Safety and Efficacy of Exenatide Once Weekly Versus Liraglutide in Subjects With Type 2 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01029886
First received: December 8, 2009
Last updated: June 6, 2014
Last verified: June 2014
Results First Received: February 14, 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 once weekly
Drug: liraglutide

  Participant Flow


  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
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily
Total Total of all reporting groups

Baseline Measures
    Exenatide Once Weekly     Liraglutide Once Daily     Total  
Number of Participants  
[units: participants]
  461     450     911  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     386     360     746  
>=65 years     75     90     165  
Age  
[units: years]
Mean ± Standard Deviation
  56.6  ± 9.43     56.7  ± 9.59     56.6  ± 9.51  
Gender  
[units: participants]
     
Female     207     205     412  
Male     254     245     499  
Glycosylated hemoglobin (HbA1c)  
[units: percentage of total hemoglobin]
Mean ± Standard Deviation
  8.45  ± 1.014     8.43  ± 0.996     8.44  ± 1.004  
Weight  
[units: kg]
Mean ± Standard Deviation
  90.88  ± 19.472     91.13  ± 19.118     91.00  ± 19.288  
Background Oral Antidiabetic Agent (OAD)  
[units: participants]
     
Metformin (MET)     150     136     286  
Sulfonylurea (SU)     18     18     36  
Pioglitazone (PIO)     1     0     1  
MET+SU     275     277     552  
MET+PIO     16     18     34  
MET+SU+PIO     1     1     2  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Change in HbA1c From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Primary
Measure Title Change in HbA1c From Baseline to Week 26
Measure Description Change in HbA1c from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population: all patients who were randomized and received study drug. All observed data from all scheduled visits (including early termination visits) were included in the mixed-model repeated measures (MMRM) analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  390     386  
Change in HbA1c From Baseline to Week 26  
[units: percentage of total hemoglobin]
Least Squares Mean ± Standard Error
  -1.28  ± 0.05     -1.48  ± 0.05  


Statistical Analysis 1 for Change in HbA1c From Baseline to Week 26
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Mixed Models Analysis
P Value [4] 0.002
Least Squares Mean Difference [5] 0.21
Standard Error of the mean ± 0.07
95% Confidence Interval ( 0.08 to 0.33 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  A sample of 408 subjects in each treatment arm would provide approximately 90% power to detect a true difference between treatments of 0.25% in change in HbA1c from baseline with a 2 sided t-test at a significance level of 0.05, assuming a common standard deviation of 1.1%. MMRM model includes treatment, baseline HbA1c, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Superiority of exenatide once weekly with respect to change in HbA1c was concluded if the upper limit of the 2-sided 95% confidence interval (CI) for the treatment difference (exenatide once weekly minus liraglutide) was less than zero. Non-inferiority was concluded if the upper limit of the CI was <0.25%.
[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.



2.  Secondary:   Percentage of Patients Achieving HbA1c <7.0% at Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Percentage of Patients Achieving HbA1c <7.0% at Week 26
Measure Description Percentage of patients achieving HbA1c <7.0% at treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. Missing data at endpoint was imputed using last observation carried forward approach.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  461     450  
Percentage of Patients Achieving HbA1c <7.0% at Week 26  
[units: percentage of patients]
  52.7     60.2  


Statistical Analysis 1 for Percentage of Patients Achieving HbA1c <7.0% at Week 26
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.011
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Percentage of patients achieving HbA1c <7.0% at Week 26 were compared between treatments using a Cochran-Mantel-Haenszel test, in which HbA1c stratum, country, and background OAD served as stratification factors.
[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:   Change in Fasting Serum Glucose From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in Fasting Serum Glucose From Baseline to Week 26
Measure Description Change in fasting serum glucose from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  403     385  
Change in Fasting Serum Glucose From Baseline to Week 26  
[units: mmol/L]
Least Squares Mean ± Standard Error
  -1.76  ± 0.11     -2.12  ± 0.12  


Statistical Analysis 1 for Change in Fasting Serum Glucose From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.021
Least Squares Mean Difference [4] 0.36
Standard Error of the mean ± 0.15
95% Confidence Interval ( 0.05 to 0.66 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline fasting serum glucose, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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 Body Weight From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in Body Weight From Baseline to Week 26
Measure Description Change in body weight from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  404     398  
Change in Body Weight From Baseline to Week 26  
[units: kg]
Least Squares Mean ± Standard Error
  -2.68  ± 0.18     -3.57  ± 0.18  


Statistical Analysis 1 for Change in Body Weight From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] <.001
Least Squares Mean Difference [4] 0.90
Standard Error of the mean ± 0.26
95% Confidence Interval ( 0.39 to 1.40 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline body weight, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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:   Change in Total Cholesterol From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in Total Cholesterol From Baseline to Week 26
Measure Description Change in total cholesterol from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  402     386  
Change in Total Cholesterol From Baseline to Week 26  
[units: mmol/L]
Least Squares Mean ± Standard Error
  -0.06  ± 0.04     -0.15  ± 0.04  


