LATITUDE-TIMI 60 Design Paper

Rationale and Design of the Further cardiovascular OUtcomes Research with PCSK9Inhibition in subjects with Elevated Risk (FOURIER) Trial Marc S. Sabatine, MD, MPH,a Robert P. Giugliano, MD, SM,aAnthony Keech, MD,bNarimon Honarpour, MD, PhD,c Huei Wang, PhD,c ThomasLiu, PhD,cScott M. Wasserman, MD,c Robert Scott, MD,c Peter S. Sever,MD,d Terje R. Pedersen, MDe aTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA bSydney Medical School, NHMRC Clinical Trials Centre, University of Sydney, Australia cAmgen, Thousand Oaks, CA1 dInternational Centre for Circulatory Health, Imperial College London, London, United Kingdom eOslo University Hospital, Ullevål and Medical Faculty, University of Oslo, NorwayFOURIER is funded by AmgenClinicalTrials.gov NCT01764633Word count: 5650 (includes references, abstract, tables)Abstract word count: 2412 AbstractBackground: Despite current therapies, patients with vascular disease remain at high risk for major adverse cardiovascular events. LDL-C is a well-established modifiable cardiovascular risk factor. Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) that reduces LDL-C by approximately 60% across various populations.Study Design: FOURIER is a randomized, placebo-controlled, double-blind, parallel-group, multinational trial testing the hypothesis that adding evolocumab to statin therapy will reduce the incidence of major adverse cardiovascular events in patients with clinically evident vascular disease. The study population consists of 27,564 patients who have had either an MI, an ischemic stroke or symptomatic peripheral artery disease and have an LDL ≥70 mg/dL or a non-HDL-C ≥100 mg/dL on an optimized statin regimen. Patients are randomized in a 1:1 ratio to receive either evolocumab (either 140 mg SC every 2 weeks or 420 mg SC every month, according to patient preference) or matching placebo injections. The primary endpoint is major cardiovascular events defined as the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint is the composite of cardiovascular death, MI, or stroke. The trial is planned to continue until 1630 patients experience the secondary endpoint, thereby providing 90% power to detect a relative reduction of 15% or more in this endpoint.3 Conclusions: FOURIER will determine whether the addition of evolocumab to statin therapy reduces cardiovascular morbidity and mortality in patients with vascular disease. IntroductionDespite advances in treatment, cardiovascular disease remains the leading cause of morbidity and mortality worldwide and is projected to cause >22 million deaths over the next 15 years.1 Cholesterol, in particular low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. Moreover, LDL-C has proven to be a modifiable risk factor with a very large body of evidence demonstrating the benefit of LDL-C lowering. Specifically, there is clear evidence from over 2 dozen trials of statins involving over 160,000 subjects in total with a median follow-up of approximately 5 years that each 1 mmoL lowering of LDL-C reduces the risk of major cardiovascular events by approximately 22%.2Similar clinical benefit has also been demonstrated for non-statin LDL-C lowering medications such as resins, niacin, and fibrates, when they have been studied in a patient population in whom they meaningfully lowered LDL-C.3-5 Data from Mendelian randomization studies recapitulate this relationship, in which there is a log-linear relationship between the LDL-C lowering associated with genetic variants in multiple different genes and the risk reduction in cardiovascular disease.6 Recently, the IMPROVE-IT trial showed that in patients recently stabilized after an acute coronary syndrome, the addition of the cholesterol absorption inhibitor ezetimibe to statin therapy reduced major adverse cardiovascular events.7 Ezetimibe decreased LDL-C by approximately 20% (from 70 to 54 mg/dL) and the magnitude of clinical risk reduction with ezetimibe was consistent with the reduction expected to be produced from that degree of LDL-C lowering by a statin. Notably, though, was the