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SUPPLEMENTAL MATERIAL TOC \t "Head 1 plain,1" Supplemental Text 1. Investigators PAGEREF _Toc424888062 \h 2Supplemental Text 2. Methods PAGEREF _Toc424888063 \h 4Supplemental Table 1. Endpoints in order of hierarchical testing PAGEREF _Toc424888064 \h 6Supplemental Table 2. Patients with skeletal muscle-related AEs during pretreatment single-blind, placebo run-in period* PAGEREF _Toc424888065 \h 7Supplemental Table 3. History of statin intolerance by randomized treatment PAGEREF _Toc424888066 \h 8Supplemental Table 4. Treatment-emergent AEs* occurring in ≥2% of patients in any group (safety population) at 24 weeks PAGEREF _Toc424888067 \h 9Supplemental Table 5. Overview of treatment-related AEs for open-label treatment period (from first to last injection of study treatment + 70 days) (up to 196 weeks) PAGEREF _Toc424888068 \h 11Supplemental Figure 1. Percent change from baseline to Week 24 in LDL-C: subgroup analyses (ITT analysis). PAGEREF _Toc424888069 \h 12Supplemental Text 1. InvestigatorsInvestigatorsAustria: Heinz Drexel (Landeskrakenhaus Feldkirch, Feldkirch); Susanne Kaser (University Clinic for Internal Medicine, Innsbruck); Hermann Toplak (Medizinische Universit?t Graz, Graz). Canada: Alexis Baass (Institute de Recherches Cliniques de Montreal, Montreal); Jean Bergeron (Clinique des Maladies Lipidique de Quebec Inc., Quebec); Daniel Gaudet (ECOGENE-21 Clinical Trial Centre, Quebec).France: Eric Bruckert (H?pital Pitié Salpêtrière, Paris); Michel Farnier (Point Médical, Dijon); Michel Krempf (CHU de Nantes, Saint-Herblain); Gérald Luc (CHRU de Lille, Lille); Philippe Moulin (Groupement Hospitalier Est, Bron); Pierre Serusclat (GHMP les Portes du Sud, Venissieux).Israel: Hofit Cohen (Institute of Lipid & Atherosclerosis Research, Tel HaShomer); Dov Gavish (Wolfson Medical Center, Holon); Osama Hussein (Ziv Medical Center, Safed); Maximo Maislos (Clalit Health Services Ofakim B, Ofakim); Daniel Schurr (Center for Research, Treatment and Prevention of Atherosclerosis, Jerusalem).Italy: Marcello Arca (Universita La Sapienza di Roma, Rome); Maurizio Averna (Universita di Palermo, Palermo); Claudio Pozzi (Ospedale E, Cinisello Balsamo). Norway: Eli Heggen (Ulleval University Hospital, Oslo); Gisle Langslet (Oslo University Hospital, Oslo).UK: Ali Al-Bahrani (Vectasearch Clinic Ltd., Isle of Wight); Mark Blagden (Ashgate Medical Practice [Research Office], Chesterfield); Maurice O’Kane (Western Health and Social Care Trust, Londonderry, N. Ireland); Tim Reynolds (Queens Hospital, Burton-on-Trent); Adie Viljoen (Lister Hospital, Stevenage).USA: James Andersen (Meridien Research – Lakeland, Lakeland, FL); Vivek Awasty (Awasty Research Network, LLC, Marion, IN); Carlos Bayron (Interventional Cardiac Consultants, Trinity, FL); William Bestermann (Holston Medical Group, Kingsport, TN); Eric Bolster (Palmetto Clinical Research, Summerville, SC); Emil deGoma (University of Pennsylvania, Philadelphia, PA); Fredrick Dunn (Dallas VAMC - VA North Texas Health Care System, Dallas, TX); Daniel Duprez (University of Minnesota, Minneapolis, MN); Marshall Elam (Memphis VA Medical Center, Memphis, TN); Mahfouz El Shahawy (Cardiovascular Center of Sarasota, Sarasota, FL); Robert Faillace (Geisinger Medical Center, Danville, CA); Mason Freeman (Massachusetts General Hospital, Boston, MA); Neil Goyal (New Jersey Physicians, LLC, Clifton, NJ); John Guyton (Duke University Medical Center, Durham, NC); Linda Hemphill (Massachusetts General Hospital, Boston, MA); Cynthia Huffman (Meridien Research, Tampa, FL); Vandana Jain (Radiant Research, Chicago, Chicago, IL); Stephen Kopecky (Mayo Clinic, Rochester, MN); Michael Koren (Jacksonville Center for Clinical Research, Jacksonville, FL); Norman Lepor (Westside Medical Associates of Los Angeles, Beverly Hills, CA); Michael Lesko (Geisinger State College, Port Matilda, PA); MacRae Linton (Vanderbilt University, Nashville, TN); Irving Loh (Westlake Medical Research, Thousand