Statistical Analysis 1 for Change in Total Cholesterol From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.079
Least Squares Mean Difference [4] 0.09
Standard Error of the mean ± 0.05
95% Confidence Interval ( -0.01 to 0.19 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline total cholesterol, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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 High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
Measure Description Change in HDL-C from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  402     386  
Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26  
[units: mmol/L]
Least Squares Mean ± Standard Error
  0.02  ± 0.01     0.02  ± 0.01  


Statistical Analysis 1 for Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.832
Least Squares Mean Difference [4] 0.00
Standard Error of the mean ± 0.01
95% Confidence Interval ( -0.02 to 0.02 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline HDL-C, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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 Fasting Triglycerides at Week 26 to Baseline   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Ratio of Fasting Triglycerides at Week 26 to Baseline
Measure Description Ratio of fasting triglycerides (measured in mmol/L) treatment endpoint at Week 26 to baseline. Log(Postbaseline fasting triglycerides) - log(Baseline fasting triglycerides); change from baseline to the treatment endpoint at Week 26 is presented as ratio of Week 26 to baseline.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  395     385  
Ratio of Fasting Triglycerides at Week 26 to Baseline  
[units: ratio]
Least Squares Mean ± Standard Error
  0.97  ± 0.02     0.89  ± 0.02  


Statistical Analysis 1 for Ratio of Fasting Triglycerides at Week 26 to Baseline
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] <.001
Least Squares Mean Difference [4] 1.09
Standard Error of the mean ± 0.03
95% Confidence Interval ( 1.04 to 1.15 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Fasting triglycerides were logarithm-transformed and the change at Week 26 to baseline, expressed as the ratio, was analyzed using a MMRM model with treatment, baseline fasting triglycerides, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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 Systolic Blood Pressure (SBP) From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in Systolic Blood Pressure (SBP) From Baseline to Week 26
Measure Description Change in SBP from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  404     398  
Change in Systolic Blood Pressure (SBP) From Baseline to Week 26  
[units: mmHg]
Least Squares Mean ± Standard Error
  -2.48  ± 0.56     -3.45  ± 0.57  


Statistical Analysis 1 for Change in Systolic Blood Pressure (SBP) From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.205
Least Squares Mean Difference [4] 0.97
Standard Error of the mean ± 0.76
95% Confidence Interval ( -0.53 to 2.47 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline SBP, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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:   Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26   [ Time Frame: Baseline, Week 26 ]

Measure Type Secondary
Measure Title Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26
Measure Description Change in DBP from baseline to the treatment endpoint at Week 26.
Time Frame Baseline, Week 26  
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 Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.

Reporting Groups
  Description
Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly
Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily

Measured Values
    Exenatide Once Weekly     Liraglutide Once Daily  
Number of Participants Analyzed  
[units: participants]
  404     398  
Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26  
[units: mmHg]
Least Squares Mean ± Standard Error
  -0.49  ± 0.37     -0.51  ± 0.37  


Statistical Analysis 1 for Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.981
Least Squares Mean Difference [4] 0.01
Standard Error of the mean ± 0.50
95% Confidence Interval ( -0.96 to 0.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  MMRM model includes treatment, baseline DBP, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.
[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:   Assessment of Event Rate of Treatment-emergent Hypoglycemic Events   [ Time Frame: Baseline to Week 26 ]

Measure Type Secondary
Measure Title Assessment of Event Rate of Treatment-emergent Hypoglycemic Events
Measure Description Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose <3.0 mmol/L [54 mg/dL]) and required the assistance of another person. Minor hypoglycemia: any sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. Event rate per subject year was calculated for each subject: (number of events observed from a subject/exposure from a subject)*365.25 where exposure = last post-baseline visit date - baseline visit date. Mean and Standard Error were then derived from ITT.
Time Frame Baseline to Week 26  
Safety Issue Yes  

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 Population.

Reporting Groups
  Description
Exenatide Once Weekly With SU Use at Screening Subcutaneous injection, 2mg, once weekly and with SU use at screening
Liraglutide Once Daily With SU Use at Screening Subcutaneous injection, forced titration to 1.8mg, once daily and with SU use at screening
Exenatide Once Weekly Without SU Use at Screening Subcutaneous injection, 2mg, once weekly and without SU use at screening
Liraglutide Once Daily Without SU Use at Screening Subcutaneous injection, forced titration to 1.8mg, once daily and without SU use at screening

Measured Values
    Exenatide Once Weekly With SU Use at Screening     Liraglutide Once Daily With SU Use at Screening     Exenatide Once Weekly Without SU Use at Screening     Liraglutide Once Daily Without SU Use at Screening  
Number of Participants Analyzed  
[units: participants]
  294     296     167     154  
Assessment of Event Rate of Treatment-emergent Hypoglycemic Events  
[units: events per subject-year]
Mean ± Standard Error
       
Major Hypoglycemia     0.00  ± 0.000     0.00  ± 0.000     0.00  ± 0.000     0.00  ± 0.000  
Minor Hypoglycemia     0.76  ± 0.143     0.55  ± 0.126     0.67  ± 0.417     0.05  ± 0.026  

No statistical analysis provided for Assessment of Event Rate of Treatment-emergent Hypoglycemic Events




  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
No text entered.


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