/ / A/ B 16/17 COPD 18mcg COPD COPD COPD 1

11 1 -------------------- 19 205.117/205.128 14/15 205.126A/205.126B 16/17 COPD 18mcg COPD 11.1 11.1.1 COPD 100 19 205.227 COPD 1 FEV1.0 %FEV1.0 70% 1 FEV1.0 / FVC 70% 2 1 200 3 40 COPD 1 10mg ACE 1 1 150 100 50 161 110 51 COPD 1 4 900 300 18mcg 1 1 MDI 1 200mcg2 100mcg2 1 3 MDI 1-5 1 52 8 11 231

11.1.1 1 2 FEV1.0 FEV1.0 1 FVC 1 COPD 2 QOLSGRQ AQ20 11.1.2 24 52 2 12 2 24 2 24 1 ACE FEV1.0 FEV1.0 FEV1.0 LOCF COPD Least Favorable prior observation carried forwardlfcf FEV1.0 Vist2 95% Visit2 52 Visit7 232

11.1.1 COPD 1 4 900 300 100 30 11.1.2 0 52 Visit Number 1 2 3 4 5 6 7-5 -1 0 4 212 624 636 652 X 1) X 2) X X X X X X X X X QOL SGRQ AQ20 3 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 1Visit 257 5 5 1 10 2 wash out 3AQ20 233

11.2 11.2.1 192 161 1 52 88.2% 97/110 84.3%43/51 9.1%10/110 7.8%4/51 11.2.1 161 110 51 FEV1.0 15 10 5 11.2.2 11.2.3 68.7 FEV1.0 0.98L%FEV1.0 36.8% 14.5%16/110 13.7%7/51 11.2.4 68.9% 67.1% p=0.1211 FEV1.0 p=0.3499365 2 (p=0.1295) FEV1.0 2 2 p=0.2972365 11.2.1 19 N (%) N (%) N (%) 192 110 100.0 51 100.0 161 100.0 97 88.2 43 84.3 140 87.0 10 9.1 4 7.8 14 8.7 1 0.9 3 5.9 4 2.5 0 0.0 1 2.0 1 0.6 2 1.8 0 0.0 2 1.2 234

161 110 51 0 FEV1.0 146 100 46 11.2.1 11.2.2 19 * Fisher 11.2.3 S.D. 19 p 109 51 160 FEV1.0(L) 0.96 0.36 1.00 0.43 0.98 0.38 0.5618 %FEV1.0(%) 36.49 13.73 37.31 13.93 36.76 13.76 0.7265 FEV1.0 / FVC(%) 36.79 8.85 38.36 10.80 37.29 9.51 0.3329 FVC(L) 2.61 0.69 2.63 0.79 2.62 0.72 0.8924 * 235

11.2.4 19 N % N % N % 110 51 161 100 (90.9%) 46 (90.2%) 146 (90.7%) 77 (70.0%) 34 (66.7%) 111 (68.9%) Flutropium 3 (2.7%) 1 (2.0%) 4 (2.5%) Ipratropium Bromide 4 (3.6%) 4 (7.8%) 8 (5.0%) Oxitropium 70 (63.6%) 29 (56.9%) 99 (61.5%) 2 31 (28.2%) 13 (25.5%) 44 (27.3%) Fenoterol 2 (1.8%) 0 (0.0%) 2 (1.2%) Procaterol 16 (14.5%) 9 (17.6%) 25 (15.5%) Salbutamol 13 (11.8%) 5 (9.8%) 18 (11.2%) Tulobuterol 2 (1.8%) 0 (0.0%) 2 (1.2%) 2 18 (16.4%) 12 (23.5%) 30 (18.6%) Clenbuterol 11 (10.0%) 2 (3.9%) 13 (8.1%) Fenoterol 0 (0.0%) 1 (2.0%) 1 (0.6%) Hexoprenaline 1 (0.9%) 1 (2.0%) 2 (1.2%) Mabuterol 1 (0.9%) 0 (0.0%) 1 (0.6%) Procaterol 4 (3.6%) 7 (13.7%) 11 (6.8%) Trimetoquinol 1 (0.9%) 0 (0.0%) 1 (0.6%) Tulobuterol 0 (0.0%) 1 (2.0%) 1 (0.6%) 2 11 (10.0%) 10 (19.6%) 21 (13.0%) Tulobuterol 11 (10.0%) 10 (19.6%) 21 (13.0%) p* 0.7159 0.8496 0.2845 0.1295 11 (10.0%) 3 (5.9%) 14 (8.7%) 0.5511 20 (18.2%) 10 (19.6%) 30 (18.6%) Beclomethasone 13 (11.8%) 6 (11.8%) 19 (11.8%) Fluticasone 7 (6.4%) 4 (7.8%) 11 (6.8%) 6 (5.5%) 0 (0.0%) 6 (3.7%) Betamethasone 1 (0.9%) 0 (0.0%) 1 (0.6%) Prednisolone 5 (4.5%) 0 (0.0%) 5 (3.1%) 74 (67.3%) 34 (66.7%) 108 (67.1%) Aminophylline 1 (0.9%) 0 (0.0%) 1 (0.6%) Theophylline 73 (66.4%) 34 (66.7%) 107 (66.5%) Fisher 0.8304 0.1779 1.0000 236