observation that even in the ezetimibe 4 plus statin arm, in which patients were also well-treated with the standard evidence-based cardiovascular medicines, the rate of major adverse cardiovascular events exceeded 30% at 7 years. Thus there remains an important unmet need for further reduction in adverse cardiovascular outcomes, which may be achievable by more potent LDL-C lowering in high- risk patients. EvolocumabLDL receptors (LDL-R) on hepatocytes clear circulating LDL-C from the blood. The LDL-R is typically able to recycle back to the cell surface over 100 times.8 However, when proprotein convertase subtilisin/kexin type 9 (PCSK9) is bound to the LDL-R, the LDL-R is targeted for degradation within the lysosome.9 A seminal finding was that loss-of-function mutations in PCSK9 resulted in lower circulating LDL-C levels and considerable protection from the development of coronary heart disease.10 This observation suggested that PCSK9 inhibitors might similarly reduce the risk of cardiovascular disease. Evolocumab is a fully human monoclonal antibody that has been studied extensively in phase 2 and 3 lipid-lowering trials. At doses of either 140 mg every 2 weeks or 420 mg every month, typically achieves approximately a 60% reduction in LDL cholesterol irrespective of whether it is used as monotherapy, added to statins or added to statins plus other agents.11-15 Evolocumab also has similarly favorable effects on other atherogenic lipoproteins such as apo-B and it decreases Lp(a) by approximately 30%.16, 17 In addition, evolocumab was generally well tolerated in these trials, without major adverse effects. Herein we describe the design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial. This phase III trial, registered5 at www.clinicaltrials.gov under number NCT01764633, is designed to test the clinical efficacy and safety of evolocumab when added to a statin in patients with clinically evident vascular disease. Study design and populationFOURIER is a randomized, placebo-controlled, double-blind, parallel-group, multinational trial (Figure 1) evaluating evolocumab in 27,564 patients with clinically evident vascular disease. The primary hypothesis is that evolocumab will reduce the incidence of major adverse cardiovascular events.Study patients must be between 40 and 85 years of age and have clinically evident cardiovascular disease defined as a history of myocardial infarction, non-hemorrhagic stroke, or symptomatic peripheral artery disease. Furthermore, patients must have additional characteristics that place them at higher cardiovascular risk. Patients must have a fasting LDL-C ≥70 mg/dL or a non-HDL-C of ≥100 mg/dL after ≥2 weeks of optimized stable lipid-lowering therapy, which would ideally include a high intensity statin, but must be at least atorvastatin 20 mg daily or equivalent (ie, at least moderate intensity statin), with or without ezetimibe. A complete listing of the inclusion and exclusion criteria is provided in Tables I and II. The first patient was enrolled on February 8, 2013 and the last on June 5, 2015. A snapshot of baseline characteristics of trial patients at the time of the drafting of this manuscript is shown in Table III. Eligible patients were randomized in a 1:1 ratio to receive either evolocumab (either 140 mg SC every 2 weeks or 420 mg SC every month, according to patient preference) or matching placebo injections. Randomized allocation of study treatment was performed via a central computerized system with stratification of randomization by LDL-C (<85 vs ≥ 85 mg/dL) and 6 region. Treatment allocation was double-blind. Randomized patients are to be followed up for all relevant clinical endpoints and adverse events until the end of this study, which will occur after 1630 patients experience the key secondary endpoint event (cardiovascular death, myocardial infarction, or stroke) confirmed by central adjudication. The study is being performed in accordance with ethical principles in a manner consistent with the Declaration of Helsinki, ICH Good Clinical Practice guidelines, and applicable regulatory requirements. The