Exenatide Versus Glimepiride in Patients with Type 2 Diabetes

Study identifier:H8O-EW-GWBE

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Long Term Treatment with Exenatide Versus Glimepiride in Patients with Type 2 Diabetes Pretreated with Metformin (EUREXA: European Exenatide Study)

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 3

Healthy volunteers

Study drug

exenatide, glimepiride

Sex

All

Actual Enrollment

1029

Study type

Interventional

Age

18 Years - 85 Years

Date

Study Start Date: 01 Sept 2006

Primary Completion Date: 01 Mar 2011

Study Completion Date: 01 Mar 2011

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Aug 2015 by AstraZeneca Pharmaceuticals

Collaborators

Eli Lilly and Company

Inclusion and exclusion criteria

Location

Research Site

Munster, Germany

Location

Research Site

Essen Schonnebeck, Germany

Location

Research Site

Essen, Germany

Location

Research Site

Witten, Germany

Location

Research Site

Hamburg-Altona, Germany

Location

Research Site

Dresden, Germany

Location

Research Site

Heidelberg, Germany

Location

Research Site

Staffelstein, Germany

Arms	Assigned Interventions
Experimental: Exenatide	Drug: exenatide subcutaneous injection (5mcg or 10mcg), twice a day Other Name: Byetta
Active Comparator: Glimepiride	Drug: glimepiride oral tablet (titrated to maximally tolerated dose), once daily Other Name: Amaryl

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients meeting defined failure of HbA1c control (primary endpoint) in Study Period II were eligible for entry to Study Period III

Reporting Groups

	Description
Period II, Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Period III, Exen + Met + Glim - Randomized	Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Exen + Met + Pio or Rosi - Randomized	Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Glim + Met + Exen - Not Randomized	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III
Period II, Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin

Participant Flow for 3 periods

Period 1: Period II

	Period II, Glim + Met	Period II, Exen + Met
STARTED	514	515
Intent to Treat (ITT) Safety Population	508	511
ITT Efficacy Population	487	490
Met Primary Endpoint	262	203
Without Treatment Failure	124	138
COMPLETED	386	341
NOT COMPLETED	128	174
Adverse Event	17	49
Protocol Violation	18	11
Physician Decision	17	23
Death	2	4
Lack of Efficacy	11	8
Lost to follow up	5	5
Entry Criteria Not Met	8	4
Subject Decision	50	70

Period 2: Period III

	Period III, Exen + Met + Glim - Randomized	Period III, Exen + Met + Pio or Rosi - Randomized	Period III, Glim + Met + Exen - Not Randomized
STARTED	77	77	166
Extension ITT Safety Population	74	76	166
Extension ITT Efficacy Population	73	75	164
COMPLETED	48	47	101
NOT COMPLETED	29	30	65
Protocol Violation	5	3	8
Adverse Event	3	4	10
Physician Decision	5	9	15
Lack of Efficacy	7	5	9
Lost to follow up	1	1	2
Entry Criteria Not Met	1	0	1
Subject Decision	7	8	20

Period 3: Period I

	Period II, Glim + Met	Period III, Exen + Met + Glim - Randomized	Period III, Exen + Met + Pio or Rosi - Randomized	Period III, Glim + Met + Exen - Not Randomized	Period II, Exen + Met
STARTED	0	0	0	0	0
COMPLETED	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Baseline Measures

	Exen + Met	Glim + Met	Total
Number of Participants [units: Participants]	490	487	977
Age Categorical [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	388	389	777
>=65 years	102	98	200
Age Continuous [units: years] Mean ± Standard Deviation	56.1 ± 10.03	56.8 ± 9.14	56.4 ± 9.60
Gender, Male/Female [units: participants]
Female	218	235	453
Male	272	252	524
Glycosylated hemoglobin (HbA1c) [units: percentage of total hemoglobin] Mean ± Standard Deviation	7.4 ± 0.69	7.4 ± 0.71	7.4 ± 0.70
Weight [units: kg] Mean ± Standard Deviation	92.8 ± 16.70	91.1 ± 14.78	92.0 ± 15.78

Outcome Measures

1. Primary Outcome Measure: Number of Patients with treatment failure [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

Measure Type	Primary
Measure Name	Number of Patients with treatment failure
Measure Description	Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.
Time Frame	Baseline to end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population: Enrolled patients with a baseline and at least one post-baseline measurement of HbA1c in Study Period II (including only Study Period II); patients analyzed according to treatment as randomized.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	490	487
Number of Patients with treatment failure [units: number of patients]
Number of patients with treatment failure	203	262
Number of patients censored	287	225

