Effect of Liraglutide or Exenatide Added to an Ongoing Treatment on Blood Glucose Control in Subjects With Type 2 Diabetes (LEAD-6)

This study has been completed.
Sponsor:
Information provided by:
Novo Nordisk A/S
ClinicalTrials.gov Identifier:
NCT00518882
First received: August 20, 2007
Last updated: June 19, 2012
Last verified: June 2012
Results First Received: February 23, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Diabetes
Diabetes Mellitus, Type 2
Interventions: Drug: liraglutide
Drug: exenatide

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 133 centres in 15 countries: Austria (4), Denmark (6), Finland (5), France (5), Germany (14), Ireland (4), Macedonia (1), Norway (4), Poland (9), Romania (3), Slovenia (3), Spain (4), Sweden (2), Switzerland (4) and United States (65).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible subjects were subjects with type 2 diabetes being treated with oral anti-diabetic (OAD) therapy(ies) for at least 3 months prior to the study. Three subjects were exposed to study drug prior to randomisation, and thus only included in safety analysis set.

Reporting Groups
  Description
Liraglutide -> Liraglutide -> Liraglutide Liraglutide 1.8 mg once daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) continued to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)
Exenatide -> Liraglutide -> Liraglutide Exenatide 10 mcg twice daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) switched to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)

Participant Flow for 2 periods

Period 1:   Double-Blind, Week 0-26
    Liraglutide -> Liraglutide -> Liraglutide     Exenatide -> Liraglutide -> Liraglutide  
STARTED     235 [1]   232 [2]
Randomised     233     231  
COMPLETED     202     187  
NOT COMPLETED     33     45  
Adverse Event                 23                 31  
Lack of Efficacy                 1                 0  
Protocol Violation                 4                 3  
Withdrawal criteria                 1                 1  
Lost to follow up                 2                 1  
Subject decision                 1                 1  
Withdrawal of consent                 1                 3  
Loss of trust                 0                 1  
Fear of hypoglycaemia                 0                 1  
Hypoglycaemia                 0                 2  
Mutual consent                 0                 1  
[1] 2 subjects exposed to study drug before randomisation. Subjects only included in safety analysis set
[2] 1 subject exposed to study drug before randomisation. Subject only included in safety analysis set

Period 2:   Open-Label Extension, Week 26-78
    Liraglutide -> Liraglutide -> Liraglutide     Exenatide -> Liraglutide -> Liraglutide  
STARTED     202     187  
COMPLETED     161     138  
NOT COMPLETED     41     49  
Adverse Event                 3                 9  
Lack of Efficacy                 6                 5  
Protocol Violation                 3                 4  
Withdrawel criteria                 1                 2  
Hypoglycaemia                 0                 1  
Lost to follow up                 1                 1  
Consent withdrawn                 2                 1  
Change in treatment                 1                 1  
Creatine increased                 1                 0  
Decreased kidney function                 1                 0  
Exclusion criteria                 2                 0  
Subject decision                 2                 0  
Completed extension 1 (weeks 26-40)                 18                 25  



  Baseline Characteristics
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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
Liraglutide -> Liraglutide -> Liraglutide Liraglutide 1.8 mg once daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) continued to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)
Exenatide -> Liraglutide -> Liraglutide Exenatide 10 mcg twice daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) switched to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)
Total Total of all reporting groups

Baseline Measures
    Liraglutide -> Liraglutide -> Liraglutide     Exenatide -> Liraglutide -> Liraglutide     Total  
Number of Participants  
[units: participants]
  233     231     464  
Age  
[units: years]
Mean ± Standard Deviation
  56.3  ± 9.8     57.1  ± 10.8     56.7  ± 10.3  
Gender  
[units: participants]
     
Female     119     104     223  
Male     114     127     241  
Ethnicity (NIH/OMB)  
[units: participants]
     
Hispanic or Latino     32     25     57  
Not Hispanic or Latino     201     206     407  
Unknown or Not Reported     0     0     0  
Race (NIH/OMB)  
[units: participants]
     
American Indian or Alaska Native     0     1     1  
Asian     0     4     4  
Native Hawaiian or Other Pacific Islander     1     1     2  
Black or African American     13     12     25  
White     216     210     426  
More than one race     0     0     0  
Unknown or Not Reported     3     3     6  
Previous OAD treatment [1]
[units: participants]
     
