Page 1919 3 × ULN at Any Post-Baseline Visits · 2017-02-17 · Table 238: Listing of Subjects Li ver Function Tests (ALT, AST) 3 × ULN at Any Post-Baseline Visits Part I (Placebo-Controlled

Table 238: Listing of Subjects Liver Function Tests (ALT, AST) ≥3 × ULN at Any Post-Baseline Visits – Part I (Placebo-Controlled Period)

Listing of subjects liver function tests (ALT, AST) >=3x ULN at any post-baseline visits -Part I (placebo-controlled period) Treatment group: Placebo Page 1 of 7 ___________________________________________________________________________________________________________ Total Alkaline ALT AST Serum Subject Bilirubin Phosphatase (SGPT) (SGOT) GGT Sex Study Collection (umol/L) (U/L) (U/L) (U/L) (U/L) Weight Day (a) Date Visit (b) (c) (c) (c) (c) ___________________________________________________________________________________________________________

-9 2014-06-09 SCREENING 8 42 9 16 10 F 52.2 kg 1 2014-06-18 BASELINE DAY 1 9 45 8 17 9 29 2014-07-16 WEEK 4 13 37 8 16 7 55 2014-08-11 WEEK 8 7 48 10 18 8 85 2014-09-10 WEEK 12 13 41 8 19 9 111 2014-10-06 WEEK 16 12 47 9 17 13 146 2014-11-10 WEEK 20 12 50 36 (*) 37 (*) 14 174 2014-12-08 BASELINE WEEK 24 9 51 119 (**) 72 (*) 19

-29 2013-09-09 SCREENING 4 92 20 20 M 65.4 kg -10 2013-09-28 UNSCHEDULED 13 81 16 20 21 -1 2013-10-07 BASELINE DAY 1 6 73 17 19 21 30 2013-11-06 WEEK 4 8 80 17 21 21 56 2013-12-02 WEEK 8 6 77 17 21 20 57 2013-12-03 UNSCHED RELAPSE1 6 89 19 23 21 ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1919

358*

371*

＊新薬承認情報提供時に置換えた


80 2013-12-26 WEEK 12 5 85 19 18 20 M 65.4 kg 112 2014-01-27 WEEK 16 6 88 31 28 17 140 2014-02-24 WEEK 20 7 97 166 (**) 78 (*) 35 159 2014-03-15 UNSCHEDULED 14 89 231 (***) 105 (*) 40 168 2014-03-24 UNSCHEDULED 8 115 245 (***) 117 (**) 50 184 2014-04-09 FU VISIT 1 - 14 93 121 (*) 65 (*) 43 PART I 218 2014-05-13 FU VISIT 2 - 11 100 31 32 28 PART I 245 2014-06-09 FU VISIT 3 - 8 91 20 23 23 PART I

-13 2014-09-10 SCREENING 6 52 15 16 23 F 75 kg 1 2014-09-23 BASELINE DAY 1 6 54 25 21 36 29 2014-10-21 WEEK 4 10 52 15 13 30 ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1920

371*



59 2014-11-20 WEEK 8 4 114 (*) 121 (**) 38 (*) 160 (**) F 75 kg 71 2014-12-02 UNSCHEDULED 10 68 24 16 72 (*) 87 2014-12-18 WEEK 12 10 58 15 14 36 115 2015-01-15 WEEK 16 9 59 16 12 38 141 2015-02-10 WEEK 20 8 58 17 12 37 164 2015-03-05 BASELINE WEEK 24 8 56 13 11 34 ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1921

Listing of subjects liver function tests (ALT, AST) >=3x ULN at any post-baseline visits -Part I (placebo-controlled period) Treatment group: BG00012 240 mg BID Page 4 of 7 ___________________________________________________________________________________________________________ Total Alkaline ALT AST Serum Subject Bilirubin Phosphatase (SGPT) (SGOT) GGT Sex Study Collection (umol/L) (U/L) (U/L) (U/L) (U/L) Weight Day (a) Date Visit (b) (c) (c) (c) (c) ___________________________________________________________________________________________________________

-22 2013-08-26 SCREENING 6 75 13 19 19 F 52.5 kg 1 2013-09-17 BASELINE DAY 1 5 70 13 18 16 30 2013-10-16 WEEK 4 6 75 17 18 17 46 2013-11-01 UNSCHED RELAPSE1 6 72 25 25 16 58 2013-11-13 WEEK 8 5 84 84 (*) 57 (*) 26 86 2013-12-11 WEEK 12 5 85 108 (**) 69 (*) 36 100 2013-12-25 UNSCHEDULED 5 89 66 (*) 44 (*) 33 114 2014-01-08 WEEK 16 5 91 51 (*) 42 (*) 31 142 2014-02-05 WEEK 20 9 74 30 32 31 170 2014-03-05 BASELINE WEEK 24 7 77 32 32 34

-22 2014-07-28 SCREENING 11 52 58 (*) 43 (*) 21 M 85.5 kg 1 2014-08-19 BASELINE DAY 1 10 55 53 (*) 21 25 29 2014-09-16 WEEK 4 8 57 137 (**) 49 (*) 33 35 2014-09-22 UNSCHEDULED 10 59 106 (*) 47 (*) 30 ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1922


57 2014-10-14 WEEK 8 9 53 57 (*) 26 28 M 85.5 kg 81 2014-11-07 WEEK 12 12 50 52 (*) 25 26 113 2014-12-09 WEEK 16 8 58 52 (*) 25 26 141 2015-01-06 WEEK 20 11 51 54 (*) 26 31 168 2015-02-02 BASELINE WEEK 24 9 52 40 21 25

-25 2013-04-16 SCREENING 12 58 12 16 19 F 65.6 kg -1 2013-05-10 BASELINE DAY 1 13 49 12 16 17 25 2013-06-04 WEEK 4 7 72 118 (**) 68 (*) 72 (*) 31 2013-06-10 UNSCHEDULED 12 93 111 (**) 75 (*) 135 (*) 43 2013-06-22 UNSCHEDULED 21 61 22 19 61 (*) 53 2013-07-02 WEEK 8 18 58 12 16 37 84 2013-08-02 WEEK 12 15 44 12 17 18 116 2013-09-03 WEEK 16 8 47 14 21 20 141 2013-09-28 WEEK 20 10 45 9 15 21 ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1923


172 2013-10-29 BASELINE WEEK 24 11 47 14 18 21 F 65.6 kg

-28 2013-07-10 SCREENING 8 33 47 (*) 34 11 F 50.7 kg 1 2013-08-07 BASELINE DAY 1 9 34 458 331 (***) 28 (****) 6 2013-08-12 UNSCHEDULED 8 48 781 447 59 (*) (*****) (****) 15 2013-08-21 UNSCHEDULED 10 56 755 436 82 (*) (*****) (****) 29 2013-09-04 WEEK 4 11 48 336 (***) 177 (***) 52 (*) 36 2013-09-11 UNSCHEDULED 6 53 186 (***) 