HOE901 A S S Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Gly

HOE901 A S S Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Gly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 S S S Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Arg 22 B Gly 23 Phe 24 Arg Arg Thr Lys Pro Thr Tyr Phe 25 32 31 30 29 28 27 26 S HOE901[15]100 µg/ml HOE901[30]100 µg/ml HOE901[80]100 µg/ml HOE31H HOE36H NPH NPH NPH 125 I-HOE901 HOE901 1,5AG ALP ALT ANCOVA ANOVA AST AUC(0-24h) %B/T BMI CHISQ CI95 CSII DCCT DF DTSQ FAS FBG FPG GHb GIR 1,5--D- Alanine aminotransferase (GPT) Aspartate aminotransferase (GOT) % Bound/Total Body Mass Index 2 95% Diabetes Control and Complications Trial Degree of freedom Full Analysis set

HbA1C HDL HGO IDDM IGDR ITT IU LDH NEC NIDDM NOS OAD PPS QOL Ra Rd Rdmax SIGN-R SMBG SU tmax tmin W-BQ WLCX -GTP A1C Intention-to treat Not Elsewhere Classified Not Otherwise Specified Per Protocol set The Well-being QuestionnaireW-BQ Wilcoxon -

-1-3 -10-10 1101-10 1019-12 1018-14 1006-16 1012-19 1 1020-22 1 1015-25 -27 1008-27 1011-29 1013-33 1001-36 -38 IDDM -40 3101-40 -40-45 -73 NIDDM 3102-75 -75-79 -101-102 3103-102 -102-106

-129-129 1 2 HOE901[30]100 HOE901[80]100 NPH 2002 US -129 1 2 HOE901[30]100 HOE901[80]100 NPH 2003 EU -140 2 2 HOE901[30]100 HOE901[80]100 NPH 2004 EU -152-161 1 NPH 3001-161 1 NPH 3004-176 1 NPH (3005 ) -191 1 NPH 3003-207 2 NPH 3002-223 2 NPH 3006-235 -249-249 -249-250 -252 1-252 1-253 2-256 2-257 2-257 2-263 -267-267 -269

-271-272 -273-280 -281-281 -281-282 -282 1 3101-282 2 3102-283 3103-283 -284-285 1 3101-285 3102-285 3103-285 -286-286 -286-286 -287-287 -287-287 -288-288 -288-289

-1 (1101) (1019) (1018) (1006) (1012) 1 (1020) 1 (1015) *: - * 18 3 16 3 16 3 13 0.1 0.2 0.3 /kg NPH 0.4 /kg NPH 0.4 /kg 1-1 1-2 HOE901[15]100 HOE901[30]100 HOE901[80]100 0.4 /kg NPH 37 0.4 /kg 1 16 1 2 20 NPH 0.3 /kg 1 1 1 11 1 1-2 -3-4 -5-6 (1008) (1011) (1013) (1001) *: 2 * 20 6 1 14 2 2 15 3 9 0.1 /kg 30 2mIU/kg/min 5 40mIU/m 2 /min 4 HOE901[15]100 5 HOE901[80]100 5 5 1 1 1 1-7 -8-9 -1 -- 1 -

IDDM (3101) NIDDM (3102) NIDDM IDDM (3103) NPH NPH () 145 148 293 280 167 168 335 320 3() (1)/NPH(1)() (1)/NPH(1)() 137 (100) 31013102 28 28 56 54-3 64-4 50-1 1 NPH 2002 1 NPH 2003 2 NPH 2004 168 88 256 223 110 333 136 68 204 3() (1)/NPH(12)() 3() (1)/NPH(12)() (1)/NPH(1)() 4 4 4 32 42 29 US -10 EU -11 EU -12 1 NPH (3001 ) 1 (3004) 1 (3005) 2 (3002) NPH NPH NPH 2 NPH (3006 ) 1 NPH (3003 ) 292 293 585 264 270 534 310 309 619 289 281 570 259 259 518 174 175 349 3 () (1 )/NPH(12 )() 3 () (1 )/NPH(12 )() 3 () (1 )/NPH(12 )() (1 )/NPH(1 )() 3 () (1 )/NPH(12 )() 3 () (1 )/NPH(12 )() 28 28 16 52 28 28 63 49 61 57 50 30 EU -13 US -14 US -15 EU -16 US -17 EU -18 -- 2 -

0.10.2 0.3 /kg 30 0.3 /kg 1 0.3 /kg 0.4 /kg 1 11 11 2 30 -- 3 -

30 1001 1 NPH 1 2 / 2 IDDMNIDDM 1 2 -- 4 -

1 3101 NPH 28 HbA1C FBG 1 145 NPH 148 HbA1C -0.15% NPH HbA1C NPH p<0.0001 FBG NPH 0.0003 7 1 28 24 11 8 NPH Dawn phenomenon Somogyi 1 p=0.4447nph 3 (2.1% 14 (10.1%p=0.0051 1 0.7% 2 1.4% 2 7 HOE901 %B/T NPH (QOL) NPH NPH -- 5 -

1 W-BQ NPH 1 24 QOL 2 3102 2 NPH 28 HbA1C FPGFBG 167 NPH 168 HbA1C -1.10%NPH -1.05%HbA1C NPH p<0.0001 FPG FBG NPH FPGp=0.0052FBGCI95=(-32.635-12.024) NPH 24 4 0.298 NPH 0.325 NPH 11:00 13:00 NPH NPH p=0.8065 11 7.0%NPH 20 12.6%p=0.1294 HOE901 %B/T NPH -- 6 -