Statistical Analysis 1 for Number of Patients with treatment failure

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	Yes
Method^[3]	Regression, Cox
P-Value^[4]	0.0020
Other^[5]	0.748
95% Confidence Interval	( 0.623 to 0.899 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis (H0) and alternative hypothesis (H1) for the primary analysis (i.e., non-inferiority) are:H0: hazards of treatment for Exenatide/hazards of treatment for Glimepiride >=1.25.H1: hazards of treatment for Exenatide/hazards of treatment for Glimepiride < 1.25. With 527 patients in each arm, the study would have approximately 90% power to conclude non-inferiority of Exenatide to Glimepiride.
[2]	Additional details about a non-inferiority or equivalence analysis:
	Non inferiority test was based on the upper 1-sided 97.5% CI for the hazard ratio of Exenatide/Glimepiride;the upper bound was compared to 1.25: if <1.25, the hypothesis that the risk of treatment failure with Exenatide is more than 1.25 times greater than the risk with Glimepiride is rejected.Superiority test was based on the 2-sided 95% CI for the hazard ratio. If CI excludes 1, the hypothesis that the risk of treatment failure with Exenatide is equal to that with Glimepiride is rejected.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Time to treatment failure was modeled using Cox regression with treatment and baseline HbA1c as predictive terms.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Time to treatment failure [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

Measure Type	Primary
Measure Name	Time to treatment failure
Measure Description	Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.
Time Frame	Baseline to end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	490	487
Time to treatment failure [units: week] Median (95% Confidence Interval)	180.0 (140.9 to NA) ^[1]	142.1 (118.6 to 161.1)

Statistical Analysis 1 for Time to treatment failure

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Log Rank
P-Value^[4]	0.0315

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Kaplan-Meier survival curves for time to treatment failure were compared between treatment groups using log rank test.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

3. Secondary Outcome Measure: Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3
Measure Description	HOMA-B at Year 3. HOMA-B is an index of beta-cell function and was calculated as: HOMA-B = (20 x fasting insulin (measured in pmol/L))/((fasting glucose (measured in mmol/L) - 3.5) x 7.175).
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	148	166
Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3 [units: ratio] Least Squares Mean (Standard Error)	66.86 (4.045)	68.52 (3.813)

Statistical Analysis 1 for Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.7648
Other^[5]	-1.66
Standard Error of the Mean	± 5.560
95% Confidence Interval	( -12.58 to 9.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mixed-model Repeated Measures (MMRM) analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Change in HOMA-B from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in HOMA-B from baseline to endpoint
Measure Description	Change in HOMA-B from baseline to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using last observation carried forward (LOCF) approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	326	329
Change in HOMA-B from baseline to endpoint [units: ratio] Least Squares Mean (Standard Error)	5.56 (6.147)	19.92 (6.340)

Statistical Analysis 1 for Change in HOMA-B from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0528
Other^[5]	-14.35
Standard Error of the Mean	± 7.399
95% Confidence Interval	( -28.88 to 0.17 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in HOMA-B from baseline to endpoint was analyzed by an analysis of covariance (ANCOVA) model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Fasting proinsulin/insulin ratio at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Fasting proinsulin/insulin ratio at Year 3
Measure Description	Fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	152	170
Fasting proinsulin/insulin ratio at Year 3 [units: ratio] Least Squares Mean (Standard Error)	0.22 (0.023)	0.23 (0.022)

Statistical Analysis 1 for Fasting proinsulin/insulin ratio at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.9040
Other^[5]	-0.00
Standard Error of the Mean	± 0.032
95% Confidence Interval	( -0.07 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Change in fasting proinsulin/insulin ratio from baseline to endpoint. [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in fasting proinsulin/insulin ratio from baseline to endpoint.
Measure Description	Change in fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio from baseline to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	326	331
Change in fasting proinsulin/insulin ratio from baseline to endpoint. [units: ratio] Least Squares Mean (Standard Error)	0.03 (0.014)	0.05 (0.015)

Statistical Analysis 1 for Change in fasting proinsulin/insulin ratio from baseline to endpoint.