Metformin/Sulphonylurea Combination     145     147     292  
Sulphonylurea     24     21     45  
Metformin     64     63     127  
BMI [2]
[units: kg/m2]
Mean ± Standard Deviation
  32.9  ± 5.5     32.9  ± 5.7     32.9  ± 5.6  
Duration of diabetes [3]
[units: years]
Mean ± Standard Deviation
  8.5  ± 6.2     7.9  ± 5.9     8.2  ± 6.0  
HbA1c [4]
[units: percentage of total haemoglobin]
Mean ± Standard Deviation
  8.4  ± 1.0     8.2  ± 1.0     8.3  ± 1.0  
Height  
[units: m]
Mean ± Standard Deviation
  1.68  ± 0.10     1.68  ± 0.10     1.68  ± 0.10  
Weight  
[units: kg]
Mean ± Standard Deviation
  93.1  ± 20.1     93.0  ± 19.5     93.1  ± 19.8  
[1] OAD = Oral Anti-diabetic Drug
[2] Body Mass Index
[3] Number of years since diagnosis
[4] Glycosylated Haemoglobin at screening



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change in Glycosylated A1c (HbA1c) at Week 26   [ Time Frame: week 0, week 26 ]

2.  Secondary:   Change in Glycosylated A1c (HbA1c), Weeks 26-78   [ Time Frame: week 26, week 78 ]

3.  Secondary:   Change in Glycosylated A1c (HbA1c) at Week 78   [ Time Frame: week 0, week 78 ]

4.  Secondary:   Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 26   [ Time Frame: week 0, week 26 ]

5.  Secondary:   Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78   [ Time Frame: week 0, week 78 ]

6.  Secondary:   Change in Body Weight at Week 26   [ Time Frame: week 0, week 26 ]

7.  Secondary:   Change in Body Weight, Weeks 26-78   [ Time Frame: week 26, week 78 ]

8.  Secondary:   Change in Body Weight at Week 78   [ Time Frame: week 0, week 78 ]

9.  Secondary:   Change in Fasting Plasma Glucose at Week 26   [ Time Frame: week 0, week 26 ]

10.  Secondary:   Change in Fasting Plasma Glucose, Weeks 26-78   [ Time Frame: week 26, week 78 ]

11.  Secondary:   Change in Fasting Plasma Glucose at Week 78   [ Time Frame: week 0, week 78 ]

12.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 26   [ Time Frame: week 0, week 26 ]

13.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 26   [ Time Frame: week 0, week 26 ]

14.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 26   [ Time Frame: week 0, week 26 ]

15.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Breakfast, Weeks 26-78   [ Time Frame: week 26, week 78 ]

16.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Lunch, Weeks 26-78   [ Time Frame: week 26, week 78 ]

17.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Dinner, Weeks 26-78   [ Time Frame: week 26, week 78 ]

18.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 78   [ Time Frame: week 0, week 78 ]

19.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 78   [ Time Frame: week 0, week 78 ]

20.  Secondary:   Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 78   [ Time Frame: week 0, week 78 ]

21.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 26   [ Time Frame: week 0, week 26 ]

22.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 26   [ Time Frame: week 0. week 26 ]

23.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 26   [ Time Frame: week 0, week 26 ]

24.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Breakfast, Weeks 26-78   [ Time Frame: week 26, week 78 ]

25.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Lunch, Weeks 26-78   [ Time Frame: week 26, week 78 ]

26.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Dinner, Weeks 26-78   [ Time Frame: week 26, week 78 ]

27.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 78   [ Time Frame: week 0, week 78 ]

28.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 78   [ Time Frame: week 0, week 78 ]

29.  Secondary:   Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 78   [ Time Frame: week 0, week 78 ]

30.  Secondary:   Change in Beta-cell Function at Week 26   [ Time Frame: week 0, week 26 ]

31.  Secondary:   Change in Beta-cell Function, Weeks 26-78   [ Time Frame: week 26, week 78 ]

32.  Secondary:   Change in Beta-cell Function at Week 78   [ Time Frame: week 0, week 78 ]

33.  Secondary:   Change in Total Cholesterol at Week 26   [ Time Frame: week 0, week 26 ]

34.  Secondary:   Change in Total Cholesterol, Weeks 26-78   [ Time Frame: week 26, week 78 ]

35.  Secondary:   Change in Total Cholesterol at Week 78   [ Time Frame: week 0, week 78 ]

36.  Secondary:   Change in Low-density Lipoprotein-cholesterol at Week 26   [ Time Frame: week 0, week 26 ]

37.  Secondary:   Change in Low-density Lipoprotein-cholesterol, Weeks 26-78   [ Time Frame: week 26, week 78 ]

38.  Secondary:   Change in Low-density Lipoprotein-cholesterol at Week 78   [ Time Frame: week 0, week 78 ]

39.  Secondary:   Change in Very Low-density Lipoprotein-cholesterol at Week 26   [ Time Frame: week 0, week 26 ]

40.  Secondary:   Change in Very Low-density Lipoprotein-cholesterol, Weeks 26-78   [ Time Frame: week 26, week 78 ]

41.  Secondary:   Change in Very Low-density Lipoprotein-cholesterol at Week 78   [ Time Frame: week 0, week 78 ]
  Hide Outcome Measure 41

