BMD E max BMD (%) Emax Emax Effect = E γ E max Css, B 0 + [ γ γ EC50 + Css, B ] E0 BMD Emax Css,B EC50 Emax 50γ
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- ちえこ しばもと
- 5 years ago
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1 BMD () mg BMD BMD BMD BMD BMD bval CATL BMI EST BMD Population Pharmacokinetic and Pharmacodynamic Analyses of Studies 7, 8, 9 Final Report appendix15.b Table 2 Θ Θ Θ Θ BMD = TVSLP (TIME [hr] /720) TVSLP = TVSLP4 - Θ9 CATL/398.8 TVSLP1: TVSLP2 = TVSLP1 (bval/0.95) Θ 8 TVSLP3 = TVSLP2 (EST/25.1) Θ10 TVSLP4 = TVSLP3 (BMI/26.8) Θ11 BMD BMD 38 Predicted Spine BMD Observed Spine BMD 38 BMD (g/cm 2 ) Population Pharmacokinetic and Pharmacodynamic Analyses of Studies 7, 8, 9 Final Report
2 BMD E max BMD (%) Emax Emax Effect = E γ E max Css, B 0 + [ γ γ EC50 + Css, B ] E0 BMD Emax Css,B EC50 Emax 50γ BMD E max Population Pharmacokinetic and Pharmacodynamic Analyses of Studies 7, 8, 9 Final Report Appendix 15.c Table 1. Θ9 MOF MOF Θ8 (EC50 50) %SEE % % % BMD = TVSLP x ( [hr]/720) TVSLP = EFCT Emax EFCT = (Css,B Θ 9 ) / [(Θ8 Θ 9 ) + (Css,B Θ 9 )] Emax 2 EC ng/ml Emax BMD Emax
3 Spine BMD - RCss EMAX Model with Progression 1.2 Fraction of Maximal Increase in Spine BMD Css Range for 30 mg Ralox HCl Css Range for 60 mg Ralox HCl Css Range for 150 mg Ralox HCl Predicted Response Raloxifene Steady- State Concentration BMD Population Pharmacokinetic and Pharmacodynamic Analyses of Studies 7, 8, 9, Final Report Appendix 15.c 1. 30mg BMD 95 60mg mg 100 BMD BMD 60mg/ 1 60mg 207
4 mg mg 120mg 24 / mg BMD 60mg 0.625mg mg 0.625mg BMD L1 L4 T-1 SD 3SD mg/ 1500mg/
5 5 2 6 D mg 60mg 0.625mg 0.625mg 60mg 0.625mg 60mg 0.625mg mg BMD 24 BMD 0.625mg I C 209
6 : mg 0.625mg 90 / / / BMD BMD IGF I/II
7 90 12 CSR 3.9. Visit ( ) ,,,,,,, ( ) ( ) PT PTT () 12 CSR
8 mg RLX mg CE RLX060 CE % RLX060 CE N=51 RLX060 N=25 CE625 N=26 N=1 N=7 N=24 N= CSR CSR 5.2. RLX060 N=25 CE625 N=26 p- 24 (96.0%) 19 (73.1%) (4.0%) 7 (26.9%) (4.0%) 6 (23.1%) (0.0%) 1 (3.8%) --- 5% RLX060 3 CE RLX060 4 CE
9 CSR RLX060 CE625 N=25 N=26 p- 25 (100) 26 (100) --- : ( ) ± ( ) (5.88) (5.72) 0.122b : (cm) ± ( ) (5.71) (7.04) 0.398b : (kg) ± ( ) (9.09) (13.41) 0.354b 19 (76.0) 24 (92.3) 0.109a 6 (24.0) 2 (7.7) (76.0) 20 (76.9) 0.938a 6 (24.0) 6 (23.1) ± ( ) (8.62) (8.44) 0.165b 19 (76.0) 14 (53.8) 0.098a 6 (24.0) 12 (46.2) 3 (50.0) 8 (66.7) 0.494a 3 (50.0) 4 (33.3) % a χ2 b RLX CE % CE625 / t p=0.157 p=0.156 RLX060 t p CSR % CE625 t p p=0.378 CSR
10 CSR 6.9. CE625 / t p t p / p=0.192/ p=0.864/ p=0.622 p=0.309/ p=0.179 p=0.171 CSR CE625 RLX060 CE625 / / / RLX060 CE625 / / p p p p CSR p / p 0.40 p 0.64 p 0.47 p 0.39 CSR
11 ( ) CSR Appendix 12b. RLX060 CE625 p a / (%) n=11 n= (p b) (0.885) (0.927) / (mm2/mm3) n=11 n= (p b) (0.685) (0.157) (mm) n=11 n= (p b) 8.02 (0.559) (0.258) (micron) n=11 n= (p b) (0.916) (0.370) (micron) n=10 n= (p b) 2.19 (0.090) 2.36 (0.308) (%) n=11 n= (p b) (0.772) (0.343) (%) n=11 n= (p b) (0.979) (0.503) / ( /mm2) n=11 n= (p b) (0.146) (0.095) / (%/ ) n=11 n= (p b) (0.686) (0.036) / (%/ ) n=11 n= (p b) (0.672) (0.043) (/ ) n=10 n= (p b) (0.580) (0.027) (micron/ ) n=11 n= (p b) (0.807) (0.039) ( ) n=10 n= (p b) 0.03 (0.556) 0.17 (0.063) % a b 1 t 215
12 BMD L1-L4 Ward BMD 94 RLX060 BMD CE625 BMD RLX060 CE625 RLX060 CE Ward BMD RLX060 CE BMD 12 CSR RLX060 CE625 p a (L-1 L-4) (g/cm2) n=24 n= (p b) (0.040) ( 0.001) (p b) (0.042) ( 0.001) (g/cm2) n=24 n= (p b) (0.006) (0.128) (p b) (0.004) (0.132) (g/cm2) n=24 n= (p b) ( 0.001) (0.027) (p b) ( 0.001) (0.054) Ward (g/cm2) n=24 n= (p b) (0.010) (0.225) (p b) (0.005) (0.268) (g/cm2) n=24 n= (p b) (0.002) ( 0.001) (p b) (0.002) ( 0.001) % a b 1 t 216
13 I C TICF / / / 41 RLX060 CE625 RLX060 CE625 RLX060 /CE625 I C / / / I C / RLX060 CE CSR ( ) RLX060 CE625 p a (µg/l) n=25 n= (p b) (0.050) ( 0.001) (µg/l) n=25 n= (p b) (0.002) ( 0.001) I C / (µg/mmol) n=25 n= (p b) (0.136) ( 0.001) / (nmol/mmol) n=19 n= (p b) (0.018) (0.050) / (µmol/mmol) n=25 n= (p b) (0.078) (0.031) % a b 1 t Mean Osteocalcin Mean Change from From Baseline (Mean with With One Standard Error) Weeks on Study Drug CE625 RLX060 Bone Specific Alkaline Phosphatase Mean Change from From Baseline (Mean with With One Standard Error) p 0.05 LSD Mean CSR Weeks on Study Drug CE625 RLX