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.2500
Other^[5]	-0.02
Standard Error of the Mean	± 0.017
95% Confidence Interval	( -0.05 to 0.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in fasting proinsulin/insulin ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Ratio of the 30 minute increment in plasma insulin concentration and the 30 minute increment in plasma glucose during the oral glucose tolerance test (DI30/DG30 ratio) at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Ratio of the 30 minute increment in plasma insulin concentration and the 30 minute increment in plasma glucose during the oral glucose tolerance test (DI30/DG30 ratio) at Year 3
Measure Description	DI30/DG30 at Year 3. DI30/DG30 ratio was calculated as (30 minute post prandial insulin - fasting insulin) (measured in pmol/L)/(30 minute post prandial glucose - fasting glucose) (measured in mmol/L).
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	130	156
Ratio of the 30 minute increment in plasma insulin concentration and the 30 minute increment in plasma glucose during the oral glucose tolerance test (DI30/DG30 ratio) at Year 3 [units: ratio] Least Squares Mean (Standard Error)	25.81 (3.323)	26.38 (3.032)

Statistical Analysis 1 for Ratio of the 30 minute increment in plasma insulin concentration and the 30 minute increment in plasma glucose during the oral glucose tolerance test (DI30/DG30 ratio) at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.9001
Other^[5]	-0.56
Standard Error of the Mean	± 4.497
95% Confidence Interval	( -9.40 to 8.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Change in DI30/DG30 ratio from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in DI30/DG30 ratio from baseline to endpoint
Measure Description	Change in DI30/DG30 ratio from baseline to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	302	311
Change in DI30/DG30 ratio from baseline to endpoint [units: ratio] Least Squares Mean (Standard Error)	12.10 (4.115)	0.91 (4.299)

Statistical Analysis 1 for Change in DI30/DG30 ratio from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0246
Other^[5]	11.19
Standard Error of the Mean	± 4.966
95% Confidence Interval	( 1.44 to 20.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in DI30/DG30 ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: Disposition index at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Disposition index at Year 3
Measure Description	Disposition Index at Year 3. Disposition index was calculated as (DI30/DG30 ratio)/(HOMA index for insulin resistance (HOMA-IR)); where HOMA-IR=(fasting insulin (measured in pmol/L) x fasting glucose (measured in mmol/L))/(22.5 x 7.175).
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	130	156
Disposition index at Year 3 [units: ratio] Least Squares Mean (Standard Error)	12.56 (1.179)	7.89 (1.078)

Statistical Analysis 1 for Disposition index at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0036
Other^[5]	4.67
Standard Error of the Mean	± 1.598
95% Confidence Interval	( 1.53 to 7.81 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

10. Secondary Outcome Measure: Change in disposition index from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in disposition index from baseline to endpoint
Measure Description	Change in disposition index from baseline to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	302	311
Change in disposition index from baseline to endpoint [units: ratio] Least Squares Mean (Standard Error)	9.15 (1.764)	1.82 (1.849)

Statistical Analysis 1 for Change in disposition index from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0006
Other^[5]	7.33
Standard Error of the Mean	± 2.128
95% Confidence Interval	( 3.15 to 11.50 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in disposition index from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

11. Secondary Outcome Measure: Change in HbA1c from baseline to Year 3 [ Time Frame: Baseline, Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Change in HbA1c from baseline to Year 3
Measure Description	Change in HbA1c from baseline to Year 3.
Time Frame	Baseline, Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	182	197
Change in HbA1c from baseline to Year 3 [units: percentage of total hemoglobin] Least Squares Mean (Standard Error)	-0.30 (0.051)	-0.12 (0.049)

Statistical Analysis 1 for Change in HbA1c from baseline to Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0128
Other^[5]	-0.18
Standard Error of the Mean	± 0.070
95% Confidence Interval	( -0.31 to -0.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

12. Secondary Outcome Measure: Change in HbA1c from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in HbA1c from baseline to endpoint
Measure Description	Change in HbA1c from baseline to endpoint. Endpoint for HbA1c was defined as the HbA1c measured at the treatment failure for patients reaching primary endpoint and was the last observation in study period II for other patients (either followed until the end of the study period II or discontinuing the study).
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	488	485
Change in HbA1c from baseline to endpoint [units: percentage of total hemoglobin] Least Squares Mean (Standard Error)	-0.36 (0.035)	-0.21 (0.035)

Statistical Analysis 1 for Change in HbA1c from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0015
Other^[5]	-0.16
Standard Error of the Mean	± 0.050
95% Confidence Interval	( -0.26 to -0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in HbA1c from baseline to endpoint was analyzed by an ANCOVA model that includes treatment as factor and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

13. Secondary Outcome Measure: Fasting plasma glucose at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Fasting plasma glucose at Year 3
Measure Description	Fasting plasma glucose at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	149	166
Fasting plasma glucose at Year 3 [units: mmol/L] Least Squares Mean (Standard Error)	7.27 (0.127)	7.96 (0.120)

Statistical Analysis 1 for Fasting plasma glucose at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<.0001
Other^[5]	-0.69
Standard Error of the Mean	± 0.174
95% Confidence Interval	( -1.03 to -0.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

