)		8/130 (6.2%)		13/278 (4.7%)
Nervous system disorders
Headache	9/148 (6.1%)		7/145 (4.8%)		15/128 (11.7%)		15/130 (11.5%)		38/278 (13.7%)
Dizziness	5/148 (3.4%)		9/145 (6.2%)		10/128 (7.8%)		10/130 (7.7%)		25/278 (9%)
Psychiatric disorders
Anxiety	2/148 (1.4%)		3/145 (2.1%)		10/128 (7.8%)		6/130 (4.6%)		18/278 (6.5%)
Depression	2/148 (1.4%)		4/145 (2.8%)		10/128 (7.8%)		12/130 (9.2%)		24/278 (8.6%)
Insomnia	4/148 (2.7%)		4/145 (2.8%)		9/128 (7%)		11/130 (8.5%)		24/278 (8.6%)
Renal and urinary disorders
Nephrolithiasis	2/148 (1.4%)		1/145 (0.7%)		13/128 (10.2%)		9/130 (6.9%)		23/278 (8.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/148 (0.7%)		1/145 (0.7%)		7/128 (5.5%)		6/130 (4.6%)		14/278 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	5/148 (3.4%)		2/145 (1.4%)		14/128 (10.9%)		14/130 (10.8%)		33/278 (11.9%)
Epistaxis	0/148 (0%)		0/145 (0%)		5/128 (3.9%)		8/130 (6.2%)		13/278 (4.7%)
Oropharyngeal pain	2/148 (1.4%)		2/145 (1.4%)		8/128 (6.3%)		12/130 (9.2%)		21/278 (7.6%)
Sinus congestion	0/148 (0%)		2/145 (1.4%)		7/128 (5.5%)		9/130 (6.9%)		16/278 (5.8%)
Skin and subcutaneous tissue disorders
Rash	0/148 (0%)		0/145 (0%)		14/128 (10.9%)		8/130 (6.2%)		22/278 (7.9%)
Vascular disorders
Hypertension	5/148 (3.4%)		4/145 (2.8%)		22/128 (17.2%)		22/130 (16.9%)		49/278 (17.6%)

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.