Measure Type Secondary
Measure Title Change in Very Low-density Lipoprotein-cholesterol at Week 78
Measure Description Change in Very Low-density Lipoprotein-cholesterol (VLDL-C) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
Time Frame week 0, week 78  
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.
Intention to Treat (ITT) analysis set using LOCF (Last Observation Carried Forward) is all randomised subjects who entered the extension period and who had been exposed to at least one dose of the study products.

Reporting Groups
  Description
Liraglutide -> Liraglutide -> Liraglutide Liraglutide 1.8 mg once daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) continued to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)
Exenatide -> Liraglutide -> Liraglutide Exenatide 10 mcg twice daily + OAD (metformin monotherapy, sulphonylurea (SU) monotherapy or a combination), Weeks 0-26 (double-blinded) switched to receive liraglutide 1.8 mg once daily + OAD in extension period (weeks 26-52 and 52-78)

Measured Values
    Liraglutide -> Liraglutide -> Liraglutide     Exenatide -> Liraglutide -> Liraglutide  
Number of Participants Analyzed  
[units: participants]
  173     168  
Change in Very Low-density Lipoprotein-cholesterol at Week 78  
[units: mmol/L]
Mean ± Standard Deviation
  0.27  ± 0.306     0.31  ± 0.346  


Statistical Analysis 1 for Change in Very Low-density Lipoprotein-cholesterol at Week 78
Groups [1] Liraglutide -> Liraglutide -> Liraglutide
Method [2] Paired t test
P Value [3] <0.0001
Mean [4] 0.27
Standard Deviation ± 0.306
95% Confidence Interval ( 0.223 to 0.315 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was made with a paired t test within the treatment group and 95% CIs for the difference between Weeks 0 and 78 were constructed. H0 was µ78– µ0=0 against HA: µ78 – µ0 ≠ 0. A difference between the two means was concluded when H0 was rejected at the 5% level.
[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.

Statistical Analysis 2 for Change in Very Low-density Lipoprotein-cholesterol at Week 78
Groups [1] Exenatide -> Liraglutide -> Liraglutide
Method [2] Paired t test
P Value [3] <0.0001
Mean [4] 0.31
Standard Deviation ± 0.346
95% Confidence Interval ( 0.259 to 0.364 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was made with a paired t test within the treatment group and 95% CIs for the difference between Weeks 0 and 78 were constructed. H0 was µ78– µ0=0 against HA: µ78 – µ0 ≠ 0. A difference between the two means was concluded when H0 was rejected at the 5% level.
[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.



42.  Secondary:   Change in High-density Lipoprotein-cholesterol at Week 26   [ Time Frame: week 0, week 26 ]

43.  Secondary:   Change in High-density Lipoprotein-cholesterol, Weeks 26-78   [ Time Frame: week 26, week 78 ]

44.  Secondary:   Change in High-density Lipoprotein-cholesterol at Week 78   [ Time Frame: week 0, week 78 ]

45.  Secondary:   Change in Triglyceride at Week 26   [ Time Frame: week 0, week 26 ]

46.  Secondary:   Change in Triglyceride, Weeks 26-78   [ Time Frame: week 26, week 78 ]

47.  Secondary:   Change in Triglyceride at Week 78   [ Time Frame: week 0, week 78 ]

48.  Secondary:   Change in Free Fatty Acid at Week 26   [ Time Frame: week 0, week 26 ]

49.  Secondary:   Change in Free Fatty Acid, Weeks 26-78   [ Time Frame: week 26, week 78 ]

50.  Secondary:   Change in Free Fatty Acid at Week 78   [ Time Frame: week 0, week 78 ]

51.  Secondary:   Change in Apolipoprotein B at Week 26   [ Time Frame: week 0, week 26 ]

52.  Secondary:   Change in Apolipoprotein B, Weeks 26-78   [ Time Frame: week 26, week 78 ]

53.  Secondary:   Change in Apolipoprotein B at Week 78   [ Time Frame: week 0, week 78 ]

54.  Secondary:   Hypoglycaemic Episodes at Week 26   [ Time Frame: weeks 0-26 ]

55.  Secondary:   Hypoglyceamic Episodes, Weeks 26-78   [ Time Frame: weeks 26-78 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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