14 RLX CE CSR 7.1. RLX060 CE625 N=25 N=26 p a 1 (4.0%) 4 (15.4%) (0.0%) 2 (7.7%) (0.0%) 1 (3.8%) (4.0%) 1 (3.8%) --- 5% a RLX CE CE RLX CE RLX060 CE625 CE CE CSR 7.4. RLX060 CE625 N=25 N=26 p a 15 (60.0%) 24 (92.3%) (24.0%) 9 (34.6%) (12.0%) 2 (7.7%) (16.0%) 4 (15.4%) (4.0%) 0 (0.0%) (4.0%) 0 (0.0%) (12.0%) 1 (3.8%) (16.0%) 3 (11.5%) (4.0%) 0 (0.0%) (0.0%) 1 (3.8%) (12.0%) 16 (61.5%) < % a 2 218
15 RLX060 p=0.007 ALT SGPT (p=0.021) -GTP GGT (p=0.026) p<0.001p=0.003p<0.001 CE625 p<0.001 AST SGOT (p=0.028) ALT SGPT (p=0.029) -GTP GGT (p=0.001) p<0.001p=0.031 p<0.001p<0.001csr appendix12.a RLX060 CE625 RLX060 p=0.144 CE625 p=0.106 CSR appendix12.a RLX060 p=0.001 p=0.038 MCH (p=0.014 p=0.002 p=0.027 CE625 p<0.001 p<0.001 p<0.001 CE625 3 CSR % CSR CSR Appendix 12.a RLX060 CE625 Overall N=25 N=25 p a mmol/l µmol/l mmol/l µmol/l U/L b b AST (SGOT) U/L b ALT (SGPT) U/L b b GTP (GGT) U/L b b U/L b b µmol/l b g/l b -3.4 b g/l b -3.5 b % a b p 0.05 Wilcoxon 219
16 99 12 CSR CSR Appendix 12.a RLX060 CE625 Overall N=23 N=23 p a mmol/l b b actual count b b /L b fl fmol b mmol/l /L /L /L 0.170b /L /L 0.025b /L /L /L % a b p 0.05 Wilcoxon RLX060 p=0.718, CE625 p=0.544 RLX060 p=0.452, CE625 p=0.686 RLX060 p=0.746, CE625 p=0.245 p=0.963 p=0.261 p=0.428 CSR 7.7. RLX mmHg p CE625 p=0.087 CSR RLX060 CE
17 BMD RLX060 CE625 CE625 CE625 RLX060 I C / CE625 RLX060 // RLX060 CE Placebo 24 RLX RLX Placebo 25 RLX RLX Placebo 24 RLX RLX Pooled RLX Placebo / / Pooled RLX / RLX060 RLX
18 CSR Overall ( ) Placebo RLX060 RLX120 Pooled RLX p b n=25 n=22 n=18 n=40 Pooled RLX p c / (%) (p a) (0.764) (0.258) (0.142) (0.052) (mm) (p a) 7.42 (0.323) 3.30 (0.604) 6.99 (0.167) 6.09 (0.221) (micron) (p a) 0.75 (0.027) 1.03 (0.033) 0.34 (0.899) 0.71 (0.111) (micron) (p a) (0.179) (0.637) (0.702) (0.423) n=25 n=22 n=18 n=40 (%) (p a) 1.12 (0.154) 0.48 (0.672) 0.01 (0.610) 0.24 (0.459) / ( /mm2) (p a) 0.17 (0.049) 0.08 (0.649) (0.899) 0.03 (0.625) (%) (p a) (0.005) (0.012) (0.012) (<0.001) / (%) (p a) (0.099) (0.539) (0.108) (0.108)
19 CSR ( ) Placebo RLX060 RLX120 Pooled RLX n=25 n=21 n=17 n=38 / Overall p- b Pooled RLX p- c (p- a) (0.297) (0.072) (0.159) (0.022) 0.762d n=24 n=20 n=12 n=32 / (p- a) (0.111) (0.388) (0.077) (0.053) / (p- a) (0.081) (0.036) (0.021) (0.001) / ) (p- a) (0.555) (0.058) (0.077) (0.006) (micron/ ) (p- a) (0.195) (0.022) (0.622) (0.032) ( ) (p- a) 0.85 (0.825) 5.11 (0.189) (0.677) 1.55 (0.596) % a b 3 (LSD) Placebo RLX060 RLX120 c Pooled RLX Placebo d p
20 mg FDA mg RLX060 1 Placebo 1 54 RLX Placebo Placebo RLX RLX 13 Placebo 27 Guidelines for counseling postmenopausal women about preventive hormone therapy, Ann Intern Med, 117, ,
21 JAMA Placebo Pooled RLX 95% NA ( ) / NA ( ) / NA ( ) ( ) 3 2 NA 42 Placebo RLX RLX Percentage of Randomized Patients Placebo Raloxifene P < p < Years Since Randomization Placebo Pooled RLX log-rank p< JAMA Placebo Placebo vs. Pooled RLX p=
22 Placebo 60mg RLX mg RLX120 1 Placebo 1 RLX060 RLX120 0 n (100.0%) (98.6%) CSR Placebo N = 97 RLX060 N = 92 RLX120 N = 95 n n (0.0%) (100.0%) (0.0%) (98.7%) (1.4%) (100.0%) (0.0%) (100.0%) 1 (1.3%) 0 (0.0%) %/n 5% a Fisher p
23 mg 0.625mg/ 2.5mg/ mg 150mg mg Grade Grade mg 2 120mg 1 Guidelines for counseling postmenopausal women about preventive hormone therapy, Ann Intern Med, 117, ,
24 mg 1 1 HRT 150mg 0.625mg/ 2.5mg/ mg 0.625mg/ 2.5mg/ mm 4.3mm Grade2 Grade Grade mg 0.625mg pmol/L 20pg/mL Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S, Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial, Lancet, 343(8909), ,
25 4 D 1000IU/ mg 150mg 0.625mg 0.625mg 2.5mg 2.5mg 150mg 0.625mg 2.5mg 150mg 0.625mg 2.5mg Grade Blaustein Kurman RJ, editor, Blaustein s Pathology of the Female Genital Tract, 4th ed, New York, Springer-Verlag, ,
