Clinical trial NCT00518882: Effect of Liraglutide or Exenatide Added to an Ongoing Treatment on Blood Glucose Control in Subjects With Type 2 Diabetes
Official title: Effect of Liraglutide or Exenatide Added to a Background Treatment of Metformin, Sulphonylurea or a Combination of Both on Glycaemic Control in Subjects With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes
Diabetes Mellitus, Type 2
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2007-08-21
Enrollment: 467
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to compare the effect on glycaemic control of liraglutide or exenatide when added to subject's ongoing OAD (oral anti-diabetic drug) treatment of either metformin, sulphonylurea or a combination of both in subjects with type 2 diabetes. Two trial periods: A 26 week randomised, followed by a 52 week extension (14 + 38 weeks) where all subjects received liraglutide + OAD after previous randomisation to either liraglutide or exenatide, both combined with OAD treatment.


Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes
* Stable treatment with Oral Anti-Diabetic Drugs (metformin, sulphonylurea or a combination of both) for at least 3 months at the discretion of the Investigator
* HbA1C equal to or greater than 7.0% and equal to or lower than 11.0%
* Body Mass Index (BMI) equal to or lower than 45.0 kg/m2

Exclusion Criteria:

* Previous treatment with insulin
* Treatment with any anti-diabetic drug other than metformin and sulphonylurea
* Any previous exposure to exenatide or liraglutide
* Impaired liver or/and renal function
* History of any significant cardiac events
* Known retinopathy or maculopathy requiring acute treatment
* Recurrent major hypoglycaemia or hypoglycaemic unawareness

Primary outcomes:
measure: Change in Glycosylated A1c (HbA1c) at Week 26
timeFrame: week 0, week 26
Secondary outcomes:
measure: Change in Glycosylated A1c (HbA1c), Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Glycosylated A1c (HbA1c) at Week 78
timeFrame: week 0, week 78
measure: Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 26
timeFrame: week 0, week 26
measure: Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78
timeFrame: week 0, week 78
measure: Change in Body Weight at Week 26
timeFrame: week 0, week 26
measure: Change in Body Weight, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Body Weight at Week 78
timeFrame: week 0, week 78
measure: Change in Fasting Plasma Glucose at Week 26
timeFrame: week 0, week 26
measure: Change in Fasting Plasma Glucose, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Fasting Plasma Glucose at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 26
timeFrame: week 0, week 26
measure: Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 26
timeFrame: week 0, week 26
measure: Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 26
timeFrame: week 0, week 26
measure: Change in Mean Prandial Increment of Plasma Glucose After Breakfast, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Lunch, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Dinner, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 26
timeFrame: week 0, week 26
measure: Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 26
timeFrame: week 0. week 26
measure: Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 26
timeFrame: week 0, week 26
measure: Change in Mean Postprandial Increment of Plasma Glucose After Breakfast, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Lunch, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Dinner, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 78
timeFrame: week 0, week 78
measure: Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 78
timeFrame: week 0, week 78
measure: Change in Beta-cell Function at Week 26
timeFrame: week 0, week 26
measure: Change in Beta-cell Function, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Beta-cell Function at Week 78
timeFrame: week 0, week 78
measure: Change in Total Cholesterol at Week 26
timeFrame: week 0, week 26
measure: Change in Total Cholesterol, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Total Cholesterol at Week 78
timeFrame: week 0, week 78
measure: Change in Low-density Lipoprotein-cholesterol at Week 26
timeFrame: week 0, week 26
measure: Change in Low-density Lipoprotein-cholesterol, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Low-density Lipoprotein-cholesterol at Week 78
timeFrame: week 0, week 78
measure: Change in Very Low-density Lipoprotein-cholesterol at Week 26
timeFrame: week 0, week 26
measure: Change in Very Low-density Lipoprotein-cholesterol, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Very Low-density Lipoprotein-cholesterol at Week 78
timeFrame: week 0, week 78
measure: Change in High-density Lipoprotein-cholesterol at Week 26
timeFrame: week 0, week 26
measure: Change in High-density Lipoprotein-cholesterol, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in High-density Lipoprotein-cholesterol at Week 78
timeFrame: week 0, week 78
measure: Change in Triglyceride at Week 26
timeFrame: week 0, week 26
measure: Change in Triglyceride, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Triglyceride at Week 78
timeFrame: week 0, week 78
measure: Change in Free Fatty Acid at Week 26
timeFrame: week 0, week 26
measure: Change in Free Fatty Acid, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Free Fatty Acid at Week 78
timeFrame: week 0, week 78
measure: Change in Apolipoprotein B at Week 26
timeFrame: week 0, week 26
measure: Change in Apolipoprotein B, Weeks 26-78
timeFrame: week 26, week 78
measure: Change in Apolipoprotein B at Week 78
timeFrame: week 0, week 78
measure: Hypoglycaemic Episodes at Week 26
timeFrame: weeks 0-26
measure: Hypoglyceamic Episodes, Weeks 26-78
timeFrame: weeks 26-78
Other outcomes:
Locations:
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country: United States
facility: Novo Nordisk Investigational Site
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state: California
city: Encino
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state: California
city: Escondido
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state: California
city: Los Angeles
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state: California
city: Orange
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state: California
city: Sacramento
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state: California
city: San Mateo
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state: California
city: Spring Valley
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state: California
city: Walnut Creek
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state: California
city: Fort Myers
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state: Florida
city: Hollywood
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state: Florida
city: Jacksonville
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state: Florida
city: Jacksonville
country: United States
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state: Florida
city: Jacksonville
country: United States
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state: Florida
city: Longwood
country: United States
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state: Florida
city: Ocala
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state: Florida
city: Pembroke Pines
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Plantation
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state: Florida
city: St. Cloud
country: United States
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state: Florida
city: Atlanta
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state: Georgia
city: Powder Springs
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state: Georgia
city: Roswell
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city: Idaho Falls
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state: Idaho
city: Chicago