final study protocol and informed consent has been reviewed and approved by the corresponding health authorities and ethics boards/IRBs for all participating study sites. Randomized patients gave written informed consent for participation in the trial.Treatment Protocol and Study AssessmentsBackground Lipid-Lowering TherapyPatients on a stable (defined as for ≥4 weeks prior to screening), optimized lipid-lowering regimen were eligible for final screening and placebo run-in (see below). Patients requiring uptitration of their lipid-lowering regimen or those who wished to switch to study-supplied atorvastatin underwent initial screening procedures and entered an uptitration/switching phase with LDL-C assessments every 2 weeks. Once the patient was on an optimized lipid-lowering regimen for ≥2 weeks during screening, final screening procedures could be performed. Patients received a placebo run-in injection (single, 1 mL SC injection) to assess tolerability of SC injections. Study Drug Study drug is dispensed as either evolocumab, 140 mg to be taken every 2 weeks or 420 mg to be taken every month (ie, every 4 weeks), or matching placebo. Given the equivalent LDL-C lowering of the 2 regimens,18 patients may choose the dosing frequency and can elect to 7 switch every 12 weeks. Dose titrations are not permitted.Visit Schedule and Follow upRandomized patients return for study visits at week 2, 4, 12 and then at 12 week intervals thereafter. During follow-up visits patients are assessed for adverse and potential endpoint events, and blood and urine are sampled for central laboratory testing. All patients are to be followed regardless of whether or not they are taking study drug.Lipid Monitoring and Compliance with Lipid-Lowering TherapyAll medical staff involved with the patient’s care are requested to refrain from obtaining lipid panels from randomization until at least 12 weeks after the patient has permanently stopped study drug. Central laboratory results of lipid panels are blinded. If a patient’s LDL-C increases by 25% and 20 mg/dL from baseline, the sites is notified by an automated system to instruct the patient on compliance. To maintain the blind, reminders are provided to additional patients so that the number of reminders is balanced between treatment arms. In general, patients are not to change open-label background lipid-lowering therapies post-randomization.Study EndpointsThe primary endpoint of the trial is major cardiovascular events defined as the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint is the composite of cardiovascular death, MI, or stroke. Other secondary endpoints include the individual components of the key secondary endpoint, death by any cause, cardiovascular death or hospitalization for heart failure, coronary revascularization, and ischemic stroke or transient ischemic attack. Exploratory endpoints include absolute and percent changes in LDL-C and other lipid parameters. Safety will be assessed through collection of adverse events, including muscle-related adverse events. In 8 addition to general adverse events, incident diabetes will be ascertained and adjudicated, periodic laboratory testing will include liver function tests, creatine kinase, fasting glucose, HbA1c, and anti-evolocumab antibodies, and formal neurocognitive testing will be done in a subset of patients (see below).An independent clinical endpoint committee (CEC, Online Appendix) that is led by the TIMI Study Group is adjudicating causes of death, all major cardiovascular outcomes of interest, and incident diabetes. Endpoint definitions are based on the United States Food and Drug Administration recommended Standardized Definitions for Cardiovascular Outcomes Trials.19 All CEC members are blinded to treatment assignment and lipid levels. Statistical ConsiderationsThe primary efficacy analysis will be based on the time from randomized treatment assignment to the first occurrence of any element of the primary composite endpoint of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. To preserve the overall type I error rate at 0.05, if