14. Secondary Outcome Measure: Change in fasting plasma glucose from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in fasting plasma glucose from baseline to endpoint
Measure Description	Change in fasting plasma glucose from baseline to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	327	329
Change in fasting plasma glucose from baseline to endpoint [units: mmol/L] Least Squares Mean (Standard Error)	-0.87 (0.155)	-0.41 (0.161)

Statistical Analysis 1 for Change in fasting plasma glucose from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0109
Other^[5]	-0.47
Standard Error of the Mean	± 0.183
95% Confidence Interval	( -0.83 to -0.11 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in fasting plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

15. Secondary Outcome Measure: Postprandial (2 hours) plasma glucose at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Postprandial (2 hours) plasma glucose at Year 3
Measure Description	Postprandial (2 hours) plasma glucose at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	138	160
Postprandial (2 hours) plasma glucose at Year 3 [units: mmol/L] Least Squares Mean (Standard Error)	12.65 (0.311)	15.45 (0.289)

Statistical Analysis 1 for Postprandial (2 hours) plasma glucose at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<.0001
Other^[5]	-2.80
Standard Error of the Mean	± 0.424
95% Confidence Interval	( -3.64 to -1.97 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

16. Secondary Outcome Measure: Change in postprandial (2 hours) plasma glucose from baseline to endpoint [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Change in postprandial (2 hours) plasma glucose from baseline to endpoint
Measure Description	Change from baseline in postprandial (2 hours) plasma glucose to endpoint.
Time Frame	Baseline, end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	310	320
Change in postprandial (2 hours) plasma glucose from baseline to endpoint [units: mmol/L] Least Squares Mean (Standard Error)	-2.72 (0.275)	-0.53 (0.286)

Statistical Analysis 1 for Change in postprandial (2 hours) plasma glucose from baseline to endpoint

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<.0001
Other^[5]	-2.19
Standard Error of the Mean	± 0.327
95% Confidence Interval	( -2.84 to -1.55 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change in postprandial (2 hours) plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

17. Secondary Outcome Measure: Change in Body weight from baseline to Year 3 [ Time Frame: Baseline, Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Change in Body weight from baseline to Year 3
Measure Description	Change in Body weight from baseline to Year 3.
Time Frame	Baseline, Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population: Enrolled patients receiving at least one dose of study medication in Study Period II with patients analyzed according to treatment actually received. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	185	201
Change in Body weight from baseline to Year 3 [units: kg] Least Squares Mean (Standard Error)	-3.92 (0.335)	1.47 (0.319)

Statistical Analysis 1 for Change in Body weight from baseline to Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<.0001
Other^[5]	-5.40
Standard Error of the Mean	± 0.463
95% Confidence Interval	( -6.31 to -4.49 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

18. Secondary Outcome Measure: Systolic Blood pressure at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Systolic Blood pressure at Year 3
Measure Description	Systolic Blood pressure at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	183	203
Systolic Blood pressure at Year 3 [units: mmHg] Least Squares Mean (Standard Error)	130.58 (0.891)	135.78 (0.845)

Statistical Analysis 1 for Systolic Blood pressure at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<.0001
Other^[5]	-5.20
Standard Error of the Mean	± 1.228
95% Confidence Interval	( -7.61 to -2.79 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

19. Secondary Outcome Measure: Diastolic Blood pressure at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Diastolic Blood pressure at Year 3
Measure Description	Diastolic Blood pressure at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	183	203
Diastolic Blood pressure at Year 3 [units: mmHg] Least Squares Mean (Standard Error)	77.45 (0.544)	79.16 (0.517)

Statistical Analysis 1 for Diastolic Blood pressure at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0228
Other^[5]	-1.71
Standard Error of the Mean	± 0.750
95% Confidence Interval	( -3.18 to -0.24 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

20. Secondary Outcome Measure: Heart rate at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Heart rate at Year 3
Measure Description	Heart rate at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	181	199
Heart rate at Year 3 [units: beats per minute] Least Squares Mean (Standard Error)	73.51 (0.583)	74.23 (0.555)

Statistical Analysis 1 for Heart rate at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.3737
Other^[5]	-0.72
Standard Error of the Mean	± 0.805
95% Confidence Interval	( -2.30 to 0.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and visit by treatment interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

21. Secondary Outcome Measure: Triglycerides at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Triglycerides at Year 3
Measure Description	Triglycerides at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	178	193
Triglycerides at Year 3 [units: mmol/L] Least Squares Mean (Standard Error)	1.69 (0.065)	1.95 (0.062)

Statistical Analysis 1 for Triglycerides at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0042
Other^[5]	-0.26
Standard Error of the Mean	± 0.089
95% Confidence Interval	( -0.43 to -0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

