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

ClinicalTrials.gov Identifier:

NCT00518882

First received: August 20, 2007

Last updated: June 19, 2012

Last verified: June 2012

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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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 ]

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 ]

Show Outcome Measure 3

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 ]

Show Outcome Measure 4

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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Measure Type	Secondary
Measure Title	Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78
Measure Description	Percentage of subjects achieving treatment target of HbA1c less than 7.0% or less than or equal to 6.5% at Week 78 (end of treatment)
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 drugs.

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]	200	186
Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78 [units: percentage (%) of subjects]
Treatment target HbA1c < 7%	47	48
Treatment target HbA1c =< 6.5%	31	35

No statistical analysis provided for Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78

6. Secondary:

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

Show Outcome Measure 6

7. Secondary:

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

Show Outcome Measure 7

8. Secondary:

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

Show Outcome Measure 8

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 ]

Show Outcome Measure 10

11. Secondary:

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

Show Outcome Measure 11

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 ]

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 ]

Show Outcome Measure 18

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 ]

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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 ]

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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44. Secondary:

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

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45. Secondary:

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

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46. Secondary:

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

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47. Secondary:

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

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48. Secondary:

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

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49. Secondary:

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

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50. Secondary:

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

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51. Secondary:

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

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52. Secondary:

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

Show Outcome Measure 52

53. Secondary:

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

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54. Secondary:

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

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55. Secondary:

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

Show Outcome Measure 55

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Novo Nordisk maintains the right to be informed of any investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.

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.

Results Point of Contact:

Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
e-mail: clinicaltrials@novonordisk.com

No publications provided by Novo Nordisk

Publications automatically indexed to this study:

Valentine WJ, Palmer AJ, Lammert M, Langer J, Brändle M. Evaluating the long-term cost-effectiveness of liraglutide versus exenatide BID in patients with type 2 diabetes who fail to improve with oral antidiabetic agents. Clin Ther. 2011 Nov;33(11):1698-712. Epub 2011 Oct 21.

Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbæk N, Holst J, Nauck M. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011 Jun;96(6):1695-702. Epub 2011 Mar 30.

Schmidt WE, Christiansen JS, Hammer M, Zychma MJ, Buse JB. Patient-reported outcomes are superior in patients with Type 2 diabetes treated with liraglutide as compared with exenatide, when added to metformin, sulphonylurea or both: results from a randomized, open-label study. Diabet Med. 2011 Jun;28(6):715-23.

Buse JB, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J; Liraglutide Effect Action in Diabetes-6 Study Group. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010 Jun;33(6):1300-3. Epub 2010 Mar 23.

Sullivan SD, Alfonso-Cristancho R, Conner C, Hammer M, Blonde L. Long-term outcomes in patients with type 2 diabetes receiving glimepiride combined with liraglutide or rosiglitazone. Cardiovasc Diabetol. 2009 Feb 26;8:12.

Responsible Party:	Public Access to Clinical Trials, Novo Nordisk A/S
ClinicalTrials.gov Identifier:	NCT00518882 History of Changes
Other Study ID Numbers:	NN2211-1797, 2006-006092-21
Study First Received:	August 20, 2007
Results First Received:	February 23, 2010
Last Updated:	June 19, 2012
Health Authority:	United States: Food and Drug Administration Finland: Finnish Medicines Agency Switzerland: Swissmedic Germany: Federal Institute for Drugs and Medical Devices Ireland: Irish Medicines Board Austria: Federal Ministry for Health and Women Poland: The Office for Registration of Medicinal Products, Medical Devices; and Biocides, Central Evidence of Clinical Trials Denmark: Danish Medicines Agency Macedonia, The Former Yugoslav Republic of: Drug Agency, Ministry of Health Slovenia: Agency of Drugs and Medicinal Products of the Slovenian Republic Romania: National Medicines Agency Sweden: Medical Products Agency

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