2 1 1 3103 3101 1 3102 2 28 56 HbA1c IDDM 3101 74 NIDDM 3102 63 IDDM 86.3 63/73 NIDDM 87.1 54/62 86.7117/135 72.6%98/135 67.4%91/135 9.6% 13/135 8.1% 11/135 HOE901 20%B/T HbA1c 56 HbA1c IDDM -0.10%NIDDM -1.12% IDDM 95.9%70/73 NIDDM 38.7% 24/62 69.6% 94/135 24 28 52 56 4 IDDM 48 41 NIDDM 14 4 1 1 1 -- 7 -

65 65 1 65 65 138 1 2 70 158 23 1 1058 29 2 612 204 2 65 23 80 70 HbA1C GHb HbA1C 1-0.20%-0.14% 2-1.22%-1.08% HbA1C GHb 1 0.16%-0.00%2-0.36%-0.53% FBG 1 0 0.0% 14 10.2%2 2 8.7% 9 6.7% 1 6 20.7% 177 17.2%2 15 7.4% 31 7.6% 1 2 1.5% 1 2 6.9% -- 8 -

53 5.2% 2 2 1.0% 2 0.5% 1 2 1 1 24 -- 9 -

1101-1 6 2-2 HOE901 18 6 HOE901[30]100 500 1mL 100 HOE901 0.1 0.2 0.3 /kg 30 12 C- HOE901[15]100HOE901[80]100 5-1 HOE901[15]100HOE901[80]100 20 1 1 4 20 -- 10 -

1000 /kg 1/600 0.1 /kg 60kg 6 0.3 /kg 60kg 18 0.10.2 0.3 /kg 3 0.3 /kg 6 2 2025 21.6 18 166.0180.6cm 173.0cm 51.474.6kg 62.7kg 12 0.3 /kg -19 -- 11 -

1019-2 NPH -3 HOE901 3 7 30 15 HOE901[30]1001 HOE901[30]100 300 1mL 100 NPH 1 NPH 300 1mL 100 HOE901 0.4 /kgnph 0.4 /kg 12 C- 1018-2 0.4 /kg 16 1 1 15 16 -- 12 -

15 21 39 28.5 164 cm 198 cm 175.3 cm 50.2 kg 100.1 kg 66.2 kg BMI 18.2 25.5kg/m 2 21.4 kg/m 2 a 1 No. 2 NPH b 12 a GIR NPH GIR 2 6 Late t50% GIRmax GIRmax 50% NPH -21 b NPH 2.5 15-23 -- 13 -

1018-2 NPH -2-4 HOE901 3 7 30 15 HOE901[30]1001 HOE901[30]100 300 1mL 100 NPH 1 NPH 300 1mL 100 HOE901 0.4 /kgnph 0.4 /kg 12 C- 16 1 1 15 16 15 1939 26.7 170190 cm 181.6 cm 58.587.5 kg 73.5kg BMI 19.725.6 kg/m 2 22.3 kg/m 2 -- 14 -

1 1 17 38.5 a GIR 4 GIR tmax 14.7 () tmax NPH GIR 2 6 GIR tmax 5.2 GIRmax 15-24 b NPH 5-26 -- 15 -

1006-3 -5 3 HOE901 HOE901[15] HOE901[30] HOE901[80] 3 3 7 24 12 1 HOE901[15]100 µg/ml HOE901[30]100 µg/ml HOE901[80]100 µg/ml 500 1mL 100 HOE901[15]100 HOE901[30]100 HOE901[80]100 0.4 /kg C- 14 1 1 1 12 13 13 2130 26 168 196cm 183cm 61.083.0kg 75kg BMI 20.5 23.9kg/m 2 21.7 kg/m 2 -- 16 -

9 23 1 7 6 1 1 HOE901[15]100 4 8 6 HOE901[15]100 2 HOE901[30]100-6 HOE901[15]100 HOE901[30]100 HOE901[80]100 3 4 3 3 2 2 1 2 1 1 1 1 1 1 1 1 1 1 1 22 -- 17 -

a 3 GIRmax GIR(AUC(0-24hr)/24hr) HOE901[30]100 HOE901[80]100 (p<0.05) GIR 2 90%20 GIRmax 3-33 b AUC(0-24hr)/24hr -34 -- 18 -

1012-4 NPH 2-7 HOE901 NPH 12 3 7 2 24 36 12 HOE901[30]1001 HOE901[30]100 300 1mL 100 NPH 1 NPH 300 1mL 100 Ultralong H-Insulin 1 100 1mL 100 HOE901 NPH 0.4 /kg 2 12 C- 37 1 NPH 1 36 37 37 1832 23.1 65.6 99.8kg 79.6kgBMI 20.026.0kg/m 2 23.5 kg/m 2 -- 19 -

a 19 32 13 19 19 2 6 6 1 No. 2 2 3 7 NPH16 9-8 NPH 4 11 4 1 3 2 2 2 1 1 2 1 1 1 b NPH 1 No. 2 3 ALT ASTALT221U/L 5-72U/L AST708U/L 5-40U/L 1 ALT51U/LAST22U/L -- 20 -

AUC(0-8hr) AUC(8-12hr) 12 NPH NPH 12 AUC(12-16hr)AUC(16-24hr) AUC(12-24hr) NPH 2 -- 21 -

1 1020-5 1-9 1 1 HOE901 1 1 NPH 1 2 CSII 16 1 HOE901[30]100 300 1mL 100 4 721 HOE901 7 21 11 HOE901 1 1 HOE901 21 HOE901 11 12 HOE901 -- 22 -

1 17 1 1 2 15 16 12 4 2349 35.8 166195cm 179.4cm 62 97kg 79.2kgBMI 20.627.9kg/m 2 24.6 kg/m 2 4 28 16.9 16 4 CSII 15 1434 23.9 16 1 15 4 6 6 3 2 3 3 17 1 16 11 5 11-10 1 (1) - 1 (5) - 1 (2) - 1 (11) - - 1 (1) - 1 (1) - 1 (1) - - - 1 (1) - - -- 23 -