the primary endpoint is significantly reduced, then the key secondary endpoint will be analyzed at a significance level of 0.05. If the key secondary endpoint is significantly reduced, then cardiovascular death will be analyzed at a significance level of 0.05. If cardiovascular death is significantly reduced, then all- cause mortality will be analyzed at a significance level of 0.04 and additional secondary endpoints will be tested at an overall significant level of 0.01 by applying the Hochberg method.20 All efficacy analyses will be conducted on an intention-to-treat basis. Safety evaluations will include all randomized patients who receive at least one dose of study treatment and for whom post-dose data are available. Trial sample size was based on the key secondary endpoint with the assumption of a 2% 9 per year event rate in the placebo arm and a hazard ratio of 0.80, which was deliberately conservative based on the non-statin mechanism of LDL-lowering and the low LDL levels anticipated to be achieved. Furthermore, due to potential treatment lag (as has been seen in some lipid-lowering trials) and an estimated non-compliance rate of 10% per year, the observed hazard ratio was assumed to be 0.85. After taking these factors into account, 1630 key secondary endpoints would provide 90% power.21 Assuming a 2% per year event rate in the placebo arm, 27,500 patients followed for a median of about 43 months should provide 1630 key secondary endpoints. Assuming an annualized event rate of 4.5% for the primary endpoint, there should be 3550 events at the end of the study, yielding >99% power to detect the hypothesized effect. The Executive Committee and Sponsor will monitor the blinded aggregate event rate data as well as other trial metrics and study duration may be adjusted to ensure assumptions are met.Data Monitoring and Lipid-Monitoring CommitteesReviews of safety are being performed by an Independent Data Monitoring Committee (Online Appendix) approximately every 3 months. All DMC recommendations will be made based on a review of the totality of evidence from the unblinded data from the trial. There are no formal statistical monitoring rules for stopping the trial based on safety or efficacy. The DMC will consider a Haybittle-Peto monitoring guideline as one component of the totality of evidence.The DMC is monitoring patients who achieve LDL-C <25 mg/dL.A Lipid Monitoring Committee (LMC, Online Appendix) will monitor the LDL-C separation between treatment groups (but not clinical events) over the course of the study and may advise the Executive Committee and Sponsor if trial assumptions (eg, if the expected LDL-C separation between treatment arms is <36 mg/dL at 12 months) are not being met globally or in certain subgroups, without revealing specific observed treatment effects.10 Planned SubstudiesSerum and plasma samples for assessment of cardiovascular biomarkers are being obtained at baseline, week 24 and end of study. The intent of the biomarker substudy is to examine the relationship between biomarkers and efficacy, safety or tolerability of evolocumab, as well as the relationship between biomarkers and cardiovascular and metabolic disease. DNA will be collected in all subjects who provide informed consent to participate in the optional genetics substudy. The intent of the genetics substudy is to examine the relationship between genetic variants and the efficacy, safety or tolerability of evolocumab, as well as the relationship between genetic variants and cardiovascular and metabolic disease. Dedicated neurocognitive testing is being performed in a subset of approximately 2000 patients, using CANTAB, a validated, tablet-based approach.22, 23Study OrganizationThe protocol was designed through a collaboration between the Executive Committee and the Sponsor (Amgen). Along with the Sponsor, the Executive Committee monitors ongoing conduct of the trial. The FOURIER trial is being conducted in 49 countries and 1272 sites. A Steering Committee composed of National Lead Investigators from the countries is responsible for the protocol and