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: January 25, 2017

Last verified: January 2017

History of Changes

Results First Received: February 23, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: No masking; 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

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)

Sex: Female, Male
[Units: Participants]
Count of Participants

Female

119 51.1%

104 45.0%

223 48.1%

Male

114 48.9%

127 55.0%

241 51.9%

Ethnicity (NIH/OMB)
[Units: Participants]
Count of Participants

Hispanic or Latino

32 13.7%

25 10.8%

57 12.3%

Not Hispanic or Latino

201 86.3%

206 89.2%

407 87.7%

Unknown or Not Reported

0 0.0%

Race (NIH/OMB)
[Units: Participants]
Count of Participants

American Indian or Alaska Native

0 0.0%

1 0.4%

1 0.2%

Asian

0 0.0%

4 1.7%

4 0.9%

Native Hawaiian or Other Pacific Islander

1 0.4%

2 0.4%

Black or African American

13 5.6%

12 5.2%

25 5.4%

White

216 92.7%

210 90.9%

426 91.8%

More than one race

0 0.0%

Unknown or Not Reported

3 1.3%

6 1.3%

Previous OAD treatment ^[1]
[Units: Participants]

Metformin/Sulphonylurea Combination

145

147

292

Sulphonylurea

Metformin

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)

Weight
[Units: Kg]
Mean (Standard Deviation)

93.1 (20.1)

93.0 (19.5)

93.1 (19.8)

Outcome Measures

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1. Primary:

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

Show Outcome Measure 1

2. Secondary:

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

Show Outcome Measure 2

3. Secondary:

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

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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 ]

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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 ]

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6. Secondary:

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

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7. Secondary:

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

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8. Secondary:

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

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9. Secondary:

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

Show Outcome Measure 9

10. Secondary:

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

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11. Secondary:

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

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12. Secondary:

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

Show Outcome Measure 12

13. Secondary:

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

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14. Secondary:

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

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15. Secondary:

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

Show Outcome Measure 15

16. Secondary:

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

Show Outcome Measure 16

17. Secondary:

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

Show Outcome Measure 17

18. Secondary:

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

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19. Secondary:

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

Show Outcome Measure 19

20. Secondary:

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

Show Outcome Measure 20

21. Secondary:

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

Show Outcome Measure 21

22. Secondary:

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

Show Outcome Measure 22

23. Secondary:

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

Show Outcome Measure 23

24. Secondary:

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

Show Outcome Measure 24

25. Secondary:

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

Show Outcome Measure 25

26. Secondary:

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

Show Outcome Measure 26

27. Secondary:

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

Show Outcome Measure 27

28. Secondary:

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

Show Outcome Measure 28

29. Secondary:

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

Show Outcome Measure 29

30. Secondary:

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

Show Outcome Measure 30

31. Secondary:

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

Show Outcome Measure 31

32. Secondary:

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

Show Outcome Measure 32

33. Secondary:

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

Show Outcome Measure 33

34. Secondary:

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

Show Outcome Measure 34

35. Secondary:

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

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36. Secondary:

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

Show Outcome Measure 36

37. Secondary:

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

Show Outcome Measure 37

38. Secondary:

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

Show Outcome Measure 38

39. Secondary:

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

Show Outcome Measure 39

40. Secondary:

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

Show Outcome Measure 40

41. Secondary:

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

Show Outcome Measure 41

42. Secondary:

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

Show Outcome Measure 42

43. Secondary:

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

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Measure Type	Secondary
Measure Title	Change in High-density Lipoprotein-cholesterol, Weeks 26-78
Measure Description	Change in High-density Lipoprotein-cholesterol (HDL-C) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
Time Frame	week 26, week 78

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
Participants Analyzed [Units: Participants]	119	180
Change in High-density Lipoprotein-cholesterol, Weeks 26-78 [Units: mmol/L] Mean (Standard Deviation)	-0.01 (0.150)	0.00 (0.141)

Statistical Analysis 1 for Change in High-density Lipoprotein-cholesterol, Weeks 26-78

Groups ^[1]	Liraglutide -> Liraglutide -> Liraglutide
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Paired t test
P Value ^[4]	0.2220
Mean ^[5]	-0.01
95% Confidence Interval	-0.034 to 0.008
Standard Deviation	(0.150)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	A paired t test was made within the group and 95% confidence intervals for the difference between Weeks 26 and 78 were constructed. H0 was µ78 – µ26 = 0 against HA: µ78 – µ26 ≠ 0. A difference between the two means (Week 26 and Week 78) was concluded when H0 was rejected at the 5% level.
[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.

Statistical Analysis 2 for Change in High-density Lipoprotein-cholesterol, Weeks 26-78

Groups ^[1]	Exenatide -> Liraglutide -> Liraglutide
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Paired t test
P Value ^[4]	0.7923
Mean ^[5]	0.00
95% Confidence Interval	-0.018 to 0.024
Standard Deviation	(0.141)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	A paired t test was made within the treatment group and 95% confidence intervals for the difference between Weeks 26 and 78 were constructed. H0 was µ78 – µ26 = 0 against HA: µ78 – µ26 ≠ 0. A difference between the two means (Week 26 and Week 78) was concluded when H0 was rejected at the 5% level.
[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.