11.3 11.3.1 FEV1.0 FEV1.0 11.3.1 0.96L 0.94 L 11.3.1 FEV1.0 19 100 46 L 0.96 0.94 S.E. 0.04 0.05 11.3.1 FEV1.0 1 24 52 FEV1.0 11.3.2 11.3.2 FEV1.0 2452 0.120.09L 0.00-0.02L p=0.0003 p=0.0005 11.3.1 FEV1.0 19 237

11.3.2 FEV1.0 19 11.3.2 FEV1.0L SE 19 (N=100) (N=46) p 95% * 0.95 0.95 24 0.12(0.02) -0.00(0.03) 0.12(0.03) 0.0003 ( 0.06, 0.18) 52 0.09(0.02) -0.02(0.03) 0.11(0.03) 0.0005 ( 0.05, 0.18) 0.16(0.01) 0.20(0.02) -0.04(0.02) 0.0515 (-0.08, 0.00) 124 0.20(0.02) 0.16(0.03) 0.04(0.04) 0.2548 (-0.03, 0.12) 52 0.18(0.02) 0.14(0.03) 0.05(0.04) 0.2236 (-0.03, 0.12) * common baseline 11.3.2 COPD COPD 4 4 6 4 COPD 11.3.3 11.3.3 COPD 19 Score N SE N SE 108 0.76 0.07 50 0.64 0.08 108 1.10 0.08 50 1.12 0.11 108 2.47 0.12 50 2.60 0.18 108 0.24 0.06 50 0.32 0.09 238

11.3.3 COPD 11.3.4 36 24 52 243652 p<0.05 11.3.3 COPD 19 239

11.3.4 COPD 19 N N P 95% * 108 0.72 50 0.72 4108 0.67(0.05) 50 0.67(0.07) -0.00(0.09) 0.9863 ( -0.17, 0.17) 12108 0.64(0.05) 50 0.61(0.07) 0.03(0.09) 0.7541 ( -0.14, 0.20) 24108 0.63(0.04) 50 0.56(0.06) 0.07(0.08) 0.3909 ( -0.09, 0.22) 36108 0.61(0.05) 50 0.61(0.07) 0.00(0.08) 0.9969 ( -0.16, 0.16) 52108 0.71(0.05) 50 0.70(0.08) 0.02(0.09) 0.8456 ( -0.17, 0.21) * 108 1.11 50 1.11 4108 0.95(0.05) 50 1.03(0.08) -0.09(0.09) 0.3426 ( -0.27, 0.09) 12108 1.00(0.05) 50 1.05(0.08) -0.05(0.09) 0.5814 ( -0.23, 0.13) 24108 1.08(0.05) 50 0.99(0.08) 0.08(0.09) 0.3832 ( -0.10, 0.27) 36108 0.91(0.05) 50 0.95(0.08) -0.04(0.09) 0.6367 ( -0.22, 0.14) 52108 1.07(0.06) 50 1.03(0.09) 0.03(0.10) 0.7482 ( -0.17, 0.24) * 108 2.51 50 2.51 4108 2.34(0.10) 50 2.44(0.15) -0.10(0.18) 0.5800 ( -0.46, 0.26) 12108 2.23(0.10) 50 2.48(0.15) -0.25(0.18) 0.1671 ( -0.61, 0.11) 24108 2.26(0.11) 50 2.79(0.16) -0.53(0.19) 0.0060 ( -0.91, -0.15) 36108 2.18(0.10) 50 2.56(0.15) -0.39(0.18) 0.0308 ( -0.73, -0.04) 52108 2.28(0.10) 50 2.72(0.15) -0.45(0.18) 0.0145 ( -0.80, -0.09) * 108 0.27 50 0.27 4108 0.14(0.03) 50 0.07(0.05) 0.07(0.06) 0.1880 ( -0.04, 0.18) 12108 0.22(0.04) 50 0.26(0.06) -0.04(0.08) 0.6127 ( -0.19, 0.11) 24108 0.15(0.04) 50 0.17(0.05) -0.02(0.07) 0.8152 ( -0.14, 0.11) 36108 0.14(0.04) 50 0.25(0.06) -0.10(0.07) 0.1381 ( -0.24, 0.03) 52108 0.22(0.04) 50 0.21(0.07) 0.01(0.08) 0.8821 ( -0.15, 0.17) * common baseline 240

11.3.3 St. George's Respiratory QuestionnaireSGRQ 3 11.3.5 11.3.5 SGRQ 19 N SE N SE Symptoms 102 51.61 2.17 46 52.54 3.03 Activity 102 56.14 2.18 46 58.90 3.03 Impact 102 27.74 1.64 46 28.57 2.55 Total 102 40.31 1.63 46 41.76 2.38 11.3.4 11.3.6 24 5.43.74.24.2 p<0.05 52 9.18.04.06.0 2 p<0.01 241