its implementation in each of the countries (Online Appendix). As noted above, an independent DMC is responsible for periodic reviews of patient safety during the trial and a LMC for LDL-C separation. The TIMI Study Group, an academic research organization within Brigham and Women’s Hospital (Boston, MA), will have full access to the complete database once the study is completed and will independently generate analyses. The Executive Committee will be responsible for submitting the results of the study for publication in a peer-reviewed medical 11 journal.The authors are solely responsible for the drafting and editing of the paper and its final contents.DiscussionA series of statin trials over time have repeatedly shown a reduction in major adverse cardiovascular events in the arm that was allocated to receive more intensive LDL-C-lowering therapy (either therapy vs placebo or more intensive vs less intensive therapy) and therefore achieved lower LDL-C. We hypothesize LDL-C lowering with evolocumab will also yield significant reductions in cardiovascular disease for several reasons. First, reductions in cardiovascular events have been seen with non-statin LDL-C lowering drugs that are proportionately comparable to what has been observed with statins.24 Second, PCSK9 inhibitors and statins share the same final common pathway for LDL-C reduction, namely by upregulating the LDL-R. Third, observational data from several cohorts have consistently shown that carriers of PCSK9 loss-of-function allele have substantially lower rates of cardiovascular events.25 Fourth, in a recent prespecified analysis of 60 cardiovascular events from open-label extensions of 12 phase 2 and phase 3 trials of evolocumab, treatment with evolocumab reduced LDL-C by 61% (from a median of 120 to 48 mg/dL) and cardiovascular events through 1 year by 53% (HR 0.47, 95% CI 0.28-0.78, P=0.003).26 Although based on a small number of events, similar results were seen in an exploratory analysis of cardiovascular outcomes with another PCSK9 inhibitor.27 Although the CTT analysis notes a 22% reduction in cardiovascular events over a median of approximately 5 years for each mmol reduction in LDL-C, it must be acknowledged that we have sparser data in patients starting at the lower end of the range of 12 LDL-C. Nonetheless, subgroup analyses from both the JUPITER trial of rosuvastatin and the IMPROVE-IT trial of ezetimibe show consistent clinical benefit even when reducing LDL-C from 50-60 mg/dL to the mid 40s or even <30 mg/dL.28, 29 Furthermore, in the exploratory cardiovascular outcomes data to date, the magnitude of reductions in cardiovascular events observed with the large decreases in LDL-C with PCSK9 inhibitors is consistent with the relationship reported in the CTT meta-analysis of statin trials.30 FOURIER will provide a robust dataset in this lower range of LDL-C to examine both the quantitative relationship between LDL-C reduction with a non-statin therapy and clinical event reduction and the relationship between achieved LDL-C and cardiovascular outcomes.Per protocol, all patients must be on a background of at least moderate intensity statin therapy and in fact the majority of patients are receiving background high intensity statin therapy. Therefore FOURIER will provide an opportunity to assess the clinical benefit of PCSK9 inhibition on top of high intensity statin therapy, use of which in patients with atherosclerotic cardiovascular disease is recommended by current guidelines.31 The results of the IMPROVE IT study demonstrate that further LDL-C reduction with ezetimibe on top of a statin provides further clinical benefit.7 In FOURIER, approximately 5% of patients in the trial are on background ezetimibe and a statin. Thus the data available for the efficacy of evolocumab on clinical outcomes in the setting of concomitant statin and ezetimibe will be more limited, although the LDL-C lowering ability of evolocumab appears comparable in patients on and off ezetimibe.11, 15FOURIER will also provide important safety data for two related issues: long-term administration