Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX TABLE OF CONTENTS Trial Committees and Investigators PAGE 2 TABLE S1: Efficacy Outcomes: Percent Changes (Arithmetic Means) From Baseline to Week 8 in Lipid Parameters (mitt Population). PAGE 3 TABLE S2: Efficacy outcomes: absolute changes from baseline to week 8 in lipid parameters (mitt population) PAGE 3 Table S3 Efficacy Outcomes: Absolute Changes [Arithmetic Means] (mg/dl) From Baseline to Week 8 in Lipid Parameters (mitt Population). PAGE 4 TABLE S4: Fasting Plasma Glucose and Hemoglobin A1C Descriptive statistics by time point during efficacy period mitt Population PAGE 5 TABLE S5: Number of subjects (%) with at least one injection site reaction and types of reactions safety population PAGE 6 TABLE S6: SAR antibody status and titer at baseline and week 8 antibody population PAGE 6 FIGURE S1 Subject Disposition. PAGE 7 FIGURE S2: Changes in PCSK9 PK population - Panel A total PCSK9 levels, Panel B free PCSK9 levels PAGE 8 1

3 Trial Committees and Investigators Data Monitoring Committee: Anders Olsson, M.D.; David Waters, M.D.; Dominique Larrey, M.D.; Robert S Rosenson, M.D.; and Geert Molenberghs, PStat. Herbert Thijs, Ph.D., Centre for Statistics, Universiteit Hasselt, Belgium, provided statistical assistance for the DMC. Study Investigators, by Site: William Abraham, Radiant Research Tucson; Patricia Buchanan, Willamette Valley Clinical Studies; Rene Casanova, In Vivo Clinical Research, Inc.; Harry Collins, Anderson and Collins Clinical Research, Inc.; Michael Davidson, Radiant Research Chicago; Matthew Davis, Rochester Clinical Research, Inc.; Mildred Farmer, Meridien Research Brooksville; John Homan, John Homan, M.D.; Eric Klein, Capital Clinical Research Center; Andrew Lewin, National Research Institute; Roger Miller, Jacksonville Impotence Treatment Center; Abel Murillo, Elite Research Institute; R. Zorba Paster, Dean Medical Center; Jeffrey Rosen, Clinical Research of South Florida; Eli Roth, Sterling Research Group, Ltd. Auburn; Gerald Shockey, Clinical Research Advantage/Desert Clinical Research; Evan Stein, Metabolic and Atherosclerosis Research Center; Ronald Surowitz, Health Awareness, Inc.; and Glen Sussman, ICCT Research International, Inc.; James McKenney, National Clinical Research - Richmond, Inc. 2

4 Supplementary Table S1 Efficacy Outcomes: Percent Changes (Arithmetic Means) From Baseline to Week 8 in Lipid Parameters (mitt Population). Arithmetic Mean ± SD % change from baseline to week 8 LDL-C 17.7 ± ± ± 14.4 <0.001 <0.001 NS HDL-C 3.4 ± ± ± NS NS ApoA1 4.6 ± ± ± 10.4 NS NS NS Supplement Table S2 Efficacy Outcomes: Absolute Changes (mg/dl) From Baseline to Week 8 in Lipid Parameters (mitt Population). Mean LS ± SE absolute change from baseline to week 8 LDL-C ± ± ± 4.1 <0.001 <0.001 NS HDL-C -2.2 ± ± ± NS NS ApoA1-9.6 ± ± ± 3.5 NS 0.05 NS Median (Q1:Q3) absolute change from baseline to week 8 TG -8.5 (-36.0:10.0) -7.0 (-30.0:14.5) (-55.5:-3.5) 0.02 NS 0.02 Lp(a) -1.0 (-5.0:2.0) -8.5 (-19.0:-3.0) -9.0 (-22.0:-2.0) <0.001 <0.001 NS TC (-49.5:-5.5) (-93.5:-67.0) (-107.5:- 76.5) <0.001 <0.001 NS Non- HDL-C (-45.5:-5.0) (-93.5:-69.0) (-106.5:- 78.0) <0.001 < ApoB (-24.0:-3.0) (-65.0:-44.5) (-65.0:-52.0) <0.001 <0.001 NS 3

5 Supplement Table S3 Efficacy Outcomes: Absolute Changes [Arithmetic Means] (mg/dl) From Baseline to Week 8 in Lipid Parameters (mitt Population). Arithmetic Mean ± SD absolute change from baseline to week 8 LDL-C ± ± ± 15.7 <0.001 <0.001 NS HDL-C -2.1 ± ± ± NS NS ApoA1-8.4 ± ± ± 17.9 NS 0.05 NS 4

6 Supplement Table S4 Fasting Plasma Glucose and Hemoglobin A1C Descriptive statistics by time point during efficacy period mitt Population SAR 150 mg Q2W + A10 A80 Hemoglobin A1C(%) Baseline Number Mean (SD) 6.03 (0.77) 5.98 (0.67) 5.70 (0.40) Week 8 including LOCF Number Mean (SD) 6.07 (0.73) 5.89 (0.63) 5.71 (0.56) Change from baseline Number Mean (SD) 0.04 (0.31) (0.24) 0.00 (0.26) Fasting Plasma Glucose (mg/dl) Baseline Number Mean (SD) (26.8) (25.4) 97.3 (15.5) Week 8 including LOCF Number Mean (SD) (30.4) (19.6) (16.2) Change from baseline Number Mean (SD) 3.8 (15.4) -5.7 (13.4) 5.9 (11.1) Note: the efficacy period is defined as the time from the first investigational product (IP) injection up to 21 days after the last IP injection. Note: For each parameter, only patients who had that parameter assessed post-baseline are included. mitt, modified intention to treat; PBO, placebo; SAR, REGN727/SAR236553; Q2W, every 2 weeks; A80, atorvastatin 80 mg; A10, atorvastatin 10 mg; LOCF, last observation carried forward; SD, standard deviation. 5

7 Supplement Table S5: Number of subjects (%) with at least one injection site reactions and type of reactions safety population (N=31) (N=31) (N=30) Total # (%) injection site reactions 2 (6.5) 0 1 (3.3%) Injection site erythema 1 (3.2) 0 1 (3.3%) Injection site induration (3.3%) Injection site pruritus 2 (6.5) 0 1 (3.3%) Injection site swelling (3.3%) PBO, placebo; SAR, REGN727/SAR236553; A80, atorvastatin 80 mg; A10, atorvastatin 10 mg. Supplement Table S6: SAR antibody status and titer at baseline and week 8 antibody population (N= 30) (N=31) (N=30) Baseline Positive status 1/30 1/31 2/30 Titre : median (min :max) 120 (120 :120) 480 (480 :480) 30 (30 :30) Week 8 Positive status 0/24 3/28 4/28 Titre : median (min :max) N/A 30 (30 :60) 90 (30 :120) PBO, placebo; SAR, REGN727/SAR236553; A80, atorvastatin 80 mg; A10, atorvastatin 10 mg. 6

8 FIGURE S1: Subject Disposition. *All patients randomized received at least one dose of study medication. prerandomization AE. SAR, REGN727/SAR236553; A80, atorvastatin 80 mg; A10, atorvastatin 10 mg; PBO, placebo; AE = adverse event; mitt = modified intent-to-treat 7

9 Supplemental Figure S2: Changes in PCSK9 PK population - Panel A total PCSK9 levels, Panel B free PCSK9 levels Panel A 8

10 Panel B 9