11.3.4 SGRQ 19 11.3.6 SGRQ SE 19 N N p 95% 102 51.90 46 51.90 24 102 45.15(1.62) 46 50.50(2.41) -5.35(2.90) 0.0673 (-11.08, 0.39) 52 102 43.03(1.76) 46 52.14(2.63) -9.11(3.16) 0.0046 (-15.36, -2.85) 102 57.00 46 57.00 24 102 53.49(1.42) 46 57.15(2.12) -3.65(2.56) 0.1550 ( -8.70, 1.40) 52 102 52.99(1.45) 46 61.02(2.16) -8.03(2.61) 0.0025 (-13.18, -2.87) 102 28.00 46 28.00 24 102 23.72(1.27) 46 27.93(1.89) -4.21(2.28) 0.0668 ( -8.71, 0.30) 52 102 25.77(1.34) 46 29.79(2.00) -4.02(2.41) 0.0971 ( -8.79, 0.74) 102 40.76 46 40.76 24 102 36.28(1.10) 46 40.46(1.64) -4.18(1.97) 0.0359 ( -8.08, -0.28) 52 102 36.93(1.16) 46 42.89(1.72) -5.96(2.08) 0.0047 (-10.06, -1.86) * common baseline 242

SGRQ 4 11.3.7 24 49.0 50.0% 50.0 45.7% 52 43.1 52.9% 30.4 32.6 p<0.05 11.3.7 4 % 19 (N=102) (N=46) (95% ) P* 24 49.02 50.00-0.98 (-18.38, 16.42) 1.0000 52 43.14 30.43 12.70 (-3.70, 29.11) 0.1514 24 50.00 45.65 4.35 (-13.01, 21.71) 0.7228 52 52.94 32.61 20.33 (3.68, 36.99) 0.0321 * Fisher 243

4 SGRQ 4 SGRQ Jones 1991 1 4 Jones 2) SGRQ 3) 4 COPD SGRQ 4 4 4) SGRQ QOL 1. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med 1991; 85: 25-31. 2. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155: 1283-9 3. Hajiro T, Nishimura K, Tsukino M, et al. Comparison of discriminative properties among disease-specific questionnaires for measuring health-related quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 785-90. 4.. COPD QOL minimum clinically important difference. 12 C-143 7 56. 244

11.3.4 COPD COPD COPD 11.3.5 Kaplan-Meier COPD COPD COPD p=0.0525, Log-rank 11.3.8 COPD 100 patient-years COPD p=0.0835p=0.0701wilcoxon Prob. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Tiotropium (N=110) Oxitropium (N=51) 0 90 180 270 360 Days The number of at risk cases Tiotropium 110 99 92 88 64 Oxitropium 51 41 36 33 26 11.3.5 Kaplan-Meier COPD 19 11.3.8 COPD 19 COPD p /100 patients-years Wilcoxon rank-sum test 18.3 419.9 0.0835 37.1 752.8 COPD P /100 patients-years Wilcoxon rank-sum test 0.0701 245

11.4 11.4.1 11.4.1 95 86.4%, 43 84.3% 331 331.6 325.3 11.4.1 19 Total N ( %) N ( %) N ( %) Exposure (days) 1 1 (0.9) 1 (2.0) 2 (1.2) 2-7 1 (0.9) 0 1 (0.6) 8-60 4 (3.6) 3 (5.9) 7 (4.3) 61-100 1 (0.9) 0 1 (0.6) 101-200 3 (2.7) 2 (3.9) 5 (3.1) 201-330 5 (4.5) 2 (3.9) 7 (4.3) 331-95 (86.4) 43 (84.3) 138 (85.7) 331.6 325.3 329.6 SD 90.5 97.7 92.6 365 365 365 1 1 1 393 393 393 110 51 161 11.4.2 3% 11.4.2 90.0% 74.5% 3% 17.3 %19/110 5.5 %6/110 3.6 %4/110 3.6 %4/110 () 7.3 %8/110 5.5 %6/110 49.1 %54/110 17.3 %19/110 5.9 %3/51 1 2 1 1 19 14 90 3 91180 2 270 47.0 3 56113225 5.5%6/110 2 1 1 2 246

2 No.1* No.2* No.3* No.4* 7 10 18 6 167 6 6 50 106 7 41 17 3.6 %4/110 8 2 1 8 3 90 2 91180 3 181270 8 5 8 7.0mg/dL 6.4 %7/110 7.8 %4/51 1 1 2 1 2.7 %3/110 1 2 1 1 1 1 247

11.4.2 3% 19 WHO Preferred Term N % N % 110 100.0 51 100.0 99 90.0 38 74.5 32 29.1 9 17.6 6 5.5 0 0.0 () 8 7.3 2 3.9 6 5.5 1 2.0 15 13.6 7 13.7 4 3.6 3 5.9 () 5 4.5 2 3.9 44 40.0 11 21.6 5 4.5 1 2.0 7 6.4 4 7.8 4 3.6 2 3.9 19 17.3 3 5.9 9 8.2 5 9.8 6 5.5 4 7.8 13 11.8 0 0.0 4 3.6 0 0.0 4 3.6 0 0.0 7 6.4 3 5.9 0 0.0 3 5.9 0 0.0 4 7.8 0 0.0 2 3.9 66 60.0 29 56.9 COPD 12 10.9 9 17.6 3 2.7 5 9.8 3 2.7 5 9.8 3 2.7 2 3.9 54 49.1 23 45.1 15 13.6 8 15.7 3 2.7 2 3.9 () 4 3.6 1 2.0 0 0.0 2 3.9 1 0.9 3 5.9 1 0.9 2 3.9 12 10.9 8 15.7 2 1.8 2 3.9 1 0.9 2 3.9 248