of evolocumab and achievement of very low LDL-C levels. Analyses from trials examining patients who achieved LDL-C <50, <40 and even <30 mg/dL showed no 13 clear excess of adverse events.28, 32, 33 An event of particular interest with statins has been incident diabetes.34 The mechanism remains debated with regard to whether it is linked to HMG-CoA reductase inhibition and altered prenylation of proteins, upregulation of the LDL-R, or some other unknown pathway.35, 36 Neurocognitive issues with statins have been noted in post-marketing reports, but not seen in randomized trials with neurocognitive testing.37, 38 Imbalances of neurocognitive adverse events have been seen with evolocumab and another PCSK9 inhibitor, although they have tended to be mild and transient. The formal neurocognitive testing substudy in FOURIER should provide definitive data. 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The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: A prove it-timi 22 substudy. J Am Coll Cardiol. 2005;46:1411-141633. Giugliano RP, Wiviott S, Blazing M, Murphy S, Zhou J, White J, Tershakovec A, Cannon C, Braunwald E. Safety and efficacy of long-term very low achieved ldl-c in the improve-it trial. Eur Heart J. 2015;36:134. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735-74235. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R,Stender S, Johnson PC, Scott RA, Leusink M, Verweij N, Sharp SJ, Guo Y, Giambartolomei C, Chung C, Peasey A, Amuzu A, Li K, Palmen J, Howard P, Cooper JA, Drenos F, Li YR, Lowe G, Gallacher J, Stewart MC, Tzoulaki I, Buxbaum SG, van der AD, Forouhi NG, Onland-Moret NC, van der Schouw YT, Schnabel RB, Hubacek JA, Kubinova R, Baceviciene M, Tamosiunas A, Pajak A, Topor-Madry R, Stepaniak U, Malyutina S, Baldassarre D, Sennblad B, Tremoli E, de Faire U, Veglia F, Ford I, JukemaJW, Westendorp RG, de Borst GJ, de Jong PA, Algra A, Spiering W, Maitland-van der Zee AH, Klungel OH, de Boer A, Doevendans PA, Eaton CB, Robinson JG, Duggan D, Consortium D, Consortium M, InterAct C, Kjekshus J, Downs JR, Gotto AM, Keech AC,20 Marchioli R, Tognoni G, Sever PS, Poulter NR, Waters DD, Pedersen TR, Amarenco P, Nakamura H, McMurray JJ, Lewsey JD, Chasman DI, Ridker PM, Maggioni AP, TavazziL, Ray KK, Seshasai SR, Manson JE, Price JF, Whincup PH, Morris RW, Lawlor DA, Smith GD, Ben-Shlomo Y, Schreiner PJ, Fornage M, Siscovick DS, Cushman M, KumariM, Wareham NJ, Verschuren WM, Redline S, Patel SR, Whittaker JC, Hamsten A, Delaney JA, Dale C, Gaunt TR, Wong A, Kuh D, Hardy R, Kathiresan S, Castillo BA, van der Harst P, Brunner EJ, Tybjaerg-Hansen A, Marmot MG, Krauss RM, Tsai M, Coresh J, Hoogeveen RC, Psaty BM, Lange LA, Hakonarson H, Dudbridge F, HumphriesSE, Talmud PJ, Kivimaki M, Timpson NJ, Langenberg C, Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Reiner AP, Keating BJ, Hingorani AD, Sattar N. Hmg- coenzyme a reductase inhibition, type 2 diabetes, and bodyweight: Evidence from genetic analysis and randomised trials. Lancet. 2015;385:351-36136. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313:1029-103637. Mrc/bhf heart protection study of cholesterol lowering with simvastatin in 20,536 high- risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360:7-2238. Trompet S, van Vliet P, de Craen AJ, Jolles J, Buckley BM, Murphy MB, Ford I, Macfarlane PW, Sattar N, Packard CJ, Stott DJ, Shepherd J, Bollen EL, Blauw GJ, Jukema JW, Westendorp RG. Pravastatin and cognitive function in the elderly. Results of the prosper study. Journal of neurology. 