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city: Peoria
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state: Illinois
city: Evansville
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state: Indiana
city: Des Moines
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state: Iowa
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state: Louisiana
city: Minneapolis
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city: St. Paul
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city: St. Peters
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state: Missouri
city: Flemington
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city: South Bound Brook
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city: Northport
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city: Cincinnati
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city: Dayton
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city: Kettering
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city: Oklahoma City
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state: Oklahoma
city: Altoona
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state: Pennsylvania
city: Philadelphia
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state: Pennsylvania
city: Pittsburgh
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state: Pennsylvania
city: Sumter
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state: South Carolina
city: Chattanooga
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state: Tennessee
city: Austin
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state: Texas
city: Corpus Christi
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state: Texas
city: Dallas
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state: Texas
city: Dallas
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state: Texas
city: Dallas
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facility: Novo Nordisk Investigational Site
state: Texas
city: Houston
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state: Texas
city: Midland
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state: Texas
city: San Antonio
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state: Texas
city: Newport News
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state: Virginia
city: Richmond
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state: Virginia
city: Olympia
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state: Washington
city: Spokane
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state: Washington
city: Milwaukee
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state: Wisconsin
city: Graz
country: Austria
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city: Wien
country: Austria
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city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Aalborg
country: Denmark
facility: Novo Nordisk Investigational Site
city: Gentofte
country: Denmark
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city: Hvidovre
country: Denmark
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city: Odense
country: Denmark
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city: Århus C
country: Denmark
facility: Novo Nordisk Investigational Site
city: Helsinki
country: Finland
facility: Novo Nordisk Investigational Site
city: Lahti
country: Finland
facility: Novo Nordisk Investigational Site
city: Oulu
country: Finland
facility: Novo Nordisk Investigational Site
city: Antibes
country: France
facility: Novo Nordisk Investigational Site
city: Dommartin Les Toul
country: France
facility: Novo Nordisk Investigational Site
city: LA ROCHELLE cedex
country: France
facility: Novo Nordisk Investigational Site
city: Narbonne
country: France
facility: Novo Nordisk Investigational Site
city: NEVERS cedex
country: France
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city: Bochum
country: Germany
facility: Novo Nordisk Investigational Site
city: Dreieich-Sprendlingen
country: Germany
facility: Novo Nordisk Investigational Site
city: Falkensee
country: Germany
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city: Frankfurt
country: Germany
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city: Hamburg
country: Germany
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city: Hannover
country: Germany
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city: Herrenberg
country: Germany
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city: Lampertheim
country: Germany
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city: Ludwigshafen
country: Germany
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city: Marburg
country: Germany
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city: Pohlheim
country: Germany
facility: Novo Nordisk Investigational Site
city: Rehlingen-Siersburg
country: Germany
facility: Novo Nordisk Investigational Site
city: Speyer
country: Germany
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city: Tübingen
country: Germany
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city: Dublin 24
country: Ireland
facility: Novo Nordisk Investigational Site
city: Dublin 9
country: Ireland
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city: Dublin
country: Ireland
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city: Dublin
country: Ireland
facility: Novo Nordisk Investigational Site
city: Skopje
country: Macedonia, The Former Yugoslav Republic of
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city: Bergen
country: Norway
facility: Novo Nordisk Investigational Site
city: Bergen
country: Norway
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city: Stavanger
country: Norway
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city: Trondheim
country: Norway
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city: Bydgoszcz
country: Poland
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city: Gniewkowo
country: Poland
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city: Krakow
country: Poland
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city: Lublin
country: Poland
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city: Poznan
country: Poland
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city: Tychy
country: Poland
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city: Warszawa
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city: Wroclaw
country: Poland
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city: Zabrze
country: Poland
facility: Novo Nordisk Investigational Site
city: Manati
country: Puerto Rico
facility: Novo Nordisk Investigational Site
city: Alba Iulia
country: Romania
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state: Alba
city: Resita
country: Romania
facility: Novo Nordisk Investigational Site
city: Suceava
country: Romania
facility: Novo Nordisk Investigational Site
city: Koper
country: Slovenia
facility: Novo Nordisk Investigational Site
city: Ljubljana
country: Slovenia
facility: Novo Nordisk Investigational Site
city: Novo mesto
country: Slovenia
facility: Novo Nordisk Investigational Site
city: Hospitalet de Llobregat
country: Spain
facility: Novo Nordisk Investigational Site
city: Oviedo
country: Spain
facility: Novo Nordisk Investigational Site
city: Palma de Mallorca
country: Spain
facility: Novo Nordisk Investigational Site
city: Puerto del Rosario
country: Spain
facility: Novo Nordisk Investigational Site
city: Stockholm
country: Sweden
facility: Novo Nordisk Investigational Site
city: Stockholm
country: Sweden
facility: Novo Nordisk Investigational Site
city: Basel
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Bern
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Genève 14
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Lugano
country: Switzerland
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
citation: 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. doi: 10.1186/1475-2840-8-12.