1 2 Cmax AUC(0-24hr) 2 5 2 12 90%5 2 12 2 2-38 -- 24 -

1 1015-6 NPH 1-11 1 1 HOE901 NPH 2 24 1 3 20 HOE901[30]1001 HOE901[30]100 300 1mL 100 NPH 1 NPH 300 1mL 100 HOE901 0.3 /kg NPH 0.3 /kg 12 1 20 12 8 20 2052 32.4 150186cm 170.6cm 4884kg 64.8kg BMI 19.625.8kg/m 2 22.1 kg/m 2 5 31 16.0 -- 25 -

22.8 NPH 13.8 20 14 24 24 NPH 14.5 tmax 1.0821.8 NPH NPH -40 -- 26 -

1008-7 -12 HOE901 2 7 6 20 HOE901[30]1001 HOE901[30]100 300 1mL 100 1 300 1mL 100 HOE901 0.1 /kg 0.1 /kg 30 30 12 C- 20 15 5 20 1840 23.9 167194cm 180.9cm 59.693.9kg 75.3kgBMI 19.825.7kg/m 2 23.0 kg/m 2 7 7 -- 27 -

4 3 1 35 6 2 3 3 2 GIR AUC(0-6hr) 90% 84.696.7% 80125%GIR -27 -- 28 -

1011-8 1-13 1 HOE901 2 7 5 1 6 1 14 HOE901[30]1001 HOE901[30]100 500 1mL 100 1 1000 1mL 100 HOE901 2mIU/kg/min 5 8575655545mg/dL 1 2mIU/kg/min 20 5 12 0 6 --OHB C- -- 29 -

20 6 1 14-14 / BMI 19 32 162.1189.0cm 53.0 104.0kg 19.7 31.0 kg/m 3 /3 2 (n=6) (26 ) (174.5cm) 76.3kg 24.5kg/m 2 1 19 45 157.2188.4cm 60.6 101.3kg 23.1 34.9 kg/m 4 /10 2 (n=14) (29 ) (169.3cm) 78.3kg 27.3kg/m 2 19 6 1 13 2 1 1 2 2 20-15 10 15 7 5 2 2 5 8-15 2 2 3 3 1 1 1 1 1 1 1 1 1 1 1 -- 30 -

5-16 GIR --OHB 2 -- 31 -

-16 (n=6) (n=13) 95% p 95% GIR 130.93 4.43 (-30.3,39.2) 0.741 97.42-4.38 (-18.6, 9.9) 0.513 (ml/hr) 126.50 101.80 63.33-0.05 (-2.4, 2.3) 0.957 63.57-0.17 (-1.3, 0.9) 0.744 (mg/dl) 63.38 63.74 p 65.32-3.98 (-21.2,13.2) 0.556 41.15-1.44 (-4.8, 1.9) 0.364 (pg/ml) 69.30 42.59 223.50-41.17 (-171,88.5) 0.428 138.10 1.01 (-39.2,41.3) 0.957 (pg/ml) 264.67 137.09 214.80 26.17 (-46.2,98.6) 0.372 245.41 5.45 (-40.6,51.5) 0.799 188.63 239.96 (pg/ml) 59.47-13.43 (-39.6, 0.227 99.93 2.79 (-25.0,30.5) 0.829 12.7) (µmol/l) 72.90 97.14 1339.70 4.60 (-271,280.0) 0.965 1190.84-128.5 (-314,56.9) 0.155 (µmol/l) 1335.10 1319.39 325.93 0.33 (-162,162.9) 0.996 268.87-38.36 (-89.0,12.3) 0.124 (µmol/l) 325.60 307.23 -OHB 61.90-26.67 (-87.5,34.1) 0.290 97.58-8.77 (-35.1,17.6) 0.479 (µmol/l) 88.57 106.35 4.97-0.67 (-2.4, 1.1) 0.350 11.59 1.83 (-1.3, 5.0) 0.229 5.64 9.77 (ng/ml) 13.44-2.41 (-8.2, 3.4) 0.311 15.96-0.17 (-2.5, 2.2) 0.879 (µg/dl) 15.85 16.12 5.33-0.43 (-1.8, 0.9) 0.424 5.29-0.53 (-2.1, 1.0) 0.475 5.77 5.81 3.33 0.13 (-1.3, 1.6) 0.812 3.48 0.12 (-0.6, 0.9) 0.728 3.20 3.36 8.67-0.30 (-2.6, 2.0) 0.732 8.77-0.39 (-2.0, 1.2) 0.603 8.97 9.16 -- 32 -

1013-9 -17 HOE901 2 7 7 4 15 HOE901[30]1001 HOE901[30]100 500 1mL 100 1 1000 1mL 100 D-[3-3 H]- 4 0.15µCi/min 3 H- HOE901 40mIU/m 2 /min 4 90mg/dL D-[3-3 H]- 20hot-GINF 3 90mg/dL 4 12 C- -- 33 -

17 15 2 15 4 12 3 40 17 17 1850 33 165.0193.0cm 176.8cm 54.787.7kg 75.6kg BMI18.127.5kg/m 2 24.1 kg/m 2 4 4 2 D-[3-3 H]- 20 hot-ginf Ra RdHepatic glucose outputhgoincremental glucose disposal rateigdrrdmax HGO Ra HGO Ra GINF HGO 50% A50 HGO IGDR Rd Rd 50% A50 IGDR 50% D50 IGDR -- 34 -

HGO 50% 56.6 73.0 p=0.0585 Rdmax 9.9 10.1mg/kg/min Rd AUC 2740mg/kg 2887mg/kg A50 IGDR D50 IGDR A50 IGDR 42.1 32.4 D50 IGDR 57.3 62.8 0.430.09 0.37mmol/L 0.450.09 0.33mmol/L -- 35 -