2010;257:85-9021 Table I: Inclusion criteria1. Signed informed consent 2. Male or female ≥40 to ≤85 years of age at signing of informed consent 3. History of clinically evident cardiovascular disease as evidenced by any of the following:  diagnosis of myocardial infarction  diagnosis of non-hemorrhagic stroke  symptomatic peripheral arterial disease (PAD), as evidenced by either intermittent claudication with ankle-brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease 4. At least 1 major risk factor or at least 2 minor risk factors below: Major Risk Factors (1 Required):  diabetes (type 1 or type 2)  age ≥65 years at randomization (and ≤85 years at time of informed consent)  MI or non-hemorrhagic stroke within 6 months of screening  additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke  current daily cigarette smoking  history of symptomatic PAD (intermittent claudication with ABI <0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease) if eligible by MI or stroke history Minor Risk Factors (2 Required):  history of non-MI related coronary revascularization  residual coronary artery disease with ≥40% stenosis in ≥2 large vessels  most recent HDL-C <40 mg/dL (1.0 mmol/L) for men and <50 mg/dL (1.3 mmol/L) for women by central laboratory before randomization  most recent hsCRP >2.0 mg/L by central laboratory before randomization  most recent LDL-C ≥130 mg/dL (3.4 mmol/L) or non-HDL-C ≥160 mg/dL (4.1 mmol/L) by central laboratory before randomization  metabolic syndrome 5. Most recent fasting LDL-C ≥70 mg/dL (1.8 mmol/L) or non-HDL-C ≥100 mg/dL (2.6 mmol/L) by central laboratory during screening after ≥2 weeks of stable lipid lowering therapy 6. Most recent fasting triglycerides ≤400 mg/dL (4.5 mmol/L) by central laboratory before randomization22 Table II: Exclusion criteria 1. Subject must not be randomized within 4 weeks of their most recent MI or stroke 2. NYHA class III or IV, or last known left ventricular ejection fraction < 30% 3. Known hemorrhagic stroke at any time 4. Uncontrolled or recurrent ventricular tachycardia 5. Planned or expected cardiac surgery or revascularization within 3 months after randomization 6. Uncontrolled hypertension defined as sitting systolic blood pressure >180 mmHg or diastolic BP >110 mmHg 7. Use of cholesteryl ester transfer protein (CETP) inhibition treatment, mipomersen, or lomitapide within 12 months prior to randomization. Fenofibrate therapy must be stable for at least 6 weeks prior to final screening at a dose that is appropriate for the duration of the study in the judgment of the investigator. Other fibrate therapy (and derivatives) are prohibited 8. Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab <12 weeks prior to final lipid screening 9. Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone < lower limit of normal or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at final screening 10. Severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <20 2 mL/min/1.73m at final screening 11. Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the ULN as determined by central laboratory analysis at final screening 12. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal) 13. Personal or family history of hereditary muscular disorders 14. LDL or plasma apheresis within 12 months prior to randomization 15. Severe, concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 3 years 16. CK >5 times the ULN at final screening 17. Known major active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator 18. Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years 19. Subject has received drugs via a systemic route that have known major interactions with background statin therapy within 1 month prior to randomization or is likely to require such treatment during the study period 20. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s) 21. Female subject who has either (1) not used acceptable method(s) of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment with IP and for an additional 15 weeks after the end of treatment with IP, unless the subject is sterilized or postmenopausal; 22. Subject is pregnant or breast feeding, or planning to become pregnant or to breastfeed during treatment with IP and/ or within 15 weeks after the end of treatment with IP 23. Known sensitivity to any of the active substances or their excipients to be administered 23 during dosing 24. Subject likely to not be available to complete all protocol-required study visits or procedures, to the best of the subject’s and investigator’s knowledge 25. History or evidence of any other clinically significant disorder, condition or disease other than those outlined