Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER®)

Tracking Information
First Submitted Date ICMJE	August 6, 2010
First Posted Date ICMJE	August 10, 2010
Results First Submitted Date	December 16, 2016
Results First Posted Date	March 1, 2017
Last Update Posted Date	February 7, 2018
Actual Study Start Date ICMJE	August 31, 2010
Actual Primary Completion Date	December 17, 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 7, 2017)	Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]; Time from randomisation to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome). The percentage of subjects experiencing a first event of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome) is presented.
Original Primary Outcome Measures ICMJE; (submitted: August 9, 2010)	Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) [ Time Frame: from randomisation up to 60 months ]
Change History	Complete list of historical versions of study NCT01179048 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 7, 2017)	Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure. [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]Time from randomisation to first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure. The percentage of subjects experiencing first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure is presented.; Time From Randomisation to All Cause Death [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]Time from randomisation to all cause death. The percentage of subjects with a death by any cause (all-cause death) is presented.; Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]Time from randomisation to each individual component of the expanded composite cardiovascular outcome. The percentage of subjects experiencing each of the individual component of the expanded composite cardiovascular outcome (defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or heart failure) is presented.; Time From Randomisation to First Occurrence of a Composite Microvascular Outcome [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]Time from randomisation to first occurrence of a composite microvascular outcome, defined as any one of the following: new onset of persistent macroalbuminuria persistent doubling of serum creatinine need for continuous renal replacement therapy death due to renal disease need for retinal photocoagulation or treatment with intravitreal agents vitreous haemorrhage diabetes-related blindness The percentage of subjects experiencing a first occurrence of a composite microvascular outcome is presented.; Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. [ Time Frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) ]Time from randomisation to each individual component of the composite microvascular outcome and to the retinopathy and nephropathy composite outcomes separately. The percentage of subjects experiencing each individual component of the composite microvascular outcome are presented.
Original Secondary Outcome Measures ICMJE; (submitted: August 9, 2010)	Time from randomisation to first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularisation, unstable angina or hospitalisation for chronic heart [ Time Frame: from randomisation up to 60 months ]; Time From Randomisation to All Cause Death [ Time Frame: from randomisation up to 60 months ]; Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome [ Time Frame: from randomisation up to 60 months ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
Official Title ICMJE	A Long-term, Multi-centre, International, Randomised Double-blind, Placebo-controlled Trial to Determine Liraglutide Effects on Cardiovascular Events
Brief Summary	This trial is conducted in Africa, Asia, Europe, and North and South America. The aim of this trial is to determine the long term effect of liraglutide on cardiovascular events in subjects with type 2 diabetes.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition ICMJE	Diabetes; Diabetes Mellitus, Type 2
Intervention ICMJE	Drug: liraglutide Maximum dose of 1.8 mg liraglutide, injected subcutaneously (under the skin) once daily. Administered in addition to the subject's standard treatment; Drug: placebo Maximum dose of 1.8 mg placebo, injected subcutaneously (under the skin) once daily. Administered in addition to the subject's standard treatment
Study Arms	Experimental: Liraglutide Intervention: Drug: liraglutide; Placebo Comparator: Placebo Intervention: Drug: placebo