26 4 / Grade 4 Grade0 0 3 Grade1 4 6 Grade Grade TVU TVU Pearson 2 8 Dallenbach-Hellweg G, Poulsen H, Atlas of endometrial histopathology: functional disturbances, Philadelphia (PA), W.B. Saunders Co, 66 76, 1985 Buckley CH, Fox H, Biopsy pathology of the endometrium, New York, Raven Press Ltd, 24 50, Sternberg SS, Histology for pathologists: uterus and fallopian tubes, Raven Press, , Gompel C, Silverberg S, Pathology in gynecology and obstetrics: cyclical variations of the endometrium, 4 th ed, Philadelphia (PA), J.B.Lippincott Company, and , Heller DS, The endometrium: a clinicopathologic approach, Histopathology of the endometrium - an overview, NewYork, Igaku-Shoin Medical Publishers Inc, 43 90, Sternberg SS, Antonioli DA et al, Diagnostic surgical pathology, 2 nd Edition, The uterine corpus, New York, Raven Press, , Glant M, Eisenhut C, Boss S, Draper M, A scale for assessing postmenopausal endometrial proliferation in response to potential or known selective estrogen receptor modulators [abstract], Am J Clin Path, 104, , Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW, Effects of raloxifene hydrochloride on the endometrium of postmenopausal women, Am J Obstet Gynecol, 177(6), ,
27 Cochran-Mantel-Haenszel CSR 3.9. ( ) Visit # ,, ECG, X, (FSH,, T 4, T 3RU, TSH),, a U-Titer b a Visit4 b hypercard 13 CSR
28 mg RLX HRT N=136 RLX150 N=67 HRT N=69 N=20 N=28 N=47 N= CSR CSR 5.2. RLX150 N=67 HRT N=69 p 47 (70.1%) 41 (59.4%) ( %) 28 ( %) (19.4%) 15 (21.7%) ( ) 0 (0.0%) 1 (1.4%) (1.5%) 1 (1.4%) (4.5%) 4 (5.8%) (3.0%) 6 (8.7%) (1.5%) 1 (1.4%) --- 5% χ RLX150 2 HRT RLX150 1 HRT
29 CSR 6.1. RLX150 HRT N=67 N=69 p : 0.405a 65 (97.0%) 67 (97.1%) / 0 (0.0%) 1 (1.4%) 0 (0.0%) 1 (1.4%) 1 (1.5%) 0 (0.0%) 1 (1.5%) 0 (0.0%) : ( ) ± ( ) (5.08) (5.01) b : (cm) ± ( ) (5.72) (5.53) b : (kg) ± ( ) (12.56) (12.64) b BMI: (kg/m2) ± ( ) (4.61) (4.60) b ± ( ) 5.75 (4.22) 5.94 (4.65) b C (mm) n ± ( ) 3.46 (2.51) 3.18 (2.13) b (ml) n ± ( ) (22.48) (19.59) b n ± ( ) 0.75 (1.44) 1.32 (2.58) b 5% a 2 b 2 t c RLX HRT
30 CSR RLX150 n=54 1 HRT n=47 12 (22.2%) 10 (21.3%) 15 (27.8%) 10 (21.3%) 5.6% 0.0% 21 (38.9%) 21 (44.7%) 14 (25.9%) 5 (10.6%) -13.0% -34.0% 0 (0.0%) 0 (0.0%) 1 (1.9%) 8 (17.0%) 1.9% 17.0% 18 (33.3%) 13 (27.7%) 18 (33.3%) 9 (19.1%) 0.0% -8.5% 0 (0.0%) 0 (0.0%) 3 (5.6%) 4 (8.5%) 5.6% 8.5% 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0.0% 2.1% 2 2 (3.7%) 3 (6.4%) 3 (5.6%) 9 (19.1%) 1.9% 12.8% 3 1 (1.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) -1.9% 0.0% 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.1%) 0.0% 2.1% CSR RLX150 n=54 HRT n=47 p a (94.4%) 44 (93.6%) 2 (3.7%) 3 (6.4%) 1 (1.9%) 0 (0.0%) / b 0 (0.0%) 0 (0.0%) (94.4%) 37 (78.7%) 3 (5.6%) 9 (19.2%) 0 (0.0%) 1 (2.1%) / b 0 (0.0%) 0 (0.0%) 5% a χ2 b Hyperplasia 234
31 Grade Inadequate Tissue for Diagnosis 74 RLX HRT 37 Grade Grade RLX t p CSR HRT t p CSR HRT 108 Grade 13 CSR RLX n= HRT n= CSR RLX150 n=37 HRT n=37 Overall p a ± ( ) (1.526) (2.250) ± ( ) (1.906) (3.197)b % a b p t TVU 44 RLX150 HRT HRT 1 t p<0.001 CSR
32 CSR Overall RLX150 HRT p a (mm) n ( ) (2.820) (1.992) ( ) (1.836) (2.204) (ml) n ( ) (22.440) (19.946) ( ) (9.887) b (16.711) < % a b p t Mean Mean Endometrial Thickness (mm) Months on Study Drug HRT CEMPACC RLX150 p 0.05 Mean Mean Uterine Volume (ml) Months on Study Drug HRT CEMPACC RLX CSR RLX HRT CSR 7.1. RLX150 N=67 HRT N=69 p a 2 (3.0%) 7 (10.1%) (3.0%) 4 (5.8%) (0.0%) 2 (2.9%) (0.0%) 1 (1.4%) (0.0%) 1 (1.4%) (0.0%) 1 (1.4%) (0.0%) 1 (1.4%) --- 5% a χ2 236
33 % RLX HRT HRT RLX HRT RLX150 RLX RLX HRT 2 CSR RLX150 2 HRT HRT 43 RLX150 HRT RLX RLX RLX CSR 7.4. RLX150 N=67 HRT N=69 p a 66 (98.5%) 64 (92.8%) (67.2%) 43 (62.3%) (38.8%) 10 (14.5%) (28.4%) 18 (26.1%) (1.5%) 1 (1.4%) (1.5%) 1 (1.4%) (26.9%) 11 (15.9%) (25.4%) 10 (14.5%) (29.9%) 23 (33.3%) (20.9%) 14 (20.3%) (20.9%) 7 (10.1%) (6.0%) 3 (4.3%) (41.8%) 56 (81.2%) < % a χ2 237
34 RLX150 HRT HRT RLX150 1 t RLX150 p=0.105 HRT p=0.189 CSR MCHC RLX150 p=0.014 ph p CSR p=0.961 CSR χ2 p=0.016 CSR HRT RLX % HRT 9.1% 238
35 113 [ 13 CSR Overall RLX150 HRT p c na U/L b na mmol/l b na µmol/l na mmol/l b na mmol/l b b na mmol/l na µmol/l b AST (GOT) na U/L b ALT (GPT) na U/L na U/L b b GTP (GGT) na U/L na µmol/l b b na g/l b b na g/l b b % a 1 b p t c 239
36 CSR Overall RLX150 HRT p c na actual count na mmol/l na /L na mmol/l b na fmol b na fl b 1.436b na /L b na /L b na /L b 0.139b na /L na /L) na /L na /L b % a 1 b p t c 240
37 BMI p=0.121 p=0.250 p=0.601 p=0.421 p=0.010 CSR 7.8. HRT 1 t p<0.001 CSR HRT Grade RLX Grade HRT RLX HRT RLX RLX HRT 1 150mg 5 241
38 mg 150mg mg 150mg 0.625mg mg 150mg 0.625mg pmol/L 20pg/mL BMD L1 L4 T- 2.0 SD2.5SD BMI 18kg/m 2 31kg/m 2 4 5mm D 1000IU/ 6 Woodruff JD, Pickar JH for the Menopause Study Group, Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone, Am J Obstet Gynecol, 170(5), ,
39 mg 60mg 150mg 150mg 60mg 0.625mg 0.625mg 60mg 0.625mg 60mg 150mg 0.625mg mg/ Blaustein WHO 2 Grade 4 Grade0 0 3 Grade1 Kurman RJ, editor, Blaustein s Pathology of the Female Genital Tract, 4th ed, New York, Springer-Verlag, , Glant M, Eisenhut C, Boss S, Draper M, A scale for assessing postmenopausal endometrial proliferation in response to potential or known selective estrogen receptor modulators [abstract], Am J Clin Path, 104, , Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW., Effects of raloxifene hydrochloride on the endometrium of postmenopausal women, Am J Obstet Gynecol, 177(6), ,
40 4 6 Grade Grade SISTVU 3 9 SIS TVU TVU SIS TVU Cochran-Mantel-Haenszel Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S, Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial, Lancet, 343(8909), ,
41 CSR 3.9. Visit ( ) , WHQ TVU TVU & SIS,, (DXA) X a ECG a Visit6 b Women's Health Questionnaire: QOL 14 CSR Placebo mg RLX RLX150 RLX mg CE CE625 CE
42 N=415 Placebo N=109 RLX060 N=101 RLX150 N=105 CE625 N=100 N=29 () N=2 N=28 N=27 N=24 () N=2 N=78 N=73 N=78 N= CSR CSR 5.1. Placebo N=109 RLX060 N=101 RLX150 N=105 CE625 N=100 p 78 (71.6%) 73 (72.3%) 78 (74.3%) 55 (55.0%) (28.4%) 28 (27.7%) 27 (25.7%) 45 (45.0%) (7.3%) 8 (7.9%) 8 (7.6%) 8 (8.0%) a 2 (1.8%) 0 (0.0%) 0 (0.0%) 21 (21.0%) < (7.3%) 6 (5.9%) 4 (3.8%) 1 (1.0%) (2.8%) 7 (6.9%) 6 (5.7%) 2 (2.0%) ( ) 6 (5.5%) 6 (5.9%) 4 (3.8%) 1 (1.0%) (0.0%) 1 (1.0%) 3 (2.9%) 4 (4.0%) (2.8%) 0 (0.0%) 0 (0.0%) 5 (5.0%) (0.0%) 0 (0.0%) 1 (1.0%) 2 (2.0%) (0.9%) 0 (0.0%) 1 (1.0%) 1 (1.0%) --- 5% 2 a Placebo 13 RLX RLX CE Placebo 8 RLX060 6 RLX150 4 CE RLX060 1 RLX150 3 CE CE mg
43 CSR 6.1. Placebo RLX60 RLX150 CE625 N=109 N=101 N=105 N=100 p : 0.200a 3 (2.8%) 1 (1.0%) 6 (5.7%) 5 (5.0%) 99 (90.8%) 97 (96.0%) 92 (87.6%) 90 (90.0%) / 4 (3.7%) 1 (1.0%) 0 (0.0%) 2 (2.0%) 3 (2.8%) 2 (2.0%) 3 (2.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 3 (2.9%) 2 (2.0%) 0 (0.0%) 0 (0.0%) 1 (1.0%) 1 (1.0%) : ( ) ± ( ) (3.54) (3.42) (3.65) (3.43) b : (cm) ± ( ) (6.2) (6.0) (6.6) (6.5) b : (kg) ± ( ) (10.77) (10.07) (10.98) (9.60) b BMI: (kg/m2) ± ( ) (3.45) (3.33) (3.48) (3.32) b ± ( ) 4.56 (1.89) 4.65 (2.01) 4.46 (1.86) 4.39 (1.87) b (mm) n ± ( ) 2.84 (1.59) 2.70 (1.18) 2.78 (1.51) 2.52 (1.05) b (ml) n ± ( ) (26.74) (28.88) (22.06) (26.66) b n ± ( ) 0.10 (0.30) 0.14 (0.57) 0.16 (0.53) 0.01 (0.12) b 5% a 2 b c 247
44 Placebo 94 RLX RLX CE % 5.0mm Placebo CE RLX CE625 2 p<0.001 CSR CE Placebo 7 RLX060 2 RLX150 3 CE Placebo 2 2.1RLX CE Placebo 1 CE Kurman RJ, editor, Blaustein s Pathology of the Female Genital Tract 4th ed New York Springer-Verlag, ,
45 CSR 7.9. Placebo n=94 RLX060 n=84 RLX150 n=92 CE625 n=88 18 (19.1%) 8 (9.5%) 11 (12.0%) 10 (11.4%) 42 (44.7%) 16 (19.0%) 28 (30.4%) 6 (6.8%) 25.5% 9.5% 18.5% -4.5% 33 (35.1%) 39 (46.4%) 43 (46.7%) 35 (39.8%) 35 (37.2%) 24 (28.6%) 22 (23.9%) 3 (3.4%) 2.1% -17.9% -22.8% -36.4% 35 (37.2%) 34 (40.5%) 33 (35.9%) 40 (45.5%) 13 (13.8%) 40 (47.6%) 40 (43.5%) 20 (22.7%) -23.4% 7.1% 7.6% -22.7% 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.1%) 0 (0.0%) 0.0% 0.0% 1.1% 0.0% / 7 (7.4%) 2 (2.4%) 3 (3.3%) 2 (2.3%) 2 (2.1%) 3 (3.6%) 0 (0.0%) 35(39.8%) -5.3% 1.2% -3.3% 37.5% 0 (0.0%) 1 (1.2%) 1 (1.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0.0% -1.2% -1.1% 0.0% 1 (1.1%) 0 (0.0%) 0 (0.0%) 1 (1.1%) 0 (0.0%) 1 (1.2%) 1 (1.1%) 2 (2.3%) -1.1% 1.2% 1.1% 1.1% 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (2.1%) 0 (0.0%) 0 (0.0%) 22 (25.0%)a 2.1% 0.0% 0.0% 25.0% 0 (0.0%) 0 (0.0%) 1 (1.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0.0% 0.0% -1.1% 0.0% a CE
46 Placebo RLX CSR
47 RLX150 CE CSR
48 CSR 7.8. Placebo RLX60 RLX150 CE Grade 223 Placebo 52 RLX RLX CE Grade Grade Grade 2 p= p<0.001 CSR Placebo RLX Grade 2 Placebo vs. RLX060 p=0.815 Placebo vs. RLX150 p=0.262 CE625 p= p=0.784 CE625 1 t p<0.001 RLX Placebo LSD Placebo vs. RLX060 p=0.704 Placebo vs. RLX150 p=0.583 CE625 3 p<0.001 (122 CSR ) 121 Grade 14 CSR Placebo n= RLX n= RLX n= CE n=
49 Placebo n=52 ± ( ) (1.324) ± ( ) (2.199) CSR RLX060 n= (2.203) 0.136b (2.826) 5% a b p 0.05 CE625 LSD c p t d p 0.05 Placebo LSD RLX150 n= (1.358) 0.364b (1.882) CE625 n= (1.117) 6.361cd (4.098) Overall p- a < Placebo 89 RLX RLX CE TVU 123 TVU 46 Placebo RLX 0.3mm RLX Placebo LSD Placebo vs. RLX060 p=0.429 Placebo vs. RLX150 p=0.556 CE625 1 t p<0.001 LSD p<0.001 (CSR ) Placebo RLX RLX Placebo LSD Placebo vs. RLX060 p=0.438 Placebo vs. RLX150 p=0.651 CE625 1 t p<0.001 LSD p<0.001 (CSR CSR Overall Placebo RLX060 RLX150 CE625 p- a (mm) n b 0.111b 5.542cd <0.001 (cm3) n c b bc cd < % a b p 0.05 CE625 LSD c p t d p 0.05 Placebo LSD 253
50 Endometrial Thickness (mm) Mean Change from Baseline (Mean with One Standard Error) Uterine Volume (cc) Mean Change from Baseline (Mean with One Standard Error) Mean Change 3 2 Mean Change Months on Study Drug Months on Study Drug CE625 PLACEBO RLX060 RLX150 CE625 PLACEBO RLX060 RLX150 p 0.05 Placebo LSD CSR Placebo 78 RLX RLX CE SIS 124 SIS 47 RLX060 RLX mm 1 t RLX060 p=0.948 RLX150 p=0.310 p=0.644 RLX Placebo LSD Placebo vs. RLX060 p=0.920 Placebo vs. RLX150 p=0.882placebo vs. RLX060 p=0.617 Placebo vs. RLX150 p=0.737placebo vs. RLX060 p=0.754 Placebo vs. RLX150 p=0.925ce625 1 t p<0.001 LSD p<0.001 (CSR 7.17.~7.19.) 254
51 124 SIS 14 CSR Placebo n=78 RLX060 n=72 RLX150 n=84 CE625 n=76 Overall p- a (mm) b b 2.430cd <0.001 (mm) b 0.093b 2.262cd <0.001 (mm) b 0.071b 4.692cd < % a b p 0.05 CE625 LSD c p t d p 0.05 Placebo LSD SIS(Total) Thickness (mm) Mean Change from Baseline (Mean with One Standard Error) Mean Change Months on Study Drug CE625 PLACEBO RLX060 RLX150 p 0.05 Placebo LSD 47 SIS 14 CSR
52 Placebo RLX060 RLX150 CE625 N=109 N=101 N=105 N=100 p a 4 (3.7%) 4 (4.0%) 5 (4.8%) 4 (4.0%) (1.8%) 2 (2.0%) 3 (2.9%) 4 (4.0%) (0.9%) 1 (1.0%) 0 (0.0%) 0 (0.0%) (0.9%) 1 (1.0%) 0 (0.0%) 1 (1.0%) (0.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) (0.0%) 1 (1.0%) 1 (1.0%) 0 (0.0%) (0.0%) 0 (0.0%) 0 (0.0%) 2 (2.0%) (1.8%) 1 (1.0%) 0 (0.0%) 0 (0.0%) (0.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) (0.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) % a χ Placebo 8 7.3RLX RLX CE CE625 2 CE RLX150 CE625 RLX060 p= CSR Placebo 1 0.9% CE
53 CSR CRT 14.T Placebo RLX060 RLX150 CE625 N=109 N=101 N=105 N=100 p- a 86 (78.9%) 74 (73.3%) 91 (86.7%) 82 (82.0%) (48.6%) 48 (47.5%) 58 (55.2%) 62 (62.0%) (13.8%) 15 (14.9%) 22 (21.0%) 12 (12.0%) (21.1%) 22 (21.8%) 25 (23.8%) 24 (24.0%) (0.0%) 2 (2.0%) 0 (0.0%) 0 (0.0%) (0.9%) 1 (1.0%) 4 (3.8%) 2 (2.0%) (6.4%) 13 (12.9%) 6 (5.7%) 8 (8.0%) (9.2%) 15 (14.9%) 15 (14.3%) 15 (15.0%) (21.1%) 19 (18.8%) 19 (18.1%) 27 (27.0%) (22.9%) 28 (27.7%) 24 (22.9%) 28 (28.0%) (10.1%) 9 (8.9%) 19 (18.1%) 17 (17.0%) (2.8%) 3 (3.0%) 6 (5.7%) 4 (4.0%) (28.4%) 27 (26.7%) 32 (30.5%) 59 (59.0%) < % a Placebo 3 LSD p<0.001 Placebo RLX150 CE625 Placebo vs. RLX150 p=0.010 Placebo vs. CE625 p<0.001 p<0.001 CE625 3 RLX060 p=0.041 p=0.039p<0.001 Placebo RLX150 CE625 Placebo vs. RLX150 p=0.007 Placebo vs. CE625 p=0.027 Placebo 3 Placebo vs. RLX060 p=0.002 Placebo vs. RLX150 p<0.001 Placebo vs. CE625 p<0.001 CE625 RLX060 RLX150 Placebo vs. RLX060 p=0.009 Placebo vs. RLX150 p=0.019 CE625 RLX060 CE625 RLX060 p=0.041 RLX060 1 t p=0.187 Placebo p=0.150 Placebo RLX Placebo vs. RLX060 p=0.029 Placebo vs. RLX150 p=0.003 AST SGOT ALT SGPT CE625 RLX150 AST p=0.024 ALT p= t AST RLX150 p=0.066 CE625 p=0.594 ALT RLX150 p=0.240 CE625 p=0.208 Placebo AST Placebo vs. RLX150 p=0.080 Placebo vs. CE625 p=0.574 ALT Placebo vs. RLX150 p=0.241 Placebo vs. CE625 p=
54 Placebo 3 p<0.001 CE625 Placebo p=0.024 RLX060 RLX150 CE625 RLX060 vs. CE625 p=0.006 RLX150 vs. CE625 p<0.001 Placebo Placebo vs. RLX060 p=0.577 Placebo vs. RLX150 p=0.110 Placebo CE625 RLX150 Placebo vs. RLX150 p=0.045 CE625 vs. RLX150 p=0.013 Placebo RLX150 CE625 Placebo vs. RLX150 p=0.026 Placebo vs. CE625 p=0.006 MCH Placebo CE625 p=0.029 Placebo RLX060 p=0.048 CSR 7.32.~
55 Overall Placebo RLX060 RLX150 CE625 p U/L na bcd bd bd <0.001 U/L na b d mmol/l na b c µmol/l na mmol/l na cd bd bd mmol/l na c cd bd bd <0.001 mmol/l na d µmol/l na AST (SGOT) U/L na c ALT (SGPT) U/L na c GGT U/L na d µmol/l na bd bd bd <0.001 g/l na d bd bd g/l na bcd bcd bd <
56 Overall Placebo RLX060 RLX150 CE625 p e mmol/l na d 1.841cd 2.289cd 0.593bd mmol/l na mmol/l na c d 1.536bcd mmol/l na b d bd bd d % a 1 b p 0.05 Placebo LSD c p 0.05 CE625 LSD d p t e 260
57 Overall Placebo RLX060 RLX150 CE625 p e na acutual count b d na mmol/l d d d na /L d bd bd na mmol/l d d d d na fmol d 0.021bd na fl d 1.682d 2.719d 2.518d na /L na /L na /L b na /L na /L na c /L d d n a /L c d d % a 1 b p 0.05 Placebo LSD c p 0.05 CE625 LSD d p t e 261
58 BMI p=0.790 p=0.631 p=0.573 p=0.433 p=0.164 CSR 7.27.~ mg 150mg 1 CE Placebo 2 2.1RLX RLX150 0 CE RLX CE625 Grade RLX Placebo CE625 TVU TVU TVU CE625 RLX Placebo SIS RLX CE625 RLX Placebo CE625 RLX Placebo RLX Placebo RLX CE625 Placebo Woodruff JD, Pickar JH for the Menopause Study Group, Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone, Am J Obstet Gynecol, 170(5), , PEPI Trial Writing Group, Effects of hormone replacement therapy on endometrial histology in postmenopausal women, JAMA, 275(5), , Ettinger B, Bainton L, Upmalis DH, Citron JT, VanGessel A, Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women, Am J Obstet Gynecol, 176, , Langer RD, Pierce JJ, O'Hanlan KA, et.al., Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease, Postmenopausal Estrogen/Progestin Interventions Trial, N Engl J Med, 337(25), ,
59 Placebo mg RLX mg RLX TVU 1 5.0mm CSR Placebo 0.2% RLX RLX RLX Placebo 1 RLX Placebo CSR Placebo RLX060 RLX120 Overall Pooled RLX n=1999 n=1948 n=2010 n=5957 p a p a ( ) 62 (3.1%) 68 (3.5%) 56 (2.8%) 186 (3.1%) (2.9%) 61 (3.1%) 51 (2.5%) 169 (2.8%) (0.3%) 7 (0.4%) 5 (0.2%) 17 (0.3%) b (Unspecified Disorder) c SEETUS d % a ~9 Fisher b 1 c / RLX120 d SEETUS spurious evaluation of endometrial thickness of undetermined significance 263
60 WHO/Blaustein 130 RLX120 Placebo RLX060 2 p=0.083 p=0.053 CSR Placebo Pooled RLX p CSR RLX CSR 7.20 Placebo n=1999 RLX060 n=1948 RLX120 n=2010 n=5957 Overall p a Pooled RLX p a (PEPI )b % a ~9 Fisher b NormalInsufficient TissueSurface Endometrium Only Inactive/Atrophic Endometrium Placebo 595 RLX RLX mm CSR RLX060Pooled RLX Placebo LSD p=0.006 CSR appendix 47. 0mm Kurman RJ, editor, Blaustein s Pathology of the Female Genital Tract. 4th ed, New York, Springer-Verlag, , Langer RD, Pierce JJ, O Hanlan KA, et al., Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease, N Engl J Med, 337(25), ,
61 CSR Pooled Placebo n=595 RLX060 n=586 RLX120 n=600 Overall p b RLX p (mm) (mm) a p p<0.001 p=0.493 p= p p<0.001 p<0.001 p< (mm) p<0.001 p=0.588 p= % a p 0.05 Placebo LSD b 48 Placebo t p CSR mm 0.27mm RLX mm 1 t p CSR Appendix mm mm RLX120 RLX mm 1 t p CSR Appendix mm 36 RLX060 RLX t 24 RLX060 p=0.106, RLX120 p= RLX060 p=0.493, RLX120 p=0.694 CSR Appendix RLX060 Placebo 0.37mm LSDp CSR RLX120 Placebo 0.36mm p CSR p=0.055 CSR Appendix
62 Endometrial Thickness (mm) Change from Baseline (Mean with One Standard Error) 2 1 Change Months from Randomization PLACEBO RLX060 RLX120 p 0.05 LSD CSR mm 5.0mm Placebo 58 RLX RLX mm 2 p=0.253 CSR CSR p CSR Placebo 1999 RLX RLX Pooled RLX Placebo Placebo RLX060 RLX
63 CSR Placebo RLX060 RLX120 (n=1999) (n=1948) (n=2010) (n=5957) Overall p a Pooled RLX p a b 19 (1.0%) 12 (0.6%) 11 (0.5%) 42 (0.7%) Uterine Atony c 11 (0.6%) 3 (0.2%) 5 (0.2%) 19 (0.3%) Endometrial Carcinoma 4 (0.2%) 4 (0.2%) 1 (0.0%) 9 (0.2%) Uterine Disorderd 1 (0.1%) 1 (0.1%) 2 (0.1%) 4 (0.1%) Vaginal Hemorrhage 1 (0.1%) 2 (0.1%) 1 (0.0%) 4 (0.1%) Endometrial Disordere 0 (0.0%) 2 (0.1%) 1 (0.0%) 3 (0.1%) Neoplasm: Endometrial or Uterine Polypf 1 (0.1%) 2 (0.1%) 0 (0.0%) 3 (0.1%) Uterine Hemorrhage 1 (0.1%) 1 (0.1%) 1 (0.0%) 3 (0.1%) Ruptured Uterusg 1 (0.1%) 1 (0.1%) 0 (0.0%) 2 (0.0%) Uterine Fibroids Enlargedh 0 (0.0%) 0 (0.0%) 1 (0.0%) 1 (0.0%) Uterine Neoplasmi 0 (0.0%) 1 (0.1%) 0 (0.0%) 1 (0.0%) % a Fisher b 1 c d e f g h i 133 RLX Placebo 9 Placebo 4 0.2RLX RLX Placebo RLX Pooled RLX CSR Placebo n=1999 Raloxifene (RLX060: n=1948) (RLX120: n=2010) (Pooled RLX: n=3958) a (95% ) Placebo RLX060 4 (0.2%) 4 (0.2%) 1.03 (0.26, 4.10) Placebo RLX120 4 (0.2%) 1 (0.0%) 0.25 (0.03, 2.22) Placebo Pooled RLX 4 (0.2%) 5 (0.1%) 0.63 (0.17, 2.35) a Placebo RLX060 RLX120 Pooled RLX Placebo RLX RLX Pooled RLX Placebo 267