11.4.3 8.2%9/110 9.8%5/51 6 2 3 1 6 1 1 6 1 85162253 29113246 253 6 3 2 2 4 1 2 1 1 2 No.5*7 29 3 No.6*5 600mg/ 5mg/ 50mcg 211 X 55 % 10mg/ 5mg/ 15mg/ 2 150160 / 0.25mg C 0.4mg 32.6mcg/mL 820mcg/mL 400mg/ 6 9 80 90 / 3 249

1 32 1 11.4.3 N % N % 110 100 51 100 9 8.2 5 9.8 6 5.5 4 7.8 2 1.8 1 0.9 1 2.0 60 61 70 71 11.4.4 71 11.4.4 (n=46) (n=17) (n=64) (n=34) N % N % N % N % 4 8.7 3 17.6 5 7.8 2 5.9 2 4.3 3 17.6 4 6.3 1 2.9 1 2.2 1 1.6 0 0 1 2.2 1 2.9 250

11.4.4 (n=19) (n=3) (n=91) (n=48) N % N % N % N % 4 21.1 1 33.3 5 5.5 4 8.3 4 21.1 1 33.3 2 2.2 3 6.3 2 2.2 1 1.1 1 2.1 60 61-70 71 (N=14) (N=9) (N=50) (N=19) (N=46) (N=23) N % N % N % N % N % N % 1 7.1 1 11.1 3 6.0 1 5.3 5 10.9 3 13.0 1 11.1 2 4.0 1 5.3 4 8.7 2 8.7 1 7.1 1 2.2 1 2.0 1 4.3 251

11.4.2 11.4.5 15.5% 2.7% 3.9%0% 1.8% 2.0% 1.8%0% 11.4.5 19 WHOWHO Preferred Term N % N % 110 100.0 51 100.0 30 27.3 9 17.6 3 2.7 0 0.0 ( ) 1 0.9 0 0.0 1 0.9 0 0.0 () 1 0.9 0 0.0 2 1.8 1 2.0 2 1.8 0 0.0 0 0.0 1 2.0 17 15.5 2 3.9 1 0.9 0 0.0 1 0.9 1 2.0 2 1.8 0 0.0 0 0.0 1 2.0 1 0.9 0 0.0 0 0.0 1 2.0 0 0.0 1 2.0 0 0.0 1 2.0 () 1 0.9 0 0.0 () 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 0 0.0 1 2.0 1 0.9 0 0.0 252

11.4.3 11.4.6 11.4.9 18.2%20/110 27.5%14/51 1 1 1 1.5 1 1 WHO ( ) 11.4.6 19 WHO Preferred Term N % N % 110 100.0 51 100.0 20 18.2 14 27.5 0 0.0 1 2.0 0 0.0 1 2.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 1 2.0 0 0.0 1 2.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 ( ) 1 0.9 0 0.0 5 4.5 1 2.0 1 0.9 1 2.0 1 0.9 0 0.0 1 0.9 0 0.0 2 1.8 0 0.0 0 0.0 1 2.0 0 0.0 1 2.0 10 9.1 7 13.7 COPD 5 4.5 3 5.9 1 0.9 0 0.0 1 0.9 0 0.0 3 2.7 4 7.8 1 0.9 0 0.0 2 1.8 0 0.0 0 0.0 1 2.0 0 0.0 1 2.0 0 0.0 3 5.9 0 0.0 1 2.0 0 0.0 1 2.0 0 0.0 1 2.0 253

No.6* 1.5 No.7* No.6* 5 1990 1991 600 mg/2000 3 14.3 mg/ml2000 5 23 0.9mL/ 2000 3 50 mcg/2000 8 7.5 mg/2000 8 2001 5 5 mg/ 2001 2 6 2001 8 24 2001 8 28 180mg/ 100mg/ 2001 9 10 2001 9 11 2001 9 18 X 55% 10mg/ 2001 9 19 5mg/ 10mg/ 2001 9 20 150-160 / 2001 9 21 32.6 mg/ml 8-20 20mg/ 600 400 mg/ 5mg/ 2001 9 25 8.2 mg/ml 2001 9 26 2001 9 28 80-90 / 400 mg/day 2001 10 2 254

2001 10 4 1.5 No.7*7 6 24 2 11.4.8 9 3 3 1.5 1 255

11.4.4 10/110 9.1% 4/51 7.8% 11.4.7 2 11.4.7 19 WHO WHO Preferred Term N % N % 110 100.0 51 100.0 10 9.1 4 7.8 1 0.9 0 0.0 1 0.9 0 0.0 ( ) 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 1 0.9 1 2.0 0 0.0 1 2.0 1 0.9 0 0.0 2 1.8 0 0.0 2 1.8 0 0.0 1 0.9 0 0.0 1 0.9 0 0.0 ( ) 4 3.6 1 2.0 1 0.9 1 2.0 1 0.9 0 0.0 () 2 1.8 0 0.0 0 0.0 1 2.0 0 0.0 1 2.0 1 0.9 1 2.0 1 0.9 1 2.0 256