Publications *	Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.; Petrie JR, Marso SP, Bain SC, Franek E, Jacob S, Masmiquel L, Leiter LA, Haluzik M, Satman I, Omar M, Shestakova M, Van Gaal L, Mann JF, Baeres FM, Zinman B, Poulter NR; LEADER investigators. LEADER-4: blood pressure control in patients with type 2 diabetes and high cardiovascular risk: baseline data from the LEADER randomized trial. J Hypertens. 2016 Jun;34(6):1140-50. doi: 10.1097/HJH.0000000000000890.; Masmiquel L, Leiter LA, Vidal J, Bain S, Petrie J, Franek E, Raz I, Comlekci A, Jacob S, van Gaal L, Baeres FM, Marso SP, Eriksson M; LEADER investigators. LEADER 5: prevalence and cardiometabolic impact of obesity in cardiovascular high-risk patients with type 2 diabetes mellitus: baseline global data from the LEADER trial. Cardiovasc Diabetol. 2016 Feb 10;15:29. doi: 10.1186/s12933-016-0341-5.; Satman I, R Rea R, Eriksson M, Mosenzon O, Pratley R, M Baeres F, D Ørsted D, F Mann J; LEADER Trial Investigators. LEADER-6: Baseline renal function and associated factors in a high cardiovascular risk type 2 diabetes population. J Diabetes Complications. 2016 Nov - Dec;30(8):1631-1639. doi: 10.1016/j.jdiacomp.2016.06.001. Epub 2016 Jun 3.; Rutten GE, Tack CJ, Pieber TR, Comlekci A, Ørsted DD, Baeres FM, Marso SP, Buse JB; LEADER Investigators. LEADER 7: cardiovascular risk profiles of US and European participants in the LEADER diabetes trial differ. Diabetol Metab Syndr. 2016 Jun 2;8:37. doi: 10.1186/s13098-016-0153-5. eCollection 2016.; Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, Pocock S, Steinberg WM, Bergenstal RM, Mann JF, Ravn LS, Frandsen KB, Moses AC, Buse JB. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J. 2013 Nov;166(5):823-30.e5. doi: 10.1016/j.ahj.2013.07.012. Epub 2013 Oct 2.; Steinberg WM, Nauck MA, Zinman B, Daniels GH, Bergenstal RM, Mann JF, Steen Ravn L, Moses AC, Stockner M, Baeres FM, Marso SP, Buse JB; LEADER Trial investigators. LEADER 3--lipase and amylase activity in subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER Trial. Pancreas. 2014 Nov;43(8):1223-31. doi: 10.1097/MPA.0000000000000229.; Daniels GH, Hegedüs L, Marso SP, Nauck MA, Zinman B, Bergenstal RM, Mann JF, Derving Karsbøl J, Moses AC, Buse JB, Tuttle RM; LEADER Trial Investigators. LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations. Diabetes Obes Metab. 2015 May;17(5):477-86. doi: 10.1111/dom.12444. Epub 2015 Feb 23.; Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering Committee; LEADER Trial Investigators. Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: Results From the LEADER Randomized Trial. Diabetes Care. 2017 Jul;40(7):966-972. doi: 10.2337/dc16-2747. Epub 2017 May 5.; Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornøe K, Zinman B, Buse JB; LEADER Steering Committee and Investigators. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Aug 31;377(9):839-848. doi: 10.1056/NEJMoa1616011.; Hegedüs L, Sherman SI, Tuttle RM, von Scholten BJ, Rasmussen S, Karsbøl JD, Daniels GH; LEADER Publication Committee on behalf of the LEADER Trial Investigators. No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial. Diabetes Care. 2018 Mar;41(3):620-622. doi: 10.2337/dc17-1956. Epub 2017 Dec 26.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 10, 2016)	9340
Original Estimated Enrollment ICMJE; (submitted: August 9, 2010)	8754
Actual Study Completion Date	December 17, 2015
Actual Primary Completion Date	December 17, 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Type 2 diabetes; Age min. 50 years at screening and concomitant cardiovascular, cerebrovascular or peripheral vascular disease or chronic renal failure or chronic heart failure OR age min. 60 years at screening and other specified risk factors of cardiovascular disease; HbA1c: 7.0% or above; Anti-diabetic drug naive or treated with one or more oral anti-diabetic drugs (OADs) or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with OAD(s) Exclusion Criteria: Type 1 diabetes; Use of a glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide or other) or pramlintide or any dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior to screening (trial start); Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior to screening. Short-term use of other insulin during this period in connection with intercurrent illness is allowed, at Investigator's discretion
Sex/Gender	Sexes Eligible for Study: All
Ages	50 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Poland, Puerto Rico, Romania, Russian Federation, Serbia, South Africa, Spain, Sweden, Taiwan, Turkey, United Arab Emirates, United Kingdom, United States
Removed Location Countries	Czech Republic
Administrative Information
NCT Number ICMJE	NCT01179048
Other Study ID Numbers ICMJE	EX2211-3748; 2009-012201-19 ( EudraCT Number ); U1111-1113-7090 ( Other Identifier: WHO ); CTR20130003 ( Other Identifier: CFDA )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Novo Nordisk A/S
Study Sponsor ICMJE	Novo Nordisk A/S
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Global Clinical Registry (GCR, 1452) Novo Nordisk A/S
PRS Account	Novo Nordisk A/S
Verification Date	January 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP