Rationale and design of LAPLACE-2: A phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy

Clinical Cardiology

Volumn 37, Issue 4, 2014, Pages 195-203

  Robinson, Jennifer G ^a   Rogers, William J ^b   Nedergaard, Bettina S ^c   Fialkow, Jonathan ^d   Neutel, Joel M ^e   Ramstad, David ^f   Somaratne, Ransi ^g   Legg, Jason C ^g   Nelson, Patric ^g   Scott, Rob ^g   Wasserman, Scott M ^g   Weiss, Robert ^h  

^a UNIVERSITY OF IOWA   (United States)

^b University of Alabama at Birmingham   (United States)

^c CENTER FOR CLINICAL AND BASIC RESEARCH   (Denmark)

^d FLORIDA INTERNATIONAL UNIVERSITY   (United States)

^e Orange County Research Center   (United States)

^f Hampton Roads Center for Clinical Research   (United States)

^g AMGEN INC   (United States)

^h Maine Research Associates   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; EVOLOCUMAB; EZETIMIBE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPOPROTEIN A; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; ROSUVASTATIN; SIMVASTATIN; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL; AZETIDINE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYPOCHOLESTEROLEMIC AGENT; MONOCLONAL ANTIBODY;

ADULT; AGED; ARTICLE; COMPARATIVE STUDY; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DYSLIPIDEMIA; FEMALE; HUMAN; HYPERCHOLESTEROLEMIA; MAJOR CLINICAL STUDY; MALE; MONOTHERAPY; MULTICENTER STUDY; PHASE 3 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; TREATMENT OUTCOME; ADOLESCENT; CLINICAL TRIAL; DRUG ADMINISTRATION; DRUG COMBINATION; DYSLIPIDEMIAS; MIDDLE AGED; VERY ELDERLY; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; ANTIBODIES, MONOCLONAL; ANTICHOLESTEREMIC AGENTS; AZETIDINES; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; DRUG THERAPY, COMBINATION; DYSLIPIDEMIAS; FEMALE; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERCHOLESTEROLEMIA; MALE; MIDDLE AGED; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84899102691     PISSN: 01609289     EISSN: 19328737     Source Type: Journal    
DOI: 10.1002/clc.22252     Document Type: Article

References (46)