11.4.5 11.4.8 11.4.8 * 19 N N 108 0 1(0.9) 50 1(2.0) 1(2.0) 108 2(1.9) 1(0.9) 50 2(4.0) 1(2.0) 108 2(1.9) 5(4.6) 50 0 3(6.0) ALT (GPT) 108 0 2(1.9) 50 0 1(2.0) AST(GOT) 108 0 2(1.9) 50 0 0 108 0 5(4.6) 50 0 1(2.0) LDH 108 1(0.9) 3(2.8) 50 0 1(2.0) 107 0 4(3.7) 50 0 1(2.0) 108 3(2.8) 0 50 1(2.0) 0 108 3(2.8) 0 50 1(2.0) 0 108 0 0 50 0 0 BUN 108 0 5(4.6) 50 0 2(4.0) 108 0 5(4.6) 50 0 3(6.0) 108 0 3(2.8) 50 0 2(4.0) ( ) % * 456 15.3.22 11.5 FEV1.0 SGRQ 52 90.0% 74.5% 17.3% 5.9% 5.5% COPD 10.9% 17.6% 1 1 1 257

258 11.4.9 19 WHO preferred * term 6* 5 211 1 X 55% 10mg/ 5mg/ 10mg/ 150 160 / 0.25mg C 0.4mg 32.6 mcg/ml 820 mcg/ml 600mg/ 400mg/ 5mg/ 6 7 9 8090 / 8* 6 54 120 MRI A 132 10 23 R *

259 11.4.9 19 (WHO preferred term) * 7* 1 7 2 86 2 D 14 20 ( ) 3 4 134 6 19 RF 28 1.7g/dL 43 A 56 1.9g/dL 61 281 23 1.5 1 *

260 11.4.9 19 WHO preferred term * 9* 7 30 3 6 14 2 10* 6 301 2001 9 17 ATP ATP40mg 1/2A ATP 1 2001 10 14 Visit 1 00 10 24 Visit 5 01 5 10 Visit 6 01 8 2 01 9 17 01 9 25 01 10 9 Visit 7 01 11 22 GOT U/L 31 33 49 H 74 H 84 H 51 52 GPT U/L 20 32 47 H 60 H 54 H 29 38 -GTP U/L 176 H 172 H 223 H 515 H 442 H 441 340 H ALP U/L 489 H 510 H 524 H - - - 785 H LDH U/L 244 H 215 251 H - - - 270 H *

261 11.4.9 19 WHO preferred term * 11* 6 220 4 X 7 8 X 11 X 25 28 12* 7 3 1 101 CT (4cm) ( ) 127 13* 6 4 4 175 2 15 S 5cm 3 *

262 11.4.9 19 WHO preferred * term 14* 6 259 9 265 7mm 2 ( ) 272 3 15* 7 57 69 CT 15mm 93 127 PL VG 16* 6 59 CT 2 ( ) 5 3 1 3 *

263 11.4.9 19 (WHO preferred term) * 17* COPD 6 33 3 T3 COPD 12 22 42 18* COPD 5 143 COPD 3 4 1.6mg/dLPaO 2 57.0mmHgPaCO 2 43.7mmHg 11 ( 14 ) 19* COPD 7 137 37.4 COPD PaO2 45.8mmHg PaCO 2 38.7mmHg X 9,700/mm 3 CRP 6.4mg/dL 10 6,200/mm 3 CRP 8 COPD *

264 11.4.9 19 WHO preferred term * 20* COPD 7 COPD 64 38.3 69 X 10 11 12 14 37.7 27 COPD 21* 6 146 PL COPD PL 2 CRP 12.9mg/dL 3 CRP 5.9mg/dL 4 8 11 22* 7 38 2 37 L 5 6 13 15 *

265 11.4.9 19 WHO preferred term 23* 6 318 (13,800 / L)CRP 6.1mg/dL 2g2/2 5 4,210 /L 11 CRP 0.6mg/dL 24* 5 272 X- 2 9 14 6 COPD 25* 6 346 WBC 11,700/mm 3 CRP 6.9 mg/dl 12 36 12 *

266 11.4.9 19 WHO preferred * term 26* 7 348 66 44 27* 4 129 L 4 X 4 X 6 7 14 28* 6 55 10 S D3 27 *

267 11.4.9 19 WHO preferred term * 29* 1 7 24 L CRP 25.2mg/dL 6 12 CRP (1.5mg/dL) 19 BOOP CRP 0.6mg/dL 23 Haemophililus influenzae BOOP 2 97 3 6 8 88 30* 6 COPD 251 2 CRP 4.05mg/dL 0.5L/min 4 5 7 9 *

268 11.4.9 19 WHO preferred term * 31* COPD 6 COPD 194 SpO 2 65 2.0L/min ph 7.18PaCO 2 84.2torrPaO 2 100torr 24 / COPD 0.51.0L/min (2 ) 0.5L/min ph 7.46PaCO 2 42torrPaO 2 60torr 32* 5 COPD 135 CRP 2.8mg/dL CRP 0.2mg/dL 24 *