1001 1-18 HOE901 3 6 9 HOE901[15]1001 HOE901[15]100 500 1mL 100 HOE901[80]1001 HOE901[80]100 500 1mL 100 1 500 1mL 100 HOE901[15]100HOE901[80]100 5 C- 9 9 1937 25.8 167188cm 179cm 6091 kg 73.3kgBMI 19.826.6kg/m 2 22.9 kg/m 2 -- 36 -

AUC AUC(0-7hr)/7hr AUC(0-1.5hr)/1.5hr tmin HOE901[15]100 HOE901[80]100-19 HOE901[15 100 HOE901[80]100 a (-) (-) (-) AUC(0-7hr)/7hr (mg/dl) 81.6 (77.0-89.6) 82.8 (76.4-91.4) 82.1 (74.5-87.5) AUC(0-1.5hr)/1.5hr (mg/dl) 64.0 (53.9-88.8) 64.1 (54.9-70.6) 64.4 (57.3-78.9) (mg/dl) 49.8 (16.0-59.0) 53.9 (43.0-63.0) 49.6 (22.0-63.0) t min (hr) b 0.50 (0.25-1.00) 0.50 (0.50-0.75) 0.50 (0.25-0.50) a:n=7 b: n=9-20 90% 90% HOE901[15]100 HOE901[80]100 vs. vs. HOE901[80]100 vs. HOE901[15]100 AUC(0-7hr)/7hr (mg/dl) a 1.14 (-0.68;3.00) 1.38 (-0.80;3.63) 0.25 (-1.92;2.47) AUC(0-1.5hr)/1.5hr (mg/dl) a 0.55 (-3.60;4.99) 0.89 (-4.08;6.28) 0.34 (-4.59;5.67) (mg/dl) a 6.68 (-5.95;23.2) 0.39 (-12.1;17.4) -6.28 (-18.8;10.7) t min (hr) b 0.00 (-0.13;0.13) 0.00 (-0.25;0.00) 0.00 (-0.13;0.00) a: 90% b: 90% 100 100-1 -- 37 -

/ / 0.10.2 0.3 /kg /1 2 / 1) 2 HbA1C DCCT UKPDS 3-4 HbA1C / HbA1C -- 38 -

BasalBolus 5 1 1 24 / 1 1 2 1 NPH 1001-36 1 1 NPH NPH 4 2002-129 2003-140 NPH 2003-140 NPH 1018-14 NPH NPH / -- 39 -

IDDM 3101-3 1 4 NPH -21 NPH 1001-36 NPH -- 40 -

-21 IDDM 1 4 1 1 1 3 HOE901Insulin glargine IDDM 1. 1665 2. 2 I D D M C- 1.0ng/mL 3. 1 12 1 1 1 3 4. HbA1C 6.5% 10.0% 5. 6. 7. 8. 1. IDDM 2. 4 3. 4. 5. 16 6. 7. 8. 9. 10. 12 12 11. 12. 13. 14. GOTGPT2 80 IU/L 2mg/dL 15. 1. 140 280 2. (1)HbA1C =1.104% (2) HbA1C ()= 0.45% HbA1c 5.7%6.7% HbA1c HbA1c 6.5[%] 10.0[%] HbA1c 8.0[%] 8.0[%] 0.057(=5.7%)0.456[%] -- 41 -

HOE901 0.5[%] 0.5[%] 0.456[%] 0.45[%] HbA1c (3) 2.590 (4) HOE901 3.0mL 100 IU/mL NPH 3.0mL100 IU/mL HOE901 NPH HOE901 NPH 1 1 28 4 28-4 0 4 8 12 16 20 24 28 2 C HbA1c 1,5AG FBG(7 ) 1 4 FBG() E. coli 3 1GOTGPT 2 24 3 4 HbA1C HbA1C 1 7 1,5- HbA1C 1,5AG -- 42 -

FBG 16 7 FBG 1 7 16 1 7 7 E. coli DTSQ W-BQ PPS ITT 2.5 5 15 PPS 2 Wilcoxon Wilcoxon HbA1C HbA1C t- 95% 2 t- Wilcoxon 95% 7 95% 1 7 7 7 95% 1 Wilcoxon -- 43 -

(1) Wilcoxon (1) 95% Fisher (2) 95% Fisher QOL 54 -- 44 -

293 145 NPH 148-2 (PPS) 258 128 NPH 130 ITT 282 138 NPH 144 370 293 NPH 77 145 148 282 11 ITT NPH NPH 7 4 138 144 272 FAS 10 FAS NPH NPH 134 138 4 6 258 PPS 14 (PPS) NPH NPH 128 130 6 8-2 -- 45 -

-22 FAS PPS 24 10 NPH 14 FAS 10 4 NPH 6 7 2 NPH 5 2 1 PPS 14 6 NPH 8 HbA1C 16 HbA1C 16-22 NPH 1 0 1 2 5 7 1 1 2 6 8 14 10 14 24-23 21 11 NPH 10 9 3 NPH 6 6 4 NPH 2 21 11 10 4 NPH 6-23 NPH 4 2 1 0 2 0 1 1 3 6 0 1 11 10 -- 46 -