Oaks, CA); Amir Malik (Amir Malik Research, Fort Worth, TX); Vernon Mascarenhas (Geisinger Health System, Wilkes-Barre, PA); Patrick Moriarty (University of Kansas Medical Center, Kansas City, KS); Mim Mulford (Mission Internal Medical Group, Viejo, CA); Derek Muse (Highland Clinical Research, Salt Lake City, UT); Daniel O’Dea (Hudson Valley Heart Center, Poughkeepsie, NY); Emanuel Shaoulian (Pacific Coast Cardiology, Newport Beach, CA); Donald Smith (Mount Sinai School of Medicine, New York, NY); Pamela Stearns (South Florida Research Solutions, Pembroke Pines, FL); Paul Thompson (Hartford Hospital, Hartford, CA); Phillip Toth (Midwest Institute for Clinical Research, Indianapolis, IN); Traci Turner (Metabolic and Atherosclerosis Research Center, Cincinnati, OH); Gil Vardi (St. Louis Heart and Vascular Cardiology, St. Louis, MO); Stephen Voyce (Advanced Cardiology Specialists, Scranton, Scranton, PA); Debra Weinstein (Atlantic Clinical Research Collaborative-Cardiology, Boynton Beach, FL); Robert Weiss (Maine Research Associates, Auburn, AL); Franklin Zieve (McGuire Research Institute, Inc./McGuire VA Medical Center, Richmond, VA).ODYSSEY Steering CommitteeChairman: Henry Ginsberg, MD (Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA). Members: Jennifer G. Robinson, MD, MPH (The University of Iowa, Iowa City, IA, USA); Daniel J. Rader, MD (Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA); Christopher P. Cannon, MD (Harvard Clinical Research Institute, Boston, MA USA); Helen M. Colhoun, MD, MFPHM (Clinical Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK); John J.P. Kastelein, MD (Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands); Michel Farnier, MD (Le Point Médical, Département d’Endocrinologie et de Lipidologie, Dijon, France).Data Monitoring CommitteeDMC Chairman: Anders Olsson, MD (Bromma, Sweden). Members: David Waters, MD (Division of Cardiology, San Francisco General Hospital, San Francisco, CA, USA); Dominique Larrey, MD (H?pital Saint-Eloi Service d'hépato-gastro-entérologie, Montpellier, France); Robert S Rosenson, MD (Director, Cardiometabolic Disorders, Mount Sinai Heart; Professor of Medicine, Mount Sinai School of Medicine, New York, NY, USA); Peter A. Patriarca, MD (Biologics Consulting Group, Inc., Alexandria, VA, USA); Geert Molenberghs, Biostatistician (Center for Statistics Universiteit Hasselt, Diepenbeek, Belgium).Clinical Events Committee (Reviewers), Duke Clinical Research Institute, Durham, NC USAPierluigi Tricoci, CEC Principal Investigator, Cardiology; Kenneth W Mahaffey, CEC Director, Cardiology; Renato D Lopes, Cardiology; Bimal R Shah, Cardiology; Rajendra H Mehta, Cardiology; Matthew T Roe, Cardiology; Zubin Eapen, Cardiology; Luciana Armaganijan, Cardiology; Adriana Bertolami, Cardiology; Sergio Leonardi, Cardiology; Bradley J. Kolls, Neurology; J. Dedrick Jordan, Neurology; Grégory Ducrocq, Cardiology; Etienne Puymirat, Cardiology; Robin Mathews, Cardiology.Independent PhysiciansIndependent physicians monitoring two consecutive LDL<25 mg/dL: Karen Alexander, and Chiara Melloni (Duke Clinical Research Institute, Durham, NC USA).Supplemental Text 2. MethodsCardiovascular risk evaluationModerate cardiovascular risk was defined as a 10-year fatal cardiovascular disease (CVD) risk Systematic Coronary Risk Evaluation (SCORE) of ≥1% and <5%.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWluZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 1,2 High cardiovascular risk was defined as the presence of at least one of the following: 10-year fatal CVD risk SCORE ≥5%; moderate chronic kidney disease (estimated glomerular filtration rate 30 to <60 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease ADDIN EN.CITE <EndNote><Cite><Author>KDIGO</Author><Year>2012</Year><RecNum>59</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="vvx2vev90vx5z3evrxh5et29fv5fwfxvdxfw">59</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>KDIGO,</author></authors></contributors><titles><title>CKD evaluation and management. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease</title></titles><number>27 July, 2014</number><dates><year>2012</year></dates><urls><related-urls><url> equation); type 1 or type 2 diabetes mellitus without target organ damage; or familial hypercholesterolemia. Very high cardiovascular risk was defined as the presence of one or more of the following: documented history of coronary heart disease, ischemic stroke, peripheral artery disease, transient ischemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis or renal artery stent procedure; or type 1 or type 2 diabetes mellitus with target organ damage. Patients at moderate or high cardiovascular risk were eligible if they had a calculated serum low-density lipoprotein cholesterol (LDL-C) concentration ≥100 mg/dL (2.6 mmol/L) at screening; those at very high risk were eligible if they had a calculated serum LDL-C ≥70 mg/dL (1.8 mmol/L). ADDIN EN.CITE <EndNote><Cite><Author>Moriarty</Author><Year>2014</Year><RecNum>24</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="vvx2vev90vx5z3evrxh5et29fv5fwfxvdxfw">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moriarty, P. M.</author><author>Jacobson, T. A.</author><author>Bruckert, E.</author><author>Thompson, P. D.</author><author>Guyton, J. R.</author><author>Baccara-Dinet, M. T.</author><author>Gipe, D.</author></authors></contributors><auth-address>Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA. Electronic address: PMORIART@kumc.edu.&#xD;Emory University, Atlanta, Georgia, USA.&#xD;Hopital de la Pitie-Salpetriere, Paris, France.&#xD;Hartford Hospital, Hartford, Connecticut, USA.&#xD;Duke University Medical Center, Durham, North Carolina, USA.&#xD;Sanofi, Montpellier, France.&#xD;Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.</auth-address><titles><title>Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial</title><secondary-title>J Clin Lipidol</secondary-title><alt-title>Journal of clinical lipidology</alt-title></titles><periodical><full-title>J Clin Lipidol</full-title><abbr-1>Journal of clinical lipidology</abbr-1></periodical><alt-periodical><full-title>J Clin Lipidol</full-title><abbr-1>Journal of clinical lipidology</abbr-1></alt-periodical><pages>554-61</pages><volume>8</volume><number>6</number><dates><year>2014</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><isbn>1933-2874 (Print)&#xD;1876-4789 (Linking)</isbn><accession-num>25499937</accession-num><urls><related-urls><url> Diet and use of nonstatin lipid-modifying therapyPatients were asked to adhere to the National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes diet ADDIN EN.CITE <EndNote><Cite><Year>2002</Year><RecNum>25</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="vvx2vev90vx5z3evrxh5et29fv5fwfxvdxfw">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>3143-421</pages><volume>106</volume><number>25</number><edition>2002/12/18</edition><keywords><keyword>Adult</keyword><keyword>Cholesterol/*blood</keyword><keyword>Cholesterol, HDL/blood</keyword><keyword>Cholesterol, LDL/blood</keyword><keyword>Coronary Disease/prevention &amp; control</keyword><keyword>Diet</keyword><keyword>Diet Therapy</keyword><keyword>Disease Management</keyword><keyword>Drug Therapy</keyword><keyword>Female</keyword><keyword>*Health Education</keyword><keyword>Humans</keyword><keyword>Hypercholesterolemia/blood/*diagnosis/ethnology/*therapy</keyword><keyword>Hyperlipidemias/blood/diagnosis/therapy</keyword><keyword>Life Style</keyword><keyword>Male</keyword><keyword>Nutrition Surveys</keyword><keyword>Reference Values</keyword><keyword>Risk Assessment</keyword><keyword>Risk Reduction Behavior</keyword><keyword>Triglycerides/blood</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec 17</date></pub-dates></dates><isbn>1524-4539 (Electronic)</isbn><accession-num>12485966</accession-num><urls><related-urls><url> or equivalent throughout the study. Patients taking bile acid sequestrants, nicotinic acid, fenofibrate, or omega-3 fatty acids