269 3.1mg/dL 108 13 11.4.9 19 WHO preferred term * 33* 7 61 CRP L 55.1mg/dL 2.8mg/dL 3 2.0mg/dL 4 1.4 mg/dl CRP 23.1 mg/dl 5 MS 6 11 25 CRP 3.3mg/dL 36 CRP 1.1mg/dL 46 CRP 58 CRP 3.0mg/dL 64 2.6mg/dL X Consolidation 73 CRP 0.8mg/dL X 74 101 34* 6 203 211 X CRP (22.73mg/dL) 15 35* 7 81 37 3 37 CRP S PL 4 36

270 11.4.9 19 (WHO preferred term) * 36* 6 158 2 CT MRI 12 37* 7 PL 2 ( ) ( ) 8 329 7 9 14 38* 7 274,, 366 14 13 31 7 39* 7 346 3 20 8 13 14 *

11. 11.6 --------------------- 141719 4 4 205.226 18 1 19 1 2 205.126A/205.126B 16/17 1 2 205.117/205.128 14/15 18mcg 1 6 24 1 FEV1.0 205.226 18 CRF Visit CRF 11.6.1 11.6.1 18mcg 271

272 11.6.1 19 205.227 14/15 205.117/205.128 16/17 205.126A/205.126B COPD COPD COPD MDI COPD 1 FEV1.0 %FEV1.0 70% 1 FEV1.0 / FVC 70% 2 1 200 10 pack-year 3 40 COPD 1 10mg ACE 1 1 COPD 1FEV1.0 %FEV1.0 65% 1 FEV1.0/FVC 70% 210 pack-year 3 40 600/mm 3 1 10mg 20mg 6 6 COPD 1FEV1.0 %FEV1.0 65% 1 FEV1.0/FVC 70% 210 pack-year 3 40 400 320 /mm 3 1 10mg 20mg 6 6 110 51 205.117 14 279 191 205.128 15 271 180 205.126A 16 191 97 205.126B 17 165 82 1 52 1 49 1 52

11. 11.6.1 19 205.227 14/15 205.117/205.128 16/17 205.126A/205.126B 1 1 FEV1.0 1 FEV1.0 ( 1 ( 1 2 FEV1.0 ) ) ( 2) 2 FEV1.0 3 FEV1.0 6 13 ) FEV1.0 1 3 13 52 FVC FEV1.0 FVC FEV1.0 FVC FEV1.0 COPD COPD 2 2 2 QOLSGRQ COPD AQ20 COPD COPD COPD QOLSGRQ SF36 Mahler Dyspnea Index QOL SGRQ SF36 Mahler Dyspnea Index Pharmaco-economic variables Pharmaco-economic variables 1 1 2 2 2 2 2 12 2 24 24 24 12 12 2 24 273

11.6.2 11.6.2 68.7 65.263.9 18.6%(30/161) 42.0%(387/921) 80.6%(431/535) 67.1%(108/161) 23.6%(217/921)15.9%(85/535) 2 27.3%(44/161) 99.2%(914/921)38.3%(205/535) 2 11.6.4 279 FEV1.0 0.98L 1.03L1.22L FEV1.0 %FEV1.0 36.8% 38.7% 43.1% 274

11. 11.6.2 19 205.117/128 14/15 205.126A/126B 16/17 Total Total 110 51 161 550 371 921 356 179 535 106 50 156 366 233 599 300 154 454 4 1 5 184 138 322 56 25 81 <41 1 0 1 1 1 2 0 0 0 41-50 1 2 3 30 21 51 28 11 39 51-60 12 7 19 119 79 198 89 38 127 61-70 50 19 69 249 155 404 166 82 248 71-80 44 21 65 140 108 248 70 47 117 >80 2 2 4 11 7 18 3 1 4 Mean 68.4 69.2 68.7 65.1 65.3 65.2 63.6 64.5 63.9 StdDev 7.3 8.2 7.6 8.5 8.9 8.7 8.2 8.1 8.2 Median 70 70 70 65 66 66 64 65 64 Min 40 44 40 40 39 39 41 42 41 Max 83 85 85 87 82 87 82 81 82 Mean 161.7 162.3 161.9 171.1 170.5 170.9 171.7 172.5 172.0 StdDev 5.7 7.1 6.1 9.5 9.5 9.5 7.9 7.4 7.7 Median 162 163 162 172.7 170.2 171.5 172 172 172 Min 142 146 142 144.8 147.3 144.8 150 153 150 Max 175 175 175 198.1 198.1 198.1 192 190 192 Mean 54.1 53.9 54.1 76.9 75.5 76.4 74.3 72.8 73.8 StdDev 8.2 9.2 8.5 17.7 17.5 17.6 13.7 11.5 13.0 Median 54.0 52.5 54.0 75.8 73.4 74.5 73.5 72 73 Min 33.0 33.8 33.0 38.3 36.9 36.9 35 43 35 Max 72.0 79.0 79.0 149.4 140.9 149.4 120.4 100 120.4 Mean 62.1 53.7 59.5 62.6 59.0 61.1 34.3 33.2 33.9 StdDev 35.7 22.4 32.2 30.5 30.3 30.5 18.6 16.7 18.0 Median Pack-years 51.4 50.0 51.0 56.5 54 55 30 30 30 Min 13.5 10.0 10.0 11 10 10 10 10 10 Max 210.0 125.0 210.0 240 160 240 140 117 140 Mean 4.0 4.9 4.3 8.6 8.1 8.4 11.4 11.2 11.5 StdDev 3.4 4.8 3.9 7.4 6.8 7.2 9.9 9.6 9.8 Median () 3.0 3.0 3.0 7.0 6.0 6.9 9.0 7.2 8.3 Min 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.1 Max 18.0 20.0 20.0 50.0 40.0 50.0 54.2 53.0 54.2 20 10 30 239 148 387 286 145 431 (18.2%) (19.6%) (18.6%) (43.5%) (39.9%) (42.0%) (80.3%) (81.0%) (80.6%) 74 34 108 123 94 217 58 27 85 (67.3%) (66.7%) (67.1%) (22.4%) (25.3%) (23.6%) (16.3%) (15.1%) (15.9%) 31 13 44 546 368 914 139 66 205 (28.2%) (25.5%) (27.3%) (99.3%) (99.2%) (99.2%) (39.0%) (36.9%) (38.3%) * 2 275