PPS258 128 NPH 130-24 2 p<0.15 p=0.0902 p=0.0519 Wilcoxon p=0.1331 HbA1C p=0.8074-25 -24 PPS NPH 128 130 258 47(36.7%) 52(40.0%) 99(38.4%) p1=0.5879 81(63.3%) 78(60.0%) 159(61.6%) 16-<20 0 1(0.8%) 1(0.4%) p1=0.1880 20-<30 31(24.2%) 39(30.0%) 70(27.1%) p2=0.5457 30-<40 33(25.8%) 33(25.4%) 66(25.6%) 40-<50 35(27.3%) 21(16.2%) 56(21.7%) 50-29(22.7%) 36(27.7%) 65(25.2%) -<150 10(7.8%) 4(3.1%) 14(5.4%) p1=0.4126 150-<160 52(40.6%) 58(44.6%) 110(42.6%) p2=0.7060 (cm) 160-<170 42(32.8%) 44(33.8%) 86(33.3%) 170-<180 23(18.0%) 24(18.5%) 47(18.2%) 180-1(0.8%) 0 1(0.4%) -<40 4(3.1%) 2(1.5%) 6(2.3%) p1=0.1832 40-<50 26(20.3%) 17(13.1%) 43(16.7%) p2=0.7980 (kg) 50-<60 47(36.7%) 67(51.5%) 114(44.2%) 60-<70 39(30.5%) 33(25.4%) 72(27.9%) 70-11(8.6%) 11(8.5%) 22(8.5%) 1(0.8%) 0 1(0.4%) -<25 111(86.7%) 112(86.2%) 223(86.4%) p1=0.5750 (kg/m 2 ) 25-<30 16(12.5%) 18(13.8%) 34(13.2%) 30-0 0 0 p2=0.7683 1(0.8%) 0 1(0.4%) 114(89.1%) 122(93.8%) 236(91.5%) p1=0.0902 * 13(10.2%) 5(3.8%) 18(7.0%) 1(0.8%) 3(2.3%) 4(1.6%) 112(87.5%) 120(92.3%) 232(89.9%) p1=0.0519 * 15(11.7%) 6(4.6%) 21(8.1%) 1(0.8%) 4(3.1%) 5(1.9%) 115(89.8%) 118(90.8%) 233(90.3%) p1=0.8188 8(6.3%) 6(4.6%) 14(5.4%) 5(3.9%) 6(4.6%) 11(4.3%) 43(33.6%) 35(26.9%) 78(30.2%) p1=0.2434 85(66.4%) 95(73.1%) 180(69.8%) -<60 39(30.5%) 45(34.6%) 84(32.6%) p1=0.6115 60-<120 28(21.9%) 30(23.1%) 58(22.5%) p2=0.2537 120-<180 20(15.6%) 22(16.9%) 42(16.3%) 180-41(32.0%) 32(24.6%) 73(28.3%) 0 1(0.8%) 1(0.4%) -<60 31(24.2%) 35(26.9%) 66(25.6%) p1=0.6084 60-<120 34(26.6%) 34(26.2%) 68(26.4%) p2=0.4185 120-<180 20(15.6%) 26(20.0%) 46(17.8%) 180-43(33.6%) 35(26.9%) 78(30.2%) -<60 90(70.3%) 100(76.9%) 190(73.6%) p1=0.4650 60-<120 32(25.0%) 26(20.0%) 58(22.5%) p2=0.2202 120-<180 6(4.7%) 4(3.1%) 10(3.9%) 180-0 0 0 81(63.3%) 89(68.5%) 170(65.9%) 47(36.7%) 41(31.5%) 88(33.7%) 100(78.1%) 99(76.2%) 199(77.1%) 28(21.9%) 31(23.8%) 59(22.9%) p 1=0.3802 p 1=0.7062 -- 47 -

-24 PPS NPH 116(90.6%) 113(86.9%) 229(88.8%) p1=0.3466 12(9.4%) 17(13.1%) 29(11.2%) 117(91.4%) 112(86.2%) 229(88.8%) 11(8.6%) 18(13.8%) 29(11.2%) p1=0.1817 -<8.0 79(61.7%) 76(58.5%) 155(60.1%) p1=0.5933 HbA1C (%) 8.0-49(38.3%) 54(41.5%) 103(39.9%) p2=0.5940 0 0 0 -<140 45(35.2%) 51(39.2%) 96(37.2%) p1=0.6693 140-<160 13(10.2%) 17(13.1%) 30(11.6%) p2=0.2609 FBG (mg/dl) 160-<180 10(7.8%) 7(5.4%) 17(6.6%) 180-<200 9(7.0%) 11(8.5%) 20(7.8%) 200-49(38.3%) 40(30.8%) 89(34.5%) 2(1.6%) 4(3.1%) 6(2.3%) 0-<2 64(50.0%) 65(50.0%) 129(50.0%) p1=0.5015 1,5AG (µg/ml) 2-<6 58(45.3%) 55(42.3%) 113(43.8%) p2=0.9954 6-6(4.7%) 8(6.2%) 14(5.4%) 0 2(1.5%) 2(0.8%) -<20 7(5.5%) 6(4.6%) 13(5.0%) p1=0.8845 20-<25 40(31.3%) 36(27.7%) 76(29.5%) p2=0.5824 (%) 25-<30 61(47.7%) 68(52.3%) 129(50.0%) 30-20(15.6%) 20(15.4%) 40(15.5%) 0 0 0 (%) Wilcoxon *: p <0.15 p 1 p p2wilcoxon p -25 PPS NPH 126 125 251 12.136.10 13.467.16 12.796.67 p1 0.1331 * 2.0 3.0 2.0 p 2=0.8074 10.50 12.00 12.00 36.0 40.0 40.0 126 126 252 9.834.30 10.104.41 9.964.35 2.0 4.0 2.0 p 1 0.7913 10.00 10.00 10.00 24.0 26.0 26.0 126 126 252 8.913.37 8.753.60 8.833.48 4.0 2.0 2.0 p 1 0.5214 8.00 8.00 8.00 18.0 24.0 24.0 126 126 252 10.024.10 10.064.63 10.044.36 2.0 2.0 2.0 p 1 0.6510 10.00 9.00 9.00 24.0 28.0 28.0 126 126 252 28.7510.45 28.9011.31 28.8310.87 10.0 10.0 10.0 p 1 0.8240 28.00 26.00 27.00 60.0 72.0 72.0 126 125 251 40.8813.90 42.2015.77 41.5414.84 16.0 18.0 16.0 p 1 0.7259 39.00 40.00 40.00 82.0 96.0 96.0 *:p1<0.15 p <0.05 p 1 Wilcoxon pp 2HbA1c -- 48 -