before screening were allowed to continue these medications, but treatment with ezetimibe, statins, red yeast rice, and fibrates (other than fenofibrate) had to have been discontinued.Open-label treatment periodIn the open-label treatment phase of the study, the alirocumab dose could be increased from 75 mg to 150 mg every 2 weeks at Week 12 of the open-label extension based on achieved LDL-C concentration and the judgment of the investigator.Efficacy outcome measures: lipid measurementLipids were measured at weeks 0, 4, 8, 12, 16, and 24 of the double-blind period and were analyzed by a central laboratory (Medpace Reference Laboratories; Cincinnati, OH, USA; Leuven, Belgium; Singapore). LDL-C values were calculated using the Friedewald formula. ADDIN EN.CITE <EndNote><Cite><Author>Friedewald</Author><Year>1972</Year><RecNum>26</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="vvx2vev90vx5z3evrxh5et29fv5fwfxvdxfw">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Friedewald, W. T.</author><author>Levy, R. I.</author><author>Fredrickson, D. S.</author></authors></contributors><titles><title>Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge</title><secondary-title>Clin Chem</secondary-title><alt-title>Clinical chemistry</alt-title></titles><periodical><full-title>Clin Chem</full-title><abbr-1>Clinical chemistry</abbr-1></periodical><alt-periodical><full-title>Clin Chem</full-title><abbr-1>Clinical chemistry</abbr-1></alt-periodical><pages>499-502</pages><volume>18</volume><number>6</number><edition>1972/06/01</edition><keywords><keyword>Blood Protein Disorders/blood</keyword><keyword>Cholesterol/*blood</keyword><keyword>Fasting</keyword><keyword>Humans</keyword><keyword>Hyperlipidemias/blood</keyword><keyword>Lipoproteins/*blood</keyword><keyword>Lipoproteins, HDL/blood</keyword><keyword>Lipoproteins, LDL/blood</keyword><keyword>Lipoproteins, VLDL/blood</keyword><keyword>Mathematics</keyword><keyword>Methods</keyword><keyword>Triglycerides/blood</keyword><keyword>Ultracentrifugation</keyword></keywords><dates><year>1972</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0009-9147 (Print)&#xD;0009-9147 (Linking)</isbn><accession-num>4337382</accession-num><work-type>Comparative Study</work-type><urls><related-urls><url> The beta-quantification method was used to measure LDL-C at Weeks 0 and 24.The atorvastatin arm was included for evaluation of adverse events (AEs) and not lipid effects. 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ADDIN EN.CITE.DATA 7-10 As such, these were not pre-specified analyses.?Safety outcome measuresStudy treatments were discontinued in patients who were convinced that previous statin-related muscle symptoms had been replicated and would be prolonged by continuing treatment. These patients underwent an end-of-treatment assessment within 5 days of discontinuing study medication, but remained in the study and attended all subsequent visits and safety assessments. Study treatment was continued in patients in whom muscle symptoms were judged tolerable by the patient. The AE period started when the first dose of study treatment was administered and stopped 70 days after the last injection. AEs commonly associated with statins, classified as of special interest in this statin-intolerant population, included study-defined myositis (i.e. myalgia with creatine kinase elevation between >3 times and ≤10 times the upper limit of normal, with the creatine kinase elevation occurring within 2 weeks of the onset of muscle symptoms) and liver function-related abnormalities (elevated concentrations of alanine aminotransferase). Injection site reactions were also AEs of special interest. Safety endpoints were assessed for alirocumab, ezetimibe, and atorvastatin arms. General safety was assessed as treatment-emergent AEs and blood biochemistry.References ADDIN EN.REFLIST 1.Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.2.Perk J, De Backer G, Gohlke H, et al. 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). Eur Heart J. 2012;33:1635-1701.3.KDIGO. CKD evaluation and management. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 2012; Access date: 27 July, 2014. PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. 2014;8:554-561.5.Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.6.Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.7.Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176:55-61.8.Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-1499.9.Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682-689.10.Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186-1194.Supplemental Table 1. Endpoints in order of hierarchical testingPrimary endpointPercent change from baseline to Week 24 in LDL-C (ITT analysis, using all LDL-C values regardless of whether on- or off-treatment)Key secondary endpoints (all are percent change from baseline to week shown unless stated otherwise)1LDL-C, Week 24 (on-treatment analysis, using all LDL-C values during the on-treatment window)2LDL-C, Week 12 (ITT)3LDL-C, Week 12 (on-treatment)4Apo B, Week 24 (ITT)5Apo B, Week 24 (on-treatment)6Non-HDL-C, Week 24 (ITT)7Non-HDL-C, Week 24 (on-treatment)8Total cholesterol, Week 24 (ITT)9Apo B, Week 12 (ITT)10Non-HDL-C, Week 12 (ITT)11Total cholesterol, Week 12 (ITT)12Proportion of very high-risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) or moderate or high-risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 (ITT)13Proportion of very high-risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) or moderate or high-risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 (on-treatment)14Proportion of patients with LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 (ITT)15Proportion of patients with LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 (on-treatment)16Lp(a), Week 24 (ITT)17HDL-C, Week 24 (ITT)18Fasting triglycerides, Week 24 (ITT)19Apo A-1, Week 24 (ITT)20Lp(a), Week 12 (ITT)21HDL-C, Week 12 (ITT)22Fasting triglycerides, Week 12 (ITT)23Apo A-1, Week 12 (ITT) Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol; Lp(a); lipoprotein(a).Supplemental Table 2. Patients with skeletal muscle-related AEs during pretreatment single-blind, placebo run-in period* Run-in failures(n = 47)All patients(n = 361)Patients with at least one skeletal-muscle AE during run-in period, n (%) 23 (48.9)30 (8.3)Myalgia9 (19.1)10 (2.8)Muscle spasms7 (14.9)7 (1.9)Pain in extremity3 (6.4)7 (1.9)Musculoskeletal pain1 (2.1)3 (0.8)Musculoskeletal stiffness2 (4.3)2 (0.6)Back pain1 (2.1)1 (0.3)Muscular weakness1 (2.1)1 (0.3)*Identified by the Custom MedDRA (Medical Dictionary for Regulatory Activities) Query by system organ class and preferred term.Supplemental Table 3. History of statin intolerance by randomized treatmentCharacteristicAlirocumab*(n = 126)Ezetimibe?(n = 125)Atorvastatin?(n = 63)Missing data, n221≥2 statin therapies taken in the past, n (%)124 (98.4)123 (98.4)62 (98.4)Muscle symptoms§ (since starting the most recent statin therapy), n (%)124 (98.4)123 (98.4)62 (98.4)Muscle symptoms§ (compared to before starting statin therapy), n (%) New104 (82.5)102 (81.6)50 (79.4) Exacerbated6 (4.8)7 (5.6)5 (7.9)The same14 (11.1)14 (11.2)7 (11.1)Muscle symptoms, n (%)Constant93 (73.8)91 (78.2)48 (76.2)Intermittent31 (24.6)32 (25.6)14 (22.2)Bilateral115 (91.3)108 (86.4)60 (95.2)LDL-C, low-density lipoprotein cholesterol; Q2W, every 2 weeks; SC, subcutaneous.*Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at Week 12 depending on Week 8 LDL-C values. ?10 mg/day oral ezetimibe. ?20 mg/day oral atorvastatin (statin-re-challenge arm). §Any of the following: muscle discomfort, aches, heaviness, stiffness, cramps, or weakness.Supplemental Table 4. Treatment-emergent AEs* occurring in ≥2% of patients in any group (safety population) at 24 weeksAE category, n (%)Alirocumab?(n = 126)Ezetimibe?