11.6.2 19 205.117/128 14/15 205.126A/126B 16/17 Total Total N 109 51 160 550 371 921 356 179 535 Mean 0.96 1.00 0.98 1.04 1.00 1.03 1.25 1.18 1.22 StdDev 0.36 0.43 0.38 0.41 0.44 0.42 0.43 0.37 0.41 * FEV1.0 L Median 0.89 0.85 0.88 0.99 0.91 0.97 1.18 1.10 1.15 Min 0.41 0.48 0.41 0.31 0.29 0.29 0.29 0.47 0.29 Max 2.08 2.53 2.53 3.03 2.63 3.03 2.60 2.45 2.60 30% 45 15 60 163 125 288 66 30 96 (40.5%) (29.4%) (37.0%) (29.6%) (33.7%) (31.3%) (18.5%) (16.8%) (17.9%) 30% 44 28 72 257 162 419 167 105 272 * 50% (39.6%) (54.9%) (44.4%) (46.7%) (43.7%) (45.5%) (46.9%) (58.7%) (50.8%) %FEV1.0(%) 50% 20 6 26 126 82 208 118 44 162 70% (18.0%) (11.8%) (16.0%) (22.9%) (22.1%) (22.6%) (33.1%) (24.6%) (30.3%) 70% 0 2 2 4 2 6 5 0 5 (0.0%) (3.9%) (1.2%) (0.7%) (0.5%) (0.7%) (1.4%) (0.0%) (0.9%) Mean 36.5 37.3 36.8 39.1 38.1 38.7 43.9 41.4 43.1 * StdDev 13.7 13.9 13.8 13.7 14.1 13.9 13.3 11.2 12.7 %FEV1.0(%) Median 34.7 33.7 34.4 38.4 36.9 37.7 42.4 41.7 42.1 Min 14.2 18.7 14.2 12.8 12.1 12.1 13.9 17.5 13.9 Max 69.7 86.6 86.6 74.6 72.5 74.6 74.1 68.2 74.1 Mean 36.8 38.4 37.3 45.8 45.4 45.7 45.7 45.5 45.7 StdDev 8.8 10.8 9.5 11.6 11.6 11.6 10.4 10.0 10.3 * FEV1.0/FVC(%) Median 35.6 35.5 35.5 44.5 45.3 44.8 45.5 44.7 45.4 Min 18.5 19.5 18.5 20.0 21.4 20.0 18.4 25.7 18.4 Max 60.9 64.2 64.2 95.4 92.3 95.4 76.9 81.6 81.6 Mean 2.61 2.63 2.62 2.31 2.23 2.28 2.76 2.62 2.71 StdDev 0.69 0.79 0.72 0.79 0.78 0.79 0.82 0.74 0.79 * Median 2.51 2.58 2.54 2.24 2.07 2.17 2.67 2.55 2.63 FVC L Min 1.35 1.34 1.34 0.69 0.63 0.63 0.71 1.24 0.71 Max 4.23 4.65 4.65 5.58 5.09 5.58 6.29 5.36 6.29 * FEV1.0%FEV1.0FEV1.0/FVC FVC ( 19) wash out 276

11. 11.6.3 FEV1.0 11.6.1 19 205.126A/126B 16/17 205.117/128 14/15 6 1 FEV1.0 11.6.3 0.02 6 (Tr205.226) (205.126A/126B) (Tr205.117/128) 0.02 1 (Tr205.226) (205.126A/126B) (Tr205.117/128) FEV1.0L 0.15 0.10 0.05 0.00 FEV1.0L 0.15 0.10 0.05 0.00-0.05-0.05 0.10 0.10 LSMean95% LSMean95% 11.6.1 FEV1.0 6 1 FEV1.0 0.12L 0.09L 95% 0.080.15L 0.050.13L 6 1 FEV1.0 FEV1.0 95% 6 1 FEV1.0 277