above that, in the opinion of the Investigator or Amgen physician, if consulted may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion24 Table III: Snapshot of Baseline CharacteristicsAll subjects randomized Characteristic (N = 27564) Age, y, mean (SD) 62.5 (9.0) Sex, male, n (%) 20795 (75.4) Race, n (%) Caucasian 23426 (85.0) Black or African American 699 (2.4) Asian or Other 3439 (12.5) Region North America 4571 (16.6) Europe 17335 (62.9) Latin America 1823 (6.6) Asia Pacific and South Africa 3835 (13.9) Cardiovascular risk factors, n (%) Hypertension 22040 (80.0) Diabetes mellitus 9333 (33.9) Current cigarette use 7770 (28.2) History of vascular disease, n (%) Myocardial infarction 22356 (81.1) Non-hemorrhagic stroke 5330 (19.3) Peripheral artery disease 3640 (13.2) Statin use, n (%) High intensity 19082 (69.2) Moderate intensity 8390 (30.4) Low intensity, unknown at this time, or no data 92 (0.3) Ezetimibe, n (%) 1393(5.1) Lipid parameters at parent study baseline, mg/dL (Q1, Q3) LDL cholesterol 91.5 (79.5, 108.0) Total cholesterol 167.0 (150.5, 188.0) HDL cholesterol 44.0 (37.0, 52.5) Triglycerides 133.0 (99.8, 181.0)Based on snapshot of database performed on October 2, 2015. HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD: standard deviation. 25 Figure LegendFigure 1. FOURIER Study Design26 Figure 1. AppendixExecutive Committee Marc S. Sabatine, MD, MPH, Co-Chair Terje R. Pedersen, MD, Co-Chair Robert P. Giugliano, MD, SM Anthony Keech, MD Peter S. Sever, MDSteering Committee includes Members of the Executive Committee and the following National Lead Investigators Alberto J. Lorenzatti, MD (Argentina) John Amerena, MBBS (Australia) Kurt Huber, MD (Austria) André Scheen, MD (Belgium) José Francisco Kerr Saraiva, MD, PhD (Brazil) Borislav Georgiev Georgiev, MD (Bulgaria) Lawrence A. Leiter, MD (Canada) Jorge Leonardo Cobos, MD (Chile) Lixin Jiang, MD, PhD (China) Jose Luis Accini Mendoza, MD (Colombia) Richard Ceska, MD, PhD (Czech Republic) Henrik Kjaerulf Jensen, MD, DMSc, PhD (Denmark) Margus Viigimaa, MD, PhD (Estonia) Matti J. Tikkanen, MD (Finland) Francois Schiele, MD (France) Ioanna Gouni-Berthold, MD (Germany) Loukianos Rallidis, MD (Greece) Chung-Wah Siu, MD (Hong Kong) Kalman Toth, MD, PhD, ScD (Hungary) Gudmundur Thorgeirsson, MD, PhD (Iceland) Prakash C. Deedwania, MD & Vijay Kumar Chopra, MD (India) Brendan McAdam, MD (Ireland) Basil S Lewis, MD (Israel) Gaetano M. De Ferrari, MD (Italy) Atsushi Hirayama, MD, PhD (Japan) Andrejs Erglis, MD, PhD (Latvia) Jolita Badariene, MD (Lithuania) Wan Azman Wan Ahmad, MD (Malaysia) Guillermo Gonzalez-Galvez (Mexico) J. Wouter Jukema, MD, PhD (Netherlands) Anthony Clifford Keech, MD (New Zealand) Terje R. Pedersen, MD (Norway) Gregorio G. Rogelio, MD (Philippines) Zbigniew A. Gaciong, MD, PhD (Poland) Jorge Ferreira, MD (Portugal) G.A. Dan, MD, PhD (Romania) Marat Vladislavovich Ezhov, MD (Russia) Leslie Tay, MD (Singapore) Slavomíra Filipová, MD, PhD (Slovakia) Lesley Burgess, MD (South Africa) 28 Donghoon Choi, MD, PhD (South Korea) Jose Lopez-Miranda, MD (Spain) Lennart Nilsson, MD, PhD (Sweden) François Mach, MD (Switzerland) Min-Ji Charng, MD, PhD (Taiwan) S. Lale Tokgozoglu, MD (Turkey) Peter S Sever, MD (United Kingdom) Robert P. Giugliano, MD, SM (United States)Sponsor Leadership Robert Scott, MD Scott M. Wasserman, MD Narimon Honarpour, MD, PhD Ransi Somaratne, MD Kelly Hanlon, MBA Beat Knusel, PhD Thomas Liu, PhD Huei Wang, PhDDMC Members Charles H. Hennekens, MD, DrPH, Chair Felicita Andreotti MD PhD Colin Baigent, FFPH W. Virgil Brown, MD Barry R. Davis, MD, PhD John Newcomer, MD Sarah K. Wood, MDLMC Members John LaRosa, MD, Chair Benjamin Ansell, MD Anders Olsson, MDCEC Members Stephen D. Wiviott, MD, Chair Cheryl Lowe, Director Eric Awtry, MD Clifford J. Berger, MD Kevin Croce, MD Akshay Desai, MD Eli Gelfand, MD Carolyn Ho, MD David E. Leeman, MD Mark S. Link, MD Andrew D. Norden, MD Ashvin Pande, MD Natalia Rost, MD Frederick Ruberg, MD Scott Silverman, MD Aneesh Singhal, MD Joseph Vita, MD (deceased) 30

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