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

History of Changes

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

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1. Primary:

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

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2. Secondary:

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

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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 ]

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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 ]

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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 ]

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16. Secondary:

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

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17. Secondary:

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

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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 ]

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20. Secondary:

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

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21. Secondary:

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

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22. Secondary:

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

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23. Secondary:

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

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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 ]

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31. Secondary:

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

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32. Secondary:

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

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33. Secondary:

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

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34. Secondary:

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

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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 ]

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37. Secondary:

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

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38. Secondary:

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

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39. Secondary:

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

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40. Secondary:

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

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41. Secondary:

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

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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
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]	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
Method ^[2]	Paired t test
P Value ^[3]	0.2220
Mean ^[4]	-0.01
Standard Deviation	± 0.150
95% Confidence Interval	( -0.034 to 0.008 )

[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]	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 High-density Lipoprotein-cholesterol, Weeks 26-78

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

[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]	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.