11.6.3 FEV1.0 95% Test Drug LSMean Day Lower Upper P-Value 0.12 0.10 0.14 <.0001 92-0.02-0.04 0.00 0.12 0.10 0.13 <.0001 176-0.04-0.06-0.01 205.117/205.128 0.12 0.10 0.14 <.0001 14/15 260-0.03-0.05-0.01 0.11 0.09 0.13 <.0001 344-0.04-0.06-0.02 0.14 0.12 0.17 <.0001 92 0.00-0.03 0.04 0.13 0.11 0.16 <.0001 182-0.03-0.07 0.00 ( 205.126A/205.126B 0.12 0.09 0.14 <.0001 16/17 273-0.02-0.06 0.01 0.12 0.10 0.15 <.0001 364-0.03-0.07 0.00 0.12 0.08 0.15 0.0003 169 0.00-0.05 0.05 ( 19) 0.09 0.05 0.13 0.0005 365-0.02-0.08 0.03 278

11. 11.6.4 FEV1.0 11.6.2 11.6.4 11.6.5 19 205.117/128 14/15 205.126A/126B 16/17 2 11.6.4 19 19 Tio 18mcg Oxitropium Total N 110 51 161 24 (21.8%) 10 (19.6%) 34 (21.1%) / 0 (0.0%) 0 (0.0%) 0 (0.0%) 20 (18.2%) 10 (19.6%) 30 (18.6%) 6 (5.5%) 0 (0.0%) 6 (3.7%) 74 (67.3%) 34 (66.7%) 108 (67.1%) 74 (67.3%) 34 (66.7%) 108 (67.1%) 49 (44.5%) 25 (49.0%) 74 (46.0%) / 0 (0.0%) 0 (0.0%) 0 (0.0%) 31 (28.2%) 13 (25.5%) 44 (27.3%) 18 (16.4%) 12 (23.5%) 30 (18.6%) 11 (10.0%) 10 (19.6%) 21 (13.0%) 11.6.5 205.117/128 14/15 205.126A/126B 16/17 Tio 18mcg Placebo Total Tio 18mcg Ipratropium Total N 550 371 921 356 179 535 247 (44.9%) 159 (42.9%) 406 (44.1%) 291 (81.7%) 146 (81.6%) 437 (81.7%) / 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.6%) 1 (0.2%) 239 (43.5%) 148 (39.9%) 387 (42.0%) 286 (80.3%) 145 (81.0%) 431 (80.6%) 31 (5.6%) 34 (9.2%) 65 (7.1%) 31 (8.7%) 19 (10.6%) 50 (9.3%) 123 (22.4%) 94 (25.3%) 217 (23.6%) 58 (16.3%) 27 (15.1%) 85 (15.9%) 123 (22.4%) 94 (25.3%) 217 (23.6%) 58 (16.3%) 27 (15.1%) 85 (15.9%) 546 (99.3%) 368 (99.2%) 914 (99.2%) 149 (41.9%) 70 (39.1%) 219 (40.9%) / 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 546 (99.3%) 368 (99.2%) 914 (99.2%) 139 (39.0%) 66 (36.9%) 205 (38.3%) 4 (0.7%) 8 (2.2%) 12 (1.3%) 14 (3.9%) 7 (3.9%) 21 (3.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 279

18.6% 42.0% 80.6% 67.1% 23.6% 15.9% 2 27.3% 99.2% 38.3% FEV1.0 FEV1.0 11.6.6 2 p=0.0798 280

11. 11.6.6 FEV1.0 95% 199-0.03-0.06 0.00 p=0.9115 Placebo 129-0.05-0.09-0.01 205.117/128 290 0.12 0.10 0.15 14/15 Tiotropium 228 0.10 0.08 0.13 33-0.08-0.16-0.00 p=0.3092 Ipratropium 128-0.02-0.06 0.02 205.126A/126B 62 0.11 0.06 0.17 16/17 Tiotropium 267 0.12 0.10 0.15 36-0.02-0.08 0.04 p=0.6585 Oxitropium 10-0.05-0.16 0.07 82 0.09 0.05 0.13 19 Tiotropium 18 0.10 0.01 0.18 246-0.05-0.07-0.02 Placebo 82-0.02-0.07 0.03 205.117/128 401 0.12 0.10 0.14 14/15 Tiotropium 117 0.09 0.05 0.13 138-0.03-0.07 0.01 Ipratropium 23-0.04-0.14 0.05 205.126A/126B 274 0.12 0.09 0.15 16/17 Tiotropium 55 0.12 0.06 0.18 15-0.05-0.14 0.04 Oxitropium 31-0.01-0.07 0.05 33 0.11 0.04 0.17 19 Tiotropium 67 0.08 0.04 0.13 3 0.03-0.22 0.28 Placebo 325-0.04-0.06-0.02 205.117/128 4 0.19-0.03 0.41 14/15 Tiotropium 514 0.11 0.09 0.13 101-0.04-0.08 0.01 Ipratropium 60-0.02-0.08 0.04 205.126A/126B 205 0.12 0.09 0.15 16/17 Tiotropium 124 0.12 0.08 0.16 34-0.01-0.07 0.05 Oxitropium 12-0.06-0.16 0.04 72 0.13 0.08 0.17 19 Tiotropium 28 0.00-0.07 0.07 p=0.0798 p=0.8014 p=0.3576 p=0.9621 p=0.7149 p=0.2854 281

11.6.5 FEV1.0 19 205.126A/126B 16/17 205.117/128 14/15 6 1 FEV1.0 FEV1.0 282