Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Exenatide Versus Glimepiride in Patients With Type 2 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00359762
First received: July 31, 2006
Last updated: August 17, 2015
Last verified: August 2015
Results First Received: March 29, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: exenatide
Drug: glimepiride

  Participant Flow
  Hide 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 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   514   0   0   0   515 
Intent to Treat (ITT) Safety Population   508   0   0   0   511 
ITT Efficacy Population   487   0   0   0   490 
Met Primary Endpoint   262   0   0   0   203 
Without Treatment Failure   124   0   0   0   138 
COMPLETED   386   0   0   0   341 
NOT COMPLETED   128   0   0   0   174 
Adverse Event                17                0                0                0                49 
Protocol Violation                18                0                0                0                11 
Physician Decision                17                0                0                0                23 
Death                2                0                0                0                4 
Lack of Efficacy                11                0                0                0                8 
Lost to follow up                5                0                0                0                5 
Entry Criteria Not Met                8                0                0                0                4 
Subject Decision                50                0                0                0                70 

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

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
  Hide Baseline Characteristics

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.
No text entered.

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
Total Total of all reporting groups

Baseline Measures
   Exen + Met   Glim + Met   Total 
Overall Participants Analyzed 
[Units: Participants]
 490   487   977 
Age 
[Units: Participants]
     
<=18 years   0   0   0 
Between 18 and 65 years   388   389   777 
>=65 years   102   98   200 
Age 
[Units: Years]
Mean (Standard Deviation)
 56.1  (10.03)   56.8  (9.14)   56.4  (9.60) 
Gender 
[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
  Hide All Outcome Measures

1.  Primary:   Number of Patients With Treatment Failure   [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

Measure Type Primary
Measure Title 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 
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
Hazard Ratio [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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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 method 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:   Time to Treatment Failure   [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

Measure Type Primary
Measure Title 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 
Participants Analyzed 
[Units: Participants]
 490   487 
Time to Treatment Failure 
[Units: Week]
Median (95% Confidence Interval)
 180.0 [1] 
 (140.9 to N/A) 
 142.1 
 (118.6 to 161.1) 
[1] Since the last observed time point, beyond which all are missing, is still within the 95% confidence interval for the median survival time, the upper bound should be no less than the last observed time point, and is unknown due to censoring.


Statistical Analysis 1 for Time to Treatment Failure
Groups [1] All groups
Method [2] Log Rank
P Value [3] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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:   Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.7648
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Change in HOMA-B From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type Secondary
Measure Title 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 
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
Method [2] ANCOVA
P Value [3] 0.0528
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Fasting Proinsulin/Insulin Ratio at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.9040
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   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 Title 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 
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
Method [2] ANCOVA
P Value [3] 0.2500
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   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 Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.9001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



8.  Secondary:   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 Title 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 
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
Method [2] ANCOVA
P Value [3] 0.0246
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



9.  Secondary:   Disposition Index at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0036
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Change in Disposition Index From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type Secondary
Measure Title 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 
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
Method [2] ANCOVA
P Value [3] 0.0006
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



11.  Secondary:   Change in HbA1c From Baseline to Year 3   [ Time Frame: Baseline, Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0128
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



12.  Secondary:   Change in HbA1c From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

Measure Type Secondary
Measure Title 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 
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
Method [2] ANCOVA
P Value [3] 0.0015
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



13.  Secondary:   Fasting Plasma Glucose at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] <.0001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



14.  Secondary:   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 Title 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 
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
Method [2] ANCOVA
P Value [3] 0.0109
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



15.  Secondary:   Postprandial (2 Hours) Plasma Glucose at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] <.0001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



16.  Secondary:   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 Title 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 
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
Method [2] ANCOVA
P Value [3] <.0001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



17.  Secondary:   Change in Body Weight From Baseline to Year 3   [ Time Frame: Baseline, Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] <.0001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] <.0001
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0228
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



20.  Secondary:   Heart Rate at Year 3   [ Time Frame: Year 3 in Period II ]

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.3737
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0042
Least Squares Mean Difference [4] -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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.7914
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0011
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title 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 
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
Method [2] Negative Binomial Model
P Value [3] <.0001
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



25.  Secondary:   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 Title 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 
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
Method [2] Mixed Models Analysis
P Value [3] 0.0508
Least Squares Mean Difference [4] 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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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.
[4] Other relevant estimation information:
  No text entered.



26.  Secondary:   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 Title 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 
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:   Hypoglycemia Rate Per Year in Period III   [ Time Frame: Start of Period III to end of study ]

Measure Type Secondary
Measure Title 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 
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


  Other Adverse Events


  Limitations and Caveats
  Hide 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.


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