HbA1C = HbA1C HbA1C NPH -26 7.71 0.84 7.570.95-0.150.66 NPH 7.840.87 7.830.92-0.000.79 NPH p<0.0001 95(-0.371,-0.010) 16 () -26 HbA1C(%)(PPS) NPH 128 128 128 7.710.84 7.570.95-0.150.66 130 130 130 7.840.87 7.830.92-0.000.79 Null hypothesis :=NPH+0.45 Alternative hypothesis :<NPH+0.45 CI95 : 95% p<0.0001 CI95=(-0.322, 0.036) p=0.1169 HbA1C HbA1C -3 7.710.84% 4 0.2% 28 7.560.96%-0.150.66% (p=0.0061)nph 7.840.87% 28 7.820.93% -0.000.79%- NPH Wilcoxon p=0.0356-27 -- 49 -

-3 HbA1C -27 HbA1C % NPH 7.710.84 7.60 128 7.840.87 7.75 130 7.570.95 7.45 128 7.830.92 7.70 130-0.150.66-0.20 128-0.000.79 0.10 130 t0=-2.475 DF=127 p=0.0146* t0=-0.033 DF=129 p=0.9735 T(1) SIGN-R WLCX S =-1023.00 p =0.0061** S =79.500 p =0.8318 = 4.416 DF=1 p = 0.0356 * *:p<0.05, **:p<0.01 T(1):Student's paired t-test SIGN-R Signed Rank WLCX Wilcoxon DCCT HbA1C 7 28 (21.9%) 36 28.1%NPH 29 (22.3%) 25 (19.2%) p=0.1076-28 7% CI95 7% CI95-28 HbA1C 7%PPS NPH * 28/128 21.9 (15.1, 30.0) 36/128 28.1 (20.5, 36.8) *:Fisher s exact test CI95:95% 29/130 22.3 (15.5, 30.4) 25/130 19.2 (12.8, 27.1) 57/258 22.1 (17.2, 27.7) 61/258 23.6 (18.6, 29.3) p=1.0000 Difference(%)=0.4 CI95=(10.6, 9.7) p=0.1076 Difference(%)=8.9 CI95=(1.4, 19.2) -- 50 -

(FBG) a FBG (FBG)-4 FBG 1 FBG 176.9169.85mg/dL 4 20mg/dL 28 140.1460.15mg/dL NPH 169.4175.80mg/dL 28 169.7176.55mg/dL -4 FBG FBG NPH FBG FBG -37.7183.65mg/dL p<0.0001 NPH 4.3594.03 mg/dl Wilcoxon p= 0.0003-29 -29 FBG(mg/dL) 176.9169.85 172.50 (126) 169.4175.80 154.00 139.2158.54 123.00 (126) 173.7678.88 160.00 37.7183.65 27.00 (126) 4.3594.03 1.50 (126) T(1) SIGN-R WLCX t0=-5.060 S=-1829.00 DF=125 p<0.0001** p<0.0001** t0=0.519 DF=125 p=0.6045 S= 322.500 p=0.4345 = 13.101 DF=1 p= 0.0003** (126) (126)!p<0.15, +p<0.10, *p<0.05, **p<0.01 T(1)Student's paired t-test SIGN-RSigned Rank WLCX Wilcoxon -- 51 -

FBG 140mg/dLNPH 51/126(40.5 ) 51/130(39.2 ) 45/126(35.7 ) 77/128(60.2%) p=0.0012-30 -30 FBG 140mg/dL * 16 28 / 45/126 60/121 73/122 77/128 p=0.0012 (35.7) (49.6) (59.8) (60.2) Difference(%)=20.9 51/126 48/122 48/119 51/130 NPH CI95=(9.0, 32.9) (40.5) (39.3) (40.3) (39.2) * Fisher s exact test 95 16 28 7-5 7 16 28 14 7 16 28 172.968 158.342 155.087mg/dL NPH 176.738172.628 177.981mg/dL 28 95%-35.610-12.581-5 -- 52 -

1 BG 7 BG-6 1 14 1 7 7 0 16 28 0 28 28 95-32.9,-3.9-49.8,-15.7-42.3,-7.2 NPH 0 28 95-40.9,-4.0 95-26.9,-4.8-34.7,-5.9-6 1 -- 53 -

1,5AG 1,5AG 2.572.15µg/mL 28 2.962.40µg/mL NPH 2.451.70µg/mL 28 2.65 1.67µg/mL (p=0.2300) 26.143.81% 28 24.933.96%NPH 26.463.90% 28 25.79 4.37% p=0.0235 (0 ) 28-7 1 40.88 13.90 28 40.8113.91 NPH 42.2015.77 28 43.6615.76 NPH 12.136.10 28 12.475.70 NPH 13.467.16 28 14.196.69 1 28.7510.45 28 28.3410.46 NPH 28.9011.31 28 29.4611.15-7 -- 54 -

p=0.0047p=0.0441p=0.0094-31 NPH FBG (126) NPH (125) (126) NPH (126) (126) NPH (126) (126) NPH (126) (126) NPH (126) (126) NPH (125) -31 () 12.13±6.10 10.50 13.46±7.16 12.00 9.83±4.30 10.00 10.10±4.41 10.00 8.91±3.37 8.00 8.75±3.60 8.00 10.02±4.10 10.00 10.06±4.63 9.00 28.75±10.45 28.00 28.90±11.31 26.00 40.88±13.90 39.00 42.20±15.77 40.00 12.48±5.70 11.00 14.00±6.70 14.00 9.47±4.06 9.00 10.06±4.25 9.00 8.59±3.51 8.00 8.91±3.69 8.00 9.85±4.15 10.00 10.40±4.97 9.00 27.90±10.54 26.50 29.37±11.54 26.00 40.39±13.89 38.00 43.22±16.14 40.00 0.36±2.76 0.00 0.54±2.77 0.00 0.35±1.50 0.00 0.03±2.20 0.00 0.33±1.36 0.00 0.17±1.33 0.00 0.17±1.42 0.00 0.34±2.22 0.00 0.85±3.06 0.00 0.48±3.93 0.00 0.49±4.44 0.00 1.02±5.54 0.00 *:p<0.05, **:p<0.01 (1) Signed Rank(2) Wilcoxon p=0.0814 p=0.0055** p=0.0059** p=0.4804 p=0.0113* p=0.1489 p=0.1718 p=0.1001 p=0.0023** p=0.3243 p=0.4434 p=0.0533 p=0.3424 p=0.2716 p=0.0047** p=0.0441* p=0.0094** p=0.0755-8 a) b) c) 50mg/dL p=0.2370p=0.8969p=0.2533 -- 55 -

Fisher's exact test -8 a) 117 91.4%NPH 112 86.2%p=0.2370 4 2.677 NPH 3.025 p=0.8203-32 -32 4 PPS NPH ** *** 128 130 (%) 99(77.3) 75(57.7) 04 p=0.0009 p=0.0127 4* 3.7110.415 3.0380.409 128 130 (%) 110(85.9) 110(84.6) 5 p=0.8610 p=0.7879 4* 2.5090.259 3.0230.353 128 130 (%) 117(91.4) 112(86.2) p=0.2370 p=0.8203 4* 2.6770.271 3.0250.352 * 28 **Fisher s exact test ***Wilcoxon -- 56 -

4 4 NPH 75 57.7% 99 77.3% p=0.00095 p=0.8610-9 -10 4 57 1012 1719 NPH 4 NPH -11-9 -10 0 4 -- 57 -

-11 4 b) 81 63.3% NPH 84 64.6% (p=0.8969) 4 0.505 NPH 0.793 p=0.2881-33 -33 4 PPS NPH ** *** 128 130 04 (%) 44(34.4) 47(36.2) p=0.7953 p=0.6701 4 * 0.6250.098 0.7380.115 128 130 5 (%) 74(57.8) 80(61.5) p=0.6119 p=0.2510 4 * 0.4860.067 0.8010.113 128 130 (%) 81(63.3) 84(64.6) p=0.8969 p=0.2881 4 * 0.5050.068 0.7930.107 * 28 **Fisher s exact test ***Wilcoxon -- 58 -

4 NPH 4 NPH 130 77-12 4 NPH 2 5-12 c) 26 20.3% NPH 19 14.6%(p=0.2533)4 4 0.068 NPH 0.045 p=0.2075-34 NPH 8 9 52 NPH 29 10 NPH 10 NPH 3 -- 59 -

-34 4 PPS NPH 128 130 04 (%) 8(6.3) 4(3.1) 4 * 0.0940.036 0.0380.020 128 130 5 (%) 23(18.0) 17(13.1) 4 * 0.0630.018 0.0440.018 128 130 (%) 26(20.3) 19(14.6) 4 * 0.0680.017 0.0450.017 ** *** p=0.2526 p=0.3054 p=0.2533 * 28 ** Fisher s exact test *** Wilcoxon p=0.2229 p=0.2762 p=0.2075-13 35 23 12 5 NPH 7 NPH 182.2mg/dL 11 116.2mg/dL 8 180.2mg/dL 166.4mg/dL 11 94.6mg/dL 109.6mg/dL 8 NPH NPH 224.3mg/dL 11 154.1mg/dL 182.7mg/dL 8 205.6mg/dL180.0mg/dL 197.9mg/dL -- 60 -

(N=5) (N=7) -13 1 Somogyi -35 90 65.2210 NPH 101 70.1206 p=0.4447-36 -- 61 -

-35 ITT (1) % : MedDRA Ver3.3 -- 62 -

-35 ITT (2) % : MedDRA Ver3.3 -- 63 -

-35 ITT (3) % : MedDRA Ver3.3 -- 64 -

14 (10.1%) NPH 3 (2.1%)p=0.0051-36 -36 95ITT NPH * / 90/138 101/144 % 65.2 70.1 95% (56.6, 73.1) (62.0, 77.5) p=0.4447 * Fisher s exact test / 14/138 3/144 % 10.1 2.1 95% (5.7, 16.4) (0.4, 6.0) p=0.0051 ALTGPTAST GOT NPH -35 1 1 1 1 1 1 10 12 2 10 2 A-I 1 1-37 -- 65 -

: () 4-37 (ITT) () () () () () ( ) ** 196 196 1 22 36 2 2 2 1 (1281421701844) 2 127 197 71 26 54 71 2 ALT 197 26 54 29 3 AST 197 26 54 29 3 ALT4 AST4 197 4 171 8 24 174 1 171197204 6 3 2 36110 5 197 218 22 11 31 50 2 5.9mEq/l4.4mEq/l(218) 3 92 176 85 22 15 85 2 5 * 68 77 10 5 28 6 2 6723:0068(A.M2:00) 6971 CT77 6 166 176 11 20 41 36 2 195 212 18 20 41 42 2 2 182 30 46 92 3 2 * 145 146 2 14 30 25 2 20%Glucose 60ml400mg/dl 500ml+R 10DIVFPG 277mg/dlR 10 311mg/dl 5 197 225 29 6 32 29 2 457/mm 3 411/mm 3 429/mm 3 HbHt 3 15 22 24 22 1 4 () 152 215 64 18 42 64 2 215 18 42 18 3 ** -- 66 -