1. Wilson PW, D'Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837-1847.
2. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med. 1990; 322: 1700-1707.
3. Grundy SM, Cleeman JI, Merz CN, et al. for the Coordinating Committee of the National Cholesterol Education Program, endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [published correction appears in Circulation. 2004;110:763]. Circulation. 2004; 110: 227-239.
4. Perk J, De Backer G, Gohlke H, et al. European Association for Cardiovascular Prevention and Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) [published correction appears in Eur Heart J. 2012;33:2126]. Eur Heart J. 2012; 33: 1635-1701.
5. Baigent C, Blackwell L, Emberson J,; Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010; 376: 1670-1681.
6. Anderson TJ, Grégoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013: 151-167.
7. Grundy SM,; Expert Dyslipidemia Panel. An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia. J Clin Lipidol. 2013; 7: 561-565.
8. Santos RD, Waters DD, Tarasenko L, et al. A comparison of non-HDL and LDL cholesterol goal attainment in a large, multinational patient population: the Lipid Treatment Assessment Project 2. Atherosclerosis. 2012; 224: 150-153.
9. LaRosa JC, Grundy SM, Waters DD, et al. the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425-1435.
10. Pedersen TR, Faergeman O, Kastelein JJ, et al. for the Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: a randomized controlled trial [published correction appears in JAMA. 2005;294:3092]. JAMA. 2005; 294: 2437-2445.
11. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; doi: 10.1016/j.jacc.2013.11.002.
12. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013; 127: 96-103.
13. Wei MY, Ito MK, Cohen JD, et al. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013; 7: 245-246.
14. LaRosa JC, He J, Vupputuri S,. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999; 282: 2340-2346.
15. Horton JD, Cohen JC, Hobbs HH,. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007; 32: 71-77.
16. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354: 1264-1272.
17. Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis. 2007; 193: 445-448.
18. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34: 154-156.
19. Maxwell KN, Breslow JL,. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004; 101: 7100-7105.
20. Chan JC, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009; 106: 9820-9825.
21. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from two randomized, double-blind, placebo-controlled, ascending-dose phase I studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012; 60: 1888-1898.
22. Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis In Myocardial Infarction (TIMI) 57 trial. Circulation. 2013; 128: 962-969.
23. Giugliano RP, Desai NR, Kohli P, et al. LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012; 380: 2007-2017.
24. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012; 380: 1995-2006.
25. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012; 126: 2408-2417.
26. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012; 308: 2497-2506.
27. Costet P, Hoffmann MM, Cariou B, et al. Plasma PCSK9 is increased by fenofibrate and atorvastatin in a non-additive fashion in diabetic patients. Atherosclerosis. 2010; 212: 246-251.
28. Agnello V, Abel G, Elfahal M, et al. Hepatitis C virus and other flaviviridae viruses enter cells via low-density lipoprotein receptor. Proc Natl Acad Sci U S A. 1999; 96: 12766-12771.
29. Monazahian M, Böhme I, Bonk S, et al. Low-density lipoptorein receptor as a candidate receptor for hepatitis C virus. J Med Virol. 1999; 57: 223-229.
30. Wünschmann S, Medh JD, Klinzmann D, et al. Characterization of hepatitis C virus (HCV) and HCV E2 interactions with CD81 and the low-density lipoprotein receptor. J Virol. 2000; 74: 10055-10062.
31. Merck Sharp, &, Dohme Ltd,. Zocor (simvastatin) tablets [highlights of prescribing information]. Cramlington, UK: Merck Sharp & Dohme Ltd; 2012.
32. Downs JR, Clearfield M, Tyroler HA, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin. Am J Cardiol. 2001; 87: 1074-1079.
33. Ridker PM, MacFadyen JG, Fonseca FA, et al. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009; 2: 616-623.
34. Sever PS, Chang CL, Gupta AK, et al. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK. Eur Heart J. 2011; 32: 2525-2532.
35. Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307.
36. Chrispin J, Martin SS, Hasan RK, et al. Landmark lipid-lowering trials in the primary prevention of cardiovascular disease. Clin Cardiol. 2013; 36: 516-523.
37. Ballantyne CM, Abate N, Yuan Z, et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study [published correction appears in Am Heart J. 2005;149:882]. Am Heart J. 2005; 149: 464-473.
38. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the PCSK9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013; 128: 2113-2120.
39. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006;354:778]. N Engl J Med. 2004; 350: 1495-1504.
40. Cariou B, Le May C, Costet P,. Clinical aspects of PCSK9. Atherosclerosis. 2011; 216: 258-265.
41. US National Institutes of Health, ClinicalTrials.gov. Open Label Study of Long Term Evaluation Against LDL-C Trial-2 (OSLER-2). http://clinicaltrials. gov/ct2/show/nct01854918. Accessed December 6, 2013.
42. US National Institutes of Health, ClinicalTrials.gov. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). http://clinicaltrials.gov/ct2/show/nct01764633. Accessed August 29, 2013.
43. US National Institutes of Health, ClinicalTrials.gov. Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2 (GAUSS-2). http://clinicaltrials.gov/ct2/show/nct01763905. Accessed August 29, 2013.
44. US National Institutes of Health, ClinicalTrials.gov. Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2 (RUTHERFORD-2). http://clinicaltrials.gov/ct2/show/nct01763918. Accessed August 29, 2013.
45. US National Institutes of Health, ClinicalTrials.gov. Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 (MENDEL-2). http://clinicaltrials.gov/ct2/ show/nct01763827. Accessed August 29, 2013.
46. US National Institutes of Health, ClinicalTrials.gov. Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV). http://clinicaltrials.gov/ct2/show/nct01813422. Accessed October 1, 2013.