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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 (Responsible Party):
Novo Nordisk A/S
ClinicalTrials.gov Identifier:
NCT00518882
First received: August 20, 2007
Last updated: November 13, 2014
Last verified: November 2014
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.
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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 
Overall Participants Analyzed 
[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 
[1] OAD = Oral Anti-diabetic Drug
BMI [1] 
[Units: Kg/m2]
Mean (Standard Deviation)
 32.9  (5.5)   32.9  (5.7)   32.9  (5.6) 
[1] Body Mass Index
Duration of diabetes [1] 
[Units: Years]
Mean (Standard Deviation)
 8.5  (6.2)   7.9  (5.9)   8.2  (6.0) 
[1] Number of years since diagnosis
HbA1c [1] 
[Units: Percentage of total haemoglobin]
Mean (Standard Deviation)
 8.4  (1.0)   8.2  (1.0)   8.3  (1.0) 
[1] Glycosylated Haemoglobin at screening
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) 


  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 ]

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
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Time Frame The adverse events were collected in a time span of 78 weeks.
Additional Description The safety analysis set included all subjects who had been exposed to at least one dose of the study products.

Frequency Threshold
Threshold above which other adverse events are reported   5  

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)

Other Adverse Events
    Liraglutide -> Liraglutide -> Liraglutide   Exenatide -> Liraglutide -> Liraglutide
Total, other (not including serious) adverse events     
# participants affected / at risk   162/235 (68.94%)   167/232 (71.98%) 
Gastrointestinal disorders     
Constipation † 1     
# participants affected / at risk   18/235 (7.66%)   10/232 (4.31%) 
# events   18   13 
Diarrhoea † 1     
# participants affected / at risk   35/235 (14.89%)   37/232 (15.95%) 
# events   47   50 
Dyspepsia † 1     
# participants affected / at risk   25/235 (10.64%)   14/232 (6.03%) 
# events   35   17 
Nausea † 1     
# participants affected / at risk   64/235 (27.23%)   68/232 (29.31%) 
# events   87   92 
Vomiting † 1     
# participants affected / at risk   19/235 (8.09%)   26/232 (11.21%) 
# events   20   31 
Infections and infestations     
Bronchitis † 1     
# participants affected / at risk   15/235 (6.38%)   20/232 (8.62%) 
# events   18   22 
Influenza † 1     
# participants affected / at risk   13/235 (5.53%)   11/232 (4.74%) 
# events   14   11 
Nasopharyngitis † 1     
# participants affected / at risk   43/235 (18.30%)   42/232 (18.10%) 
# events   59   71 
Sinusitis † 1     
# participants affected / at risk   12/235 (5.11%)   9/232 (3.88%) 
# events   14   13 
Upper respiratory tract infection † 1     
# participants affected / at risk   26/235 (11.06%)   28/232 (12.07%) 
# events   33   30 
Metabolism and nutrition disorders     
Anorexia † 1     
# participants affected / at risk   10/235 (4.26%)   12/232 (5.17%) 
# events   10   12 
Musculoskeletal and connective tissue disorders     
Back pain † 1     
# participants affected / at risk   22/235 (9.36%)   12/232 (5.17%) 
# events   30   13 
Nervous system disorders     
Dizziness † 1     
# participants affected / at risk   14/235 (5.96%)   9/232 (3.88%) 
# events   16   9 
Headache † 1     
# participants affected / at risk   29/235 (12.34%)   28/232 (12.07%) 
# events   38   40 
Vascular disorders     
Hypertension † 1     
# participants affected / at risk   10/235 (4.26%)   12/232 (5.17%) 
# events   10   12 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (12.0)



  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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