-37 (ITT) :NPH () 4 () () () () () () 197 8 18 1 3 2 212 4 22 1 3 2 22 6 22 36 2 63 65 3 6 23 23 2 2 157 7 23 28 2 ** 2 1.4%2 NPH 2 1.4%2 7 7 NPH 7 8 2 NPH 1-259 ALPHDL Ca NPH GOTGPTHDL NaCl p<0.0001nph p=0.1395nph p=0.0228hdl p<0.0001nph -- 67 -

p=0.0336p=0.0165 p=0.0002nph p<0.0001 p=0.0496 57.8410.24kg 28 58.4310.33kg NPH 57.628.52kg 28 58.058.51kg 22 13 NPH 9 4 2 NPH 2 1 E.coli E.coli 4 NPH 3 ⅺ HOE901-14 HOE901 132 19.484 15.824% B/T 24.05316.229%B/T NPH 138 18.83615.675%B/T 18.24614.297%B/T p=0.0608 19.101 16.637%B/T 20.23614.381%B/T NPH 18.24216.053%B/T 17.71915.016%B/T -- 68 -

p=0.6778 HOE901 20%B/T 20%B/T HOE901 21 NPH 1 p=0.0001 12 NPH 1 p=0.0012 20%B/T HOE901 4 NPH 0 4 NPH 0 HOE901 (p=0.0558p=0.0558) 1 13 4 HOE901 20%B/T 22-38 -14 HOE901 ( B/T) -- 69 -

-38 20B/T HOE901 HbA1c (%B/T) (%B/T) (%) 5/ 36.09 15.98-20.11 6.9 5.5-1.4 55.0 47.0-8.0 2/ 48.52 18.84-29.68 49.63 18.48-31.15 9.3 8.1-1.2 48.0 46.0-2.0 4/ 54.86 32.06-22.80 7.2 6.7-0.5 32.0 32.0 0.0 4/ 40.84 18.26-22.58 48.47 18.41-30.06 7.2 7.2 0.0 26.0 26.0 0.0 5/ 49.13 27.71-21.42 47.02 25.77-21.25 8.1 7.8-0.3 31.0 28.5-2.5 3/ 45.63 71.63 26.00 9.8 10.0 0.2 27.0 24.0-3.0 3/ 9.61 30.36 20.75 6.7 6.8 0.1 20.0 22.0 2.0 5/ 8.33 43.77 35.44 7.68 37.27 29.59 7.1 6.7-0.4 28.0 25.0-3.0 4/ 6.55 55.83 49.28 5.55 32.13 26.58 7.2 6.2-1.0 39.0 31.0-8.0 4/ 10.53 53.78 43.25 10.25 47.61 37.36 7.3 7.1-0.2 53.0 53.0 0.0 3/ 15.85 43.93 28.08 8.5 9.5 1.0 36.0 38.0 2.0 3/ 7.37 53.23 45.86 6.43 49.10 42.67 7.4 8.3 0.9 44.0 38.0-6.0 5/ 7.79 35.90 28.11 6.29 35.37 29.08 6.2 6.4 0.2 40.0 38.0-2.0 4/ 10.18 41.01 30.83 8.40 29.35 20.95 8.1 7.1-1.0 25.0 24.0-1.0 2/ 9.19 36.98 27.79 8.20 36.66 28.46 7.8 7.5-0.3 54.0 54.0 0.0 3/ 10.10 32.47 22.37 6.9 6.4-0.5 28.0 32.0 4.0 5/ 24.30 57.91 33.61 8.4 7.8-0.6 40.0 42.0 2.0 2/ 19.66 43.83 24.17 19.55 40.34 20.79 8.9 9.5 0.6 58.0 56.0-2.0 4/ 9.50 40.55 31.05 11.07 36.74 25.67 7.0 6.9-0.1 56.0 43.0-13.0 4/ 7.45 48.68 41.23 7.4 8.0 0.6 46.0 50.0 4.0 2/ 30.20 53.83 23.63 9.4 7.4-2.0 69.0 60.0-9.0 5/ 9.96 37.27 27.31 8.23 31.04 22.81 6.9 7.3 0.4 37.0 38.0 1.0 3/ 13.04 67.50 54.46 12.46 61.07 48.61 8.3 7.9-0.4 60.0 50.0-10.0 4/ 7.53 29.22 21.69 6.70 27.50 20.80 6.9 6.5-0.4 38.0 40.0 2.0 4/ 12.96 38.87 25.91 9.7 9.4-0.3 34.0 27.0-7.0 4/ 19.27 55.38 36.11 8.1 7.6-0.5 35.0 38.0 3.0 NPH 3/ 14.29 38.06 23.77 11.99 37.17 25.18 8.6 6.9-1.7 25.0 41.0 16.0 20%B/T -- 70 -

QOL DTSQ 6 W-BQ 7-15 DTSQ W-BQ Negative Energy Positive DTSQ 20.9 22.7 NPH 22.2 22.6 (p=0.0940) NPH p=0.0038 3.4 3.0 NPH 3.5 3.4 p=0.0200 2.3 2.2 NPH 2.2 2.4 (p=0.1092) NPH NPH 1 8) -- 71 -

* p<0.05-15 W-BQ NPH (p=0.0479) NPH p=0.0163 NPH -16 -- 72 -

* p<0.05-16 W-BQ 2 NPH QOL HbA1C NPH (p<0.0001) FBG 1 28 24 NPH Somogyi 4 1 0.7% 2 1.4% -- 73 -

HOE901 20%B/T QOL QOL 1 QOL -- 74 -