(n = 124)Atorvastatin§(n = 63)Myalgia31 (24.6)29 (23.4)17 (27.0)Nasopharyngitis8 (6.3)10 (8.1)2 (3.2)Upper respiratory tract infection7 (5.6)5 (4.0)2 (3.2)Arthralgia7 (5.6)9 (7.3)5 (7.9)Sinusitis6 (4.8)4 (3.2)1 (1.6)Headache6 (4.8)6 (4.8)4 (6.3)Vertigo6 (4.8)2 (1.6)1 (1.6)Diarrhea6 (4.8)6 (4.8)2 (3.2)Fatigue6 (4.8)4 (3.2)5 (7.9)Injection-site reaction6 (4.8)6 (4.8)1 (1.6)Bronchitis5 (4.0)5 (4.0)2 (3.2)Insomnia5 (4.0)2 (1.6)1 (1.6)Rash5 (4.0)2 (1.6)1 (1.6)Back pain5 (4.0)7 (5.6)5 (7.9)Muscle spasms5 (4.0)9 (7.3)7 (11.1)Osteoarthritis5 (4.0)2 (1.6)1 (1.6)Pain in extremity5 (4.0)4 (3.2)0Cough4 (3.2)2 (1.6)0Fall4 (3.2)2 (1.6)1 (1.6)Hypertension4 (3.2)4 (3.2)0Ligament sprain4 (3.2)1 (0.8)0Paresthesia4 (3.2)04 (6.3)Palpitations4 (3.2)2 (1.6)0Pharyngitis4 (3.2)00Urinary tract infection4 (3.2)3 (2.4)2 (3.2)Vomiting3 (2.4)1 (0.8)4 (6.3)Abdominal distension3 (2.4)2 (1.6)0Constipation3 (2.4)5 (4.0)0Gastroesophageal reflux disease3 (2.4)1 (0.8)1 (1.6)Hypoesthesia3 (2.4)1 (0.8)0Muscle strain3 (2.4)02 (3.2)Non-cardiac chest pain3 (2.4)4 (3.2)2 (3.2)Pyrexia3 (2.4)2 (1.6)0Acute sinusitis2 (1.6)3 (2.4)1 (1.6)Asthenia2 (1.6)4 (3.2)0Dizziness2 (1.6)3 (2.4)1 (1.6)Dyspnea2 (1.6)4 (3.2)0Musculoskeletal discomfort2 (1.6)3 (2.4)0Musculoskeletal pain2 (1.6)02 (3.2)Anxiety1 (0.8)3 (2.4)0Contusion1 (0.8)1 (0.8)2 (3.2)Coronary artery disease1 (0.8)02 (3.2)Muscular weakness1 (0.8)2 (1.6)4 (6.3)Nausea1 (0.8)1 (0.8)2 (3.2)Pneumonia1 (0.8)02 (3.2)Tendonitis1 (0.8)1 (0.8)2 (3.2)Chest discomfort06 (4.8)0Foot fracture002 (3.2)Herpes simplex002 (3.2)Herpes zoster01 (0.8)2 (3.2)Intervertebral disc degeneration002 (3.2)Edema peripheral01 (0.8)2 (3.2)Oral herpes002 (3.2)AE, adverse event; LDL-C, low-density lipoprotein cholesterol; Q2W, every 2 weeks; SC, subcutaneous.*Treatment-emergent AEs are AEs that developed, worsened, or became serious during the AE period (defined as the time from the first dose of double-blind study treatment to the last injection plus 70 days [10 weeks], as residual effect of alirocumab was expected until 10 weeks after last injection). AEs are sorted by decreasing frequency in alirocumab group.?Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at Week 12 depending on Week 8 LDL-C values.?10 mg/day oral ezetimibe.§20 mg/day oral atorvastatin (statin-re-challenge arm).Supplemental Table 5. Overview of treatment-related AEs for open-label treatment period (from first to last injection of study treatment + 70 days) (up to 196 weeks)ODYSSEY ALTERNATIVEDouble-blind treatment periodOpen-label treatment period (ongoing)Alirocumab* (n = 126)Ezetimibe? (n = 124)Atorvastatin? (n = 63)Alirocumab*(n = 281)Mean (SD) duration of treatment (weeks)21.5 (5.9)19.8 (7.3)19.4 (7.8)41.2 (11.3)Adverse event, %§82.580.685.779.0Adverse event leading to discontinuation, %18.325.025.44.6Any skeletal-muscle related AE, %§32.541.146.024.2Skeletal-muscle related AE§ leading to discontinuation, %15.920.222.22.1AE, adverse event; LDL-C, low-density lipoprotein cholesterol; Q2W, every 2 weeks; SD, standard deviation. *Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at Week 12 depending on Week 8 LDL-C values.?10 mg/day oral ezetimibe.?20 mg/day oral atorvastatin (statin-re-challenge arm).§Predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.Post database lock for the ALTERNATIVE study, 20 patients in the open-label extension provided, in retrospect, information about 26 treatment-emergent AEs that they had experienced but not reported during the double-blind period.?None of these events led to treatment discontinuation. Given that these events have been reported at a considerable time (average 1 year, range 305 to 569 days) after the actual event date and there is minimal documentation about the events, we consider their reliability to be limited.Supplemental Figure 1. Percent change from baseline to Week 24 in LDL-C: subgroup analyses (ITT analysis). BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; HDL-C, high-density lipoprotein cholesterol; ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; LMT, lipid modifying therapy; LS, least squares; MI, myocardial infarction; TG, triglyceride. ................
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