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Exenatide Versus Glimepiride in Patients With Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT00359762
Recruitment Status : Completed
First Posted : August 2, 2006
Results First Posted : March 14, 2013
Last Update Posted : September 15, 2015
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: exenatide
Drug: glimepiride

  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

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

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

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

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

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

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

6.  Secondary:   Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint.   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]
  Show Outcome Measure 6

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 ]
  Show Outcome Measure 7

8.  Secondary:   Change in DI30/DG30 Ratio From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]
  Show Outcome Measure 8

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

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

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

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

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

14.  Secondary:   Change in Fasting Plasma Glucose From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]
  Hide Outcome Measure 14

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)  

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   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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
P Value [4] 0.0109
Least Squares Mean Difference [5] -0.47
95% Confidence Interval -0.83 to -0.11
Standard Error of the mean (0.183)
[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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method 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:   Postprandial (2 Hours) Plasma Glucose at Year 3   [ Time Frame: Year 3 in Period II ]
  Show Outcome Measure 15

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) ]
  Show Outcome Measure 16

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

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

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

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

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

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

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

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

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 ]
  Show Outcome Measure 25

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 ]
  Show Outcome Measure 26

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


  Serious Adverse Events


  Other Adverse Events


  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.


  More Information