22. Secondary Outcome Measure: Total Cholesterol at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	Total Cholesterol at Year 3
Measure Description	Total Cholesterol at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	178	193
Total Cholesterol at Year 3 [units: mmol/L] Least Squares Mean (Standard Error)	4.77 (0.057)	4.75 (0.054)

Statistical Analysis 1 for Total Cholesterol at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.7914
Other^[5]	0.02
Standard Error of the Mean	± 0.079
95% Confidence Interval	( -0.13 to 0.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

23. Secondary Outcome Measure: High-density Lipoprotein (HDL) Cholesterol at Year 3 [ Time Frame: Year 3 in Period II ]

Measure Type	Secondary
Measure Name	High-density Lipoprotein (HDL) Cholesterol at Year 3
Measure Description	HDL Cholesterol at Year 3.
Time Frame	Year 3 in Period II
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	178	195
High-density Lipoprotein (HDL) Cholesterol at Year 3 [units: mmol/L] Least Squares Mean (Standard Error)	1.31 (0.013)	1.25 (0.013)

Statistical Analysis 1 for High-density Lipoprotein (HDL) Cholesterol at Year 3

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0011
Other^[5]	0.06
Standard Error of the Mean	± 0.019
95% Confidence Interval	( 0.02 to 0.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

24. Secondary Outcome Measure: Hypoglycemia Rate Per Year [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

Measure Type	Secondary
Measure Name	Hypoglycemia Rate Per Year
Measure Description	All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration <=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration <=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination.
Time Frame	Baseline to end of Period II (up to 4.5 years)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Safety Population.

Reporting Groups

	Description
Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin

Measured Values

	Exen + Met	Glim + Met
Number of Participants Analyzed [units:participants]	511	508
Hypoglycemia Rate Per Year [units: events per subject-year] Least Squares Mean (Standard Error)	1.52 (0.142)	5.32 (0.473)

Statistical Analysis 1 for Hypoglycemia Rate Per Year

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Negative Binomial Model]
P-Value^[4]	<.0001
Other^[5]	0.29
Standard Error of the Mean	± 0.037
95% Confidence Interval	( 0.22 to 0.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The number of hypoglycemic episodes by patient were compared between treatment groups using a negative binomial model with effects for treatment and baseline HbA1c and the logarithm of the days of exposure as the offset variable.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

25. Secondary Outcome Measure: Change in HbA1c from baseline to Year 2 for patients randomized at entry in Period III [ Time Frame: Baseline in Period III, Year 2 in Period III ]

Measure Type	Secondary
Measure Name	Change in HbA1c from baseline to Year 2 for patients randomized at entry in Period III
Measure Description	Change in HbA1c from baseline to Year 2.
Time Frame	Baseline in Period III, Year 2 in Period III
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Extension ITT Efficacy Population: Extension enrolled patients with at least one post-baseline measurement of HbA1c in Study Period III. The analysis included patients randomized at entry in study period III. Missing data at Year 2 was not imputed.

Reporting Groups

	Description
Exen + Met + Glim - Randomized	Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Exen + Met + Pio or Rosi - Randomized	Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III

Measured Values

	Exen + Met + Glim - Randomized	Exen + Met + Pio or Rosi - Randomized
Number of Participants Analyzed [units:participants]	44	42
Change in HbA1c from baseline to Year 2 for patients randomized at entry in Period III [units: percentage of total hemoglobin] Least Squares Mean (Standard Error)	-0.19 (0.099)	-0.47 (0.100)

Statistical Analysis 1 for Change in HbA1c from baseline to Year 2 for patients randomized at entry in Period III

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0508
Other^[5]	0.28
Standard Error of the Mean	± 0.141
95% Confidence Interval	( -0.00 to 0.55 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value at Period III as a covariate. The compound symmetric covariance structure was assumed.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

26. Secondary Outcome Measure: Change in HbA1c from baseline to Year 2 for patients not randomized at entry in Period III [ Time Frame: Baseline in Period III, Year 2 in Period III ]

Measure Type	Secondary
Measure Name	Change in HbA1c from baseline to Year 2 for patients not randomized at entry in Period III
Measure Description	Change in HbA1c from baseline to Year 2.
Time Frame	Baseline in Period III, Year 2 in Period III
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Extension ITT Efficacy population. The analysis included patients not randomized at entry in study period III. Missing data at Year 2 was not imputed.