citation: McGill JB. Insights from the Liraglutide Clinical Development Program--the Liraglutide Effect and Action in Diabetes (LEAD) studies. Postgrad Med. 2009 May;121(3):16-25. doi: 10.3810/pgm.2009.05.1998.
citation: Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009 Jul 4;374(9683):39-47. doi: 10.1016/S0140-6736(09)60659-0. Epub 2009 Jun 8.
citation: 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. doi: 10.2337/dc09-2260. Epub 2010 Mar 23.
citation: 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. doi: 10.1111/j.1464-5491.2011.03276.x.
citation: Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbaek 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. doi: 10.1210/jc.2010-2822. Epub 2011 Mar 30.
citation: Valentine WJ, Palmer AJ, Lammert M, Langer J, Brandle 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. doi: 10.1016/j.clinthera.2011.09.022. Epub 2011 Oct 21.
citation: Bode BW, Brett J, Falahati A, Pratley RE. Comparison of the efficacy and tolerability profile of liraglutide, a once-daily human GLP-1 analog, in patients with type 2 diabetes >/=65 and <65 years of age: a pooled analysis from phase III studies. Am J Geriatr Pharmacother. 2011 Dec;9(6):423-33. doi: 10.1016/j.amjopharm.2011.09.007. Epub 2011 Nov 4.
citation: Henry RR, Buse JB, Sesti G, Davies MJ, Jensen KH, Brett J, Pratley RE. Efficacy of antihyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program. Endocr Pract. 2011 Nov-Dec;17(6):906-13. doi: 10.4158/ep.17.6.906.
citation: Zinman B, Schmidt WE, Moses A, Lund N, Gough S. Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme. Diabetes Obes Metab. 2012 Jan;14(1):77-82. doi: 10.1111/j.1463-1326.2011.01493.x. Epub 2011 Oct 30.
citation: Niswender K, Pi-Sunyer X, Buse J, Jensen KH, Toft AD, Russell-Jones D, Zinman B. Weight change with liraglutide and comparator therapies: an analysis of seven phase 3 trials from the liraglutide diabetes development programme. Diabetes Obes Metab. 2013 Jan;15(1):42-54. doi: 10.1111/j.1463-1326.2012.01673.x. Epub 2012 Sep 9.
citation: Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract. 2012 Nov;98(2):271-84. doi: 10.1016/j.diabres.2012.09.008. Epub 2012 Sep 23.
citation: King AB, Montanya E, Pratley RE, Blonde L, Svendsen CB, Donsmark M, Sesti G. Liraglutide achieves A1C targets more often than sitagliptin or exenatide when added to metformin in patients with type 2 diabetes and a baseline A1C <8.0%. Endocr Pract. 2013 Jan-Feb;19(1):64-72. doi: 10.4158/EP12232.OR.
citation: Jensen TM, Saha K, Steinberg WM. Is there a link between liraglutide and pancreatitis? A post hoc review of pooled and patient-level data from completed liraglutide type 2 diabetes clinical trials. Diabetes Care. 2015 Jun;38(6):1058-66. doi: 10.2337/dc13-1210. Epub 2014 Dec 12.
citation: Davidson JA, Orsted DD, Campos C. Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 analogue, in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials. Diabetes Obes Metab. 2016 Jul;18(7):725-8. doi: 10.1111/dom.12653. Epub 2016 Apr 28.
citation: Fonseca VA, Devries JH, Henry RR, Donsmark M, Thomsen HF, Plutzky J. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials. J Diabetes Complications. 2014 May-Jun;28(3):399-405. doi: 10.1016/j.jdiacomp.2014.01.009. Epub 2014 Jan 21.