64 2262 Placebo 759 RLX RLX Placebo RLX RLX CSR p CSR Pooled RLX Placebo 2 p CSR RLX120 1 Weakly proliferative endometrium with focal cystic hyperplasia Placebo 3 0.2RLX RLX Pooled RLX Placebo CSR Placebo RLX060 RLX120 (n=1999) (n=1948) (n=2010) (n=5957) Overall p- a Pooled RLX p a b 181 (9.1%) 202 (10.4%) 190 (9.5%) 573 (9.6%) Uterine Disorderc 46 (2.3%) 64 (3.3%) 74 (3.7%) 184 (3.1%) Vaginal Hemorrhage 56 (2.8%) 57 (2.9%) 47 (2.3%) 160 (2.7%) Uterine Fibroids Enlargedd 41 (2.1%) 34 (1.7%) 38 (1.9%) 113 (1.9%) Uterine Atonye 27 (1.4%) 32 (1.6%) 31 (1.5%) 90 (1.5%) Neoplasm: Endometrial or Uterine Polypf 19 (1.0%) 31 (1.6%) 27 (1.3%) 77 (1.3%) Endometrial Disorderg 21 (1.1%) 28 (1.4%) 24 (1.2%) 73 (1.2%) Uterine Hemorrhage 4 (0.2%) 9 (0.5%) 7 (0.3%) 20 (0.3%) Uterine Neoplasmh 3 (0.2%) 8 (0.4%) 1 (0.0%) 12 (0.2%) Endometrial Carcinoma 4 (0.2%) 4 (0.2%) 1 (0.0%) 9 (0.2%) Endometrial Hyperplasia 2 (0.1%) 4 (0.2%) 1 (0.0%) 7 (0.1%) Ruptured Uterusi 1 (0.1%) 1 (0.1%) 0 (0.0%) 2 (0.0%) Withdrawal Bleeding 0 (0.0%) 0 (0.0%) 1 (0.0%) 1 (0.0%) % a Fisher b 1 c d e f g h i Placebo RLX 268
65 0.3mm
66 Placebo 0 RLX060 2 RLX CSR Placebo N = 97 RLX060 N = 92 RLX120 N = 95 n n n (100.0%) 0 (0.0%) (97.0%) 2 (3.0%) (98.5%) 1 (1.5%) p a %/n 5% a Fisher p CSR Placebo n=60 RLX060 n=57 RLX120 n=64 p (mm) (mm) (mm) a 52 (mm) (%) LOCF 5% 270
67 mg 120mg 6 LDL / / / 13 4 / LDL HDL / mg 120mg 1 1 HRT 60mg 120mg 0.625mg/ 2.5mg/ mg 120mg 0.625mg/ 2.5mg/ LDL-C 0.22mmol/L 6 271
68 HDL-C 0.08mmol/L F nmol/L 25 LDL-C SD 0.48mmol/L 3.67mmol/L HDL-C SD 0.16mmol/L 1.67mmol/L F1 2 SD 0.53nmol/L 1.50nmol/L 0.625mg 1 FSH 30IU/L 40pg/mL 147pmol/L BMI 18kg/m 2 31kg/m Walsh BW, Li H, Sacks FM, Effects of postmenopausal hormone replacement with oral and transdermal estrogen on high density lipoprotein metabolism, J Lipid Res, 35 (11), , Caine YG, Bauer KA, Barzegar S, ten Cate H, Sacks FM, Walsh BW, Schiff I, Rosenberg RD, Coagulation activation following estrogen administration to postmenopausal women, Thromb Haemost, 68, ,
69 60mg 60mg 0.625mg 0.625mg 2.5mg 2.5mg 60mg 0.625mg 2.5mg 60mg 120mg 0.625mg 2.5mg HDL-C LDL-C VLDL-C HDL HDL-C2 HDL-C3 a Lp a A1 B 1 2 F1 2 A FPA 1 PAI
70 HDL LDL F1+2 HDL LDL F CSR 3.9. ( ) : Visit : 1 2a 3a 4a 2A 2B 2C 3A 3B 3C 4A 4B 4C,,, ECG a Visit CSR Placebo 95 60mg RLX mg RLX HRT HRT Fisher Placebo vs. HRT p=0.033 RLX060 vs. HRT p=0.049 RLX120 vs. HRT p=0.010 Placebo vs. HRT p=0.011 RLX060 vs. HRT p=0.008 RLX120 vs. HRT p=0.010 CSR
71 N=390 Placebo N=98 RLX060 N=95 RLX120 N=101 HRT N=96 N=13 N=14 N=12 N=26 N=85 N=81 N=89 N= CSR CSR 5.2. Placebo N=98 RLX060 N=95 RLX120 N=101 HRT N=96 Overall p 84 (85.7%) 81 (85.3%) 89 (88.1%) 70 (72.9%) (14.3%) 14 (14.7%) 12 (11.9%) 26 (27.1%) (7.1%) 6 (6.3%) 7 (6.9%) 19 (19.8%) (2.0%) 6 (6.3%) 1 (1.0%) 6 (6.3%) (3.1%) 1 (1.1%) 1 (1.0%) 0 (0.0%) ( ) 0 (0.0%) 1 (1.1%) 2 (2.0%) 1 (1.0%) (1.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) --- a 1 (1.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) --- 5% χ2 a Placebo Placebo 4 RLX060 6 RLX120 2 HRT 4 5 Placebo 2 HRT 3 2 Placebo 1 RLX Placebo 3 RLX060 1 RLX / χ2 p=0.869 p=0.285, 0.297p=0.569 χ2 p=0.970 CSR 6.1. p=0.957 p=0.971p=0.927p=0.603 p=0.053 p=0.547 p=0.361 p=