Reporting Groups

	Description
Glim + Met + Exen - Not Randomized	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III

Measured Values

	Glim + Met + Exen - Not Randomized
Number of Participants Analyzed [units:participants]	89
Change in HbA1c from baseline to Year 2 for patients not randomized at entry in Period III [units: percentage of total hemoglobin] Mean (Standard Deviation)	-0.47 (0.984)

No statistical analysis provided for Change in HbA1c from baseline to Year 2 for patients not randomized at entry in Period III

27. Secondary Outcome Measure: Hypoglycemia Rate Per Year in Period III [ Time Frame: Start of Period III to end of study ]

Measure Type	Secondary
Measure Name	Hypoglycemia Rate Per Year in Period III
Measure Description	All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration <=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration <=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination.
Time Frame	Start of Period III to end of study
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Extension ITT Safety Population: Extension enrolled patients receiving at least one dose of study medication in Study Period III.

Reporting Groups

	Description
Exen + Metformin + Glim - Randomized	Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Exen + Met + Pio or Rosi - Randomized	Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Glim + Met + Exen - Not Randomized	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III

Measured Values

	Exen + Metformin + Glim - Randomized	Exen + Met + Pio or Rosi - Randomized	Glim + Met + Exen - Not Randomized
Number of Participants Analyzed [units:participants]	74	76	166
Hypoglycemia Rate Per Year in Period III [units: events per subject-year] Mean (Standard Deviation)	2.78 (5.456)	0.60 (1.674)	4.62 (10.411)

No statistical analysis provided for Hypoglycemia Rate Per Year in Period III

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
Period II, Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Period III, Exen + Met + Glim - Randomized	Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Exen + Met + Pio or Rosi - Randomized	Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Glim + Met + Exen - Not Randomized	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III
Period II, Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin

Serious Adverse Events

Period II, Glim + Met

Period III, Exen + Met + Glim - Randomized

Period III, Exen + Met + Pio or Rosi - Randomized

Period III, Glim + Met + Exen - Not Randomized

Period II, Exen + Met

Total, serious adverse events

# participants affected / at risk

68/508 (13.39%)

7/74 (9.46%)

13/76 (17.11%)

19/166 (11.45%)

73/511 (14.29%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Breast cancer¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

1/76 (1.32%)

1/166 (0.60%)

3/511 (0.59%)

Injury, poisoning and procedural complications

Fall¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

3/511 (0.59%)

Renal and urinary disorders

Nephrolithiasis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

3/511 (0.59%)

Cardiac disorders

Atrial fibrillation¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Nervous system disorders

Cerebrovascular accident¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Hepatobiliary disorders

Cholelithiasis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

2/511 (0.39%)

Infections and infestations

Erysipelas¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Cardiac disorders

Ischaemic cardiomyopathy¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Injury, poisoning and procedural complications

Lower limb fracture¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Musculoskeletal and connective tissue disorders

Osteoarthritis¹

# participants affected / at risk

4/508 (0.79%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Prostate cancer¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Renal and urinary disorders

Renal colic¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Respiratory, thoracic and mediastinal disorders

Sleep apnoea syndrome¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Musculoskeletal and connective tissue disorders

Spinal column stenosis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Nervous system disorders

Syncope¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Cardiac disorders

Tachyarrhythmia¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

2/511 (0.39%)

Gastrointestinal disorders

Abdominal pain¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Abscess¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Abscess limb¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Acute coronary syndrome¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

1/511 (0.20%)

Blood and lymphatic system disorders

Anaemia¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Anal fissure¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Angina pectoris¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Atrial flutter¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Basal cell carcinoma¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Brain contusion¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Respiratory, thoracic and mediastinal disorders

Bullous lung disease¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Cardiac failure¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Carotid arteriosclerosis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Cellulitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Musculoskeletal and connective tissue disorders

Cervical spinal stenosis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

General disorders and administration site conditions

Chest pain¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

1/511 (0.20%)

Hepatobiliary disorders

Cholecystitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Colon cancer¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

1/511 (0.20%)

Gastrointestinal disorders

Colonic polyp¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Colorectal cancer¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Constipation¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Contusion¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Renal and urinary disorders

Cystitis haemorrhagic¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Vascular disorders

Deep vein thrombosis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Encephalitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Faecaloma¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Femoral neck fracture¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Gallbladder cancer¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Gastroenteritis norovirus¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Glioblastoma¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

HIV infection¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Congenital, familial and genetic disorders

Haemophilia A with anti factor VIII¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Helicobacter gastritis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Influenza¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Inguinal hernia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Injury¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Musculoskeletal and connective tissue disorders

Intervertebral disc degeneration¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Ischaemic stroke¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Limb crushing injury¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung squamous cell carcinoma stage unspecified¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Myocardial infarction¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Musculoskeletal and connective tissue disorders

Pain in extremity¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Cardiac disorders

Palpitations¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Musculoskeletal and connective tissue disorders

Periarthritis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

1/166 (0.60%)

1/511 (0.20%)