72 p=0.615p=0.418 CSR 6.2. p CSR CSR 6.1. Placebo RLX060 RLX120 HRT N=98 N=95 N=101 N=96 p : 3 (3.1) 4 (4.2) 7 (6.9) 3 (3.1) 0.114a 87 (88.8) 85 (89.5) 89 (88.1) 85 (88.5) / 5 (5.1) 6 (6.3) 4 (4.0) 3 (3.1) 2 (2.0) (1.0) 0 1 (1.0) 5 (5.2) : ( ) ± ( ) (5.97) (6.82) (5.89) (6.35) 0.846b : (cm) ± ( ) (6.69) (7.98) (6.60) (6.60) 0.692b : (kg) ± ( ) (11.20) (10.92) (10.12) (8.66) 0.763b : 77 (78.6) 79 (83.2) 80 (79.2) 80 (83.3) 0.750a 21 (21.4) 16 (16.8) 21 (20.8) 16 (16.7) 1 3 : 76 (77.6) 73 (76.8) 73 (72.3) 76 (79.2) 0.571a (1.0) 22 (22.4) 22 (23.2) 28 (27.7) 19 (19.8) : ± ( ) 9.72 (6.88) (7.12) 9.84 (7.30) (8.87) 0.031b (Visit: 1) 79 (81.4) 71 (75.5) 77 (77.8) 66 (69.5) 0.263a 18 (18.6) 23 (24.5) 22 (22.2) 29 (30.5) : (Visit: 1) (3.4) 0.885a 7 (38.9) 9 (39.1) 9 (40.9) 10 (34.5) 11 (61.1) 14 (60.9) 13 (59.1) 18 (62.1) % a 2 b Placebo RLX HRT 50 4 LDL-C HDL-C RLX060 RLX120 Placebo LDL-C LDL-C/HDL-C Lp a LSD 140 LDL-C LDL-C/HDL-C Placebo vs. RLX060 Placebo vs. RLX120 p<0.001 Lp a Placebo vs. RLX060 p=0.004 Placebo vs. RLX120 p=0.025 CSR 6.6., 6.12., 6.15.,
73 RLX120 Placebo A1 p=0.001 CSR B p<0.001 CSR HDL-C RLX060 RLX120 HDL-C2 RLX Placebo Placebo vs. RLX060 p=0.009 Placebo vs. RLX120 p=0.005 CSR HRT HDL-C Placebo p<0.001 CSR 6.9., 6.18.RLX HRT RLX060 vs. HRT p=0.452 RLX120 vs. HRT p=0.411 CSR 6.6. LDL-C RLX060 vs. HRT p=0.080 RLX120 vs. HRT p=0.110 CSR VLDL-C RLX060 vs. HRT p=0.377 RLX120 vs. HRT p=0.216 CSR RLX HRT B RLX HRT LDL-C/HDL-C HDL-C2 Lp a A1 RLX HRT 277
74 CSR Overall Placebo RLX060 RLX120 HRT p e na (mmol/l) bc -0.40bc -0.30bc bc -6.68bc -4.43bc HDL-C na (mmol/l) d 0.05bd 0.14bc d 3.89bd 10.58bc LDL-C na (mmol/l) bc -0.43bc -0.48bc bc bc bc LDL-C/HDL-C na bcd -0.33bcd -0.53bc bcd bcd bc na (mmol/l) d -0.01d 0.19bc d -0.47d 20.00bc VLDL-C na (mmol/l) c HDL-C2 na (mmol/l) bcd 0.03bcd 0.10bc bd 16.67b 33.33bc HDL-C3 na (mmol/l) cd cd Lp(a) na (g/l) bcd -0.01cd -0.03bc bcd -4.28cd bc A1 na (mmol/l) d 0.07bcd 0.18bc d 4.49bcd 11.56bc B na (mmol/l) bcd -0.10bc bcd -8.64bc % a 1 b p 0.05 c p 0.05 Placebo LSD d p 0.05 RLX060 RLX120 HRT LSD e 278
75 15 CSR 4.1. Variable, LDL-C, LDL-C/HDL-C 2/3 a 1/4 b HDL-C, A 1 2/3 a 1/4 b 2/3 a 2/3 a -1/4 c 2/3 a VLDL-C -2/3 d HDL-C 2 1/4 b -2/3 d HDL-C 3 2/3 a Lp(a) 2/3 a a X X 2/3 b X X 2/3 c X X (-1/4) d X X ( - 2/3) CSR 6.4. RLX060 RLX120 HRT a a a HDL-C b b a LDL-C a a a LDL-C/HDL-C a, b a, b a b b a VLDL-C HDL-C2 a, b a, b a HDL-C3 a, b Lp(a) a, b a, b a A1 b a, b a B a, b a -- a Placebo p 0.05 a Placebo p 0.05 b HRT p 0.05 b HRT p
76 Median Total Cholesterol (mmol/l) Percentage Change from Baseline (Median with One Standard Error) Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 Median HDL Cholesterol(mmol/L) Percentage Change from Baseline (Median with One Standard Error) Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 Median LDL Cholesterol(mmol/L) Percentage Change from Baseline (Median with One Standard Error) Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 Median Triglycerides(mmol/L) Percentage Change from Baseline (Median with One Standard Error) Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 CEMPACCHRT p 0.05 Placebo LSD CSR
77 Placebo RLX HRT 51 4 RLX Placebo HRT LSD p<0.001 CSR HRT Placebo RLX PAI-1 p<0.001 CSR F1 2 FPA CSR Overall Placebo RLX060 RLX120 HRT p e F 1+2 (nmol/l) na b b FPA (ng/ml) na b b b b (g/l) na bcd -0.46bcd < bcd bcd <0.001 PAI-1 (µ/ml) na d -0.15d -1.68bc < d -2.38d bc < % a 1 b p 0.05 c p 0.05 Placebo [F1+2-2/3 ] LSD d p 0.05 RLX060 RLX120 HRT [F1+2-2/3 ] LSD e [F1+2-2/3 ] CSR RLX060 RLX120 HRT F 1+2 (nmol/l) FPA a, b a, b -- PAI-1 b b a a Placebo p 0.05 a Placebo p 0.05 b HRT p 0.05 b HRT p
78 F1+2 Percentage Change from Baseline (Median with One Standard Error) 30 FPA Percentage Change from Baseline (Median with One Standard Error) Median 10 Median Months on Study Drug CEMPACC PLACEBO RLX060 RLX Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 FIB Percentage Change from Baseline (Median with One Standard Error) 10 PAI Percentage Change from Baseline (Median with One Standard Error) 10 0 Median 0-10 Median Months on Study Drug Months on Study Drug CEMPACC PLACEBO RLX060 RLX120 CEMPACC PLACEBO RLX060 RLX120 CEMPACCHRT p 0.05 Placebo [F1+2-2/3 ] LSD CSR Placebo 2 2.0RLX RLX HRT CSR 7.1. Placebo RLX060 RLX120 HRT N= 98 N= 95 N= 101 N= 96 p a 2 (2.0%) 3 (3.2%) 4 (4.0%) 3 (3.1%) (1.0%) 1 (1.1%) 1 (1.0%) 1 (1.0%) (1.0%) 1 (1.1%) 1 (1.0%) 0 (0.0%) (0.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) (0.0%) 0 (0.0%) 1 (1.0%) 1 (1.0%) (1.0%) 2 (2.1%) 1 (1.0%) 0 (0.0%) (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.0%) --- 5% a 2 282
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