Infections and infestations

Pneumonia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Pubis fracture¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Radiculopathy¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Radius fracture¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rectal cancer¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Renal and urinary disorders

Renal failure acute¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Road traffic accident¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Sciatica¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Sinusitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Sternal fracture¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Subdural haemorrhage¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

General disorders and administration site conditions

Sudden cardiac death¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Injury, poisoning and procedural complications

Tendon rupture¹

# participants affected / at risk

3/508 (0.59%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Nervous system disorders

Transient ischaemic attack¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Umbilical hernia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Reproductive system and breast disorders

Uterine cervical erosion¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uterine leiomyoma¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Infections and infestations

Viral labyrinthitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

1/511 (0.20%)

Gastrointestinal disorders

Abdominal adhesions¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Abdominal hernia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Accident¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Acute abdomen¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Acute myocardial infarction¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Anal abscess¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Angina unstable¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

2/166 (1.20%)

0/511 (0.00%)

Eye disorders

Angle closure glaucoma¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Appendicitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Arthralgia¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Respiratory, thoracic and mediastinal disorders

Asthma¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder cancer¹

# participants affected / at risk

2/508 (0.39%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder neoplasm¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Breast cancer metastatic¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Bronchitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Bursitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Renal and urinary disorders

Calculus ureteric¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Cardiac disorder¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Nervous system disorders

Carpal tunnel syndrome¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Chondropathy¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Clavicle fracture¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Coronary artery disease¹

# participants affected / at risk

3/508 (0.59%)

1/74 (1.35%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Psychiatric disorders

Depression¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Congenital, familial and genetic disorders

Dermoid cyst¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Diverticulum intestinal¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Dyspepsia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Endometrial cancer¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Reproductive system and breast disorders

Endometrial hyperplasia¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Reproductive system and breast disorders

Endometrial hypertrophy¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Exostosis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Fibula fracture¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Foot deformity¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Foot fracture¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Gastric neoplasm¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Gastritis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Infections and infestations

Gastroenteritis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Gastrointestinal inflammation¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Endocrine disorders

Goitre¹

# participants affected / at risk

3/508 (0.59%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Haemorrhoids¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Vascular disorders

Hypertension¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Metabolism and nutrition disorders

Hypoglycaemia¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Metabolism and nutrition disorders

Hypokalaemia¹

# participants affected / at risk

0/508 (0.00%)

1/74 (1.35%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Infected epidermal cyst¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Intervertebral discitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Joint effusion¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Knee deformity¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Localised infection¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Eye disorders

Macular oedema¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Meniscus lesion¹

# participants affected / at risk

4/508 (0.79%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Psychiatric disorders

Mental disorder¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Metastases to bone¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Metastases to liver¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Reproductive system and breast disorders

Metrorrhagia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Psychiatric disorders

Mood altered¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Myocardial ischaemia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Nervous system disorders

Nervous system disorder¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Renal and urinary disorders

Nocturia¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

General disorders and administration site conditions

Non-cardiac chest pain¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Metabolism and nutrition disorders

Obesity¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Musculoskeletal and connective tissue disorders

Osteitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Osteomyelitis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Reproductive system and breast disorders

Ovarian cyst¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Gastrointestinal disorders

Pancreatitis¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

0/76 (0.00%)

1/166 (0.60%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Pelvic fracture¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Cardiac disorders

Pericarditis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Post procedural haematoma¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Postoperative wound infection¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rectosigmoid cancer¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Renal neoplasm¹

# participants affected / at risk

0/508 (0.00%)

0/74 (0.00%)

1/76 (1.32%)

0/166 (0.00%)

0/511 (0.00%)

Skin and subcutaneous tissue disorders

Skin ulcer¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Small cell lung cancer stage unspecified¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Sports injury¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Staphylococcal sepsis¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Infections and infestations

Subcutaneous abscess¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Nervous system disorders

Transient global amnesia¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Upper limb fracture¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Injury, poisoning and procedural complications

Ureteric injury¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Renal and urinary disorders

Urinary bladder polyp¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Renal and urinary disorders

Urinary tract inflammation¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uterine cancer¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

Reproductive system and breast disorders

Uterine polyp¹

# participants affected / at risk

1/508 (0.20%)

0/74 (0.00%)

0/76 (0.00%)

0/166 (0.00%)

0/511 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 13.1
2	Term from vocabulary,

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Period II, Glim + Met	Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Period III, Exen + Met + Glim - Randomized	Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Exen + Met + Pio or Rosi - Randomized	Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Glim + Met + Exen - Not Randomized	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III
Period II, Exen + Met	Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin

Other Adverse Events

Period II, Glim + Met

Period III, Exen + Met + Glim - Randomized

Period III, Exen + Met + Pio or Rosi - Randomized

Period III, Glim + Met + Exen - Not Randomized

Period II, Exen + Met

Total, other (not including serious) adverse events

# participants affected / at risk

248/508 (48.82%)

39/74 (52.70%)

39/76 (51.32%)

91/166 (54.82%)

311/511 (60.86%)

Gastrointestinal disorders

Nausea¹

# participants affected / at risk

11/508 (2.17%)

10/74 (13.51%)

9/76 (11.84%)

38/166 (22.89%)

147/511 (28.77%)

Infections and infestations

Nasopharyngitis¹

# participants affected / at risk

93/508 (18.31%)

20/74 (27.03%)

15/76 (19.74%)

27/166 (16.27%)

96/511 (18.79%)

Gastrointestinal disorders

Diarrhoea¹

# participants affected / at risk

33/508 (6.50%)

7/74 (9.46%)

7/76 (9.21%)

13/166 (7.83%)

62/511 (12.13%)

Nervous system disorders

Headache¹

# participants affected / at risk

48/508 (9.45%)

11/74 (14.86%)

7/76 (9.21%)

10/166 (6.02%)

56/511 (10.96%)

Infections and infestations

Influenza¹

# participants affected / at risk

35/508 (6.89%)

7/74 (9.46%)

6/76 (7.89%)

8/166 (4.82%)

54/511 (10.57%)

Musculoskeletal and connective tissue disorders

Back pain¹

# participants affected / at risk

54/508 (10.63%)

5/74 (6.76%)

9/76 (11.84%)

9/166 (5.42%)

52/511 (10.18%)

Gastrointestinal disorders

Vomiting¹

# participants affected / at risk

12/508 (2.36%)

4/74 (5.41%)

1/76 (1.32%)

13/166 (7.83%)

44/511 (8.61%)

Infections and infestations

Bronchitis¹

# participants affected / at risk

31/508 (6.10%)

2/74 (2.70%)

7/76 (9.21%)

5/166 (3.01%)

34/511 (6.65%)

Gastrointestinal disorders

Dyspepsia¹

# participants affected / at risk

14/508 (2.76%)

4/74 (5.41%)

0/76 (0.00%)

14/166 (8.43%)

26/511 (5.09%)

Infections and infestations

Pharyngitis¹

# participants affected / at risk

21/508 (4.13%)

2/74 (2.70%)

2/76 (2.63%)

5/166 (3.01%)

26/511 (5.09%)

Gastrointestinal disorders

Abdominal pain upper¹

# participants affected / at risk

13/508 (2.56%)

6/74 (8.11%)

2/76 (2.63%)

6/166 (3.61%)

21/511 (4.11%)

Musculoskeletal and connective tissue disorders

Arthralgia¹

# participants affected / at risk

41/508 (8.07%)

2/74 (2.70%)

2/76 (2.63%)

6/166 (3.61%)

21/511 (4.11%)

Respiratory, thoracic and mediastinal disorders

Cough¹

# participants affected / at risk

25/508 (4.92%)

4/74 (5.41%)

4/76 (5.26%)

10/166 (6.02%)

18/511 (3.52%)

Infections and infestations

Gastroenteritis¹

# participants affected / at risk

13/508 (2.56%)

4/74 (5.41%)

3/76 (3.95%)

9/166 (5.42%)

18/511 (3.52%)

Musculoskeletal and connective tissue disorders

Pain in extremity¹

# participants affected / at risk

22/508 (4.33%)

3/74 (4.05%)

2/76 (2.63%)

10/166 (6.02%)

16/511 (3.13%)

Vascular disorders

Hypertension¹

# participants affected / at risk

24/508 (4.72%)

6/74 (8.11%)

3/76 (3.95%)

9/166 (5.42%)

15/511 (2.94%)

Infections and infestations

Cystitis¹

# participants affected / at risk

19/508 (3.74%)

5/74 (6.76%)

3/76 (3.95%)

4/166 (2.41%)

14/511 (2.74%)

Gastrointestinal disorders

Abdominal pain¹

# participants affected / at risk

10/508 (1.97%)

4/74 (5.41%)

1/76 (1.32%)

4/166 (2.41%)

11/511 (2.15%)

General disorders and administration site conditions

Oedema peripheral¹

# participants affected / at risk

11/508 (2.17%)

0/74 (0.00%)

5/76 (6.58%)

2/166 (1.20%)

6/511 (1.17%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 13.1
2	Term from vocabulary,

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Only patients who reached primary endpoint 12 months or more before the projected end of the study could enter period III.

Results Point of Contact

Name/Title:	Peter Ohman, Medical Science Director
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

James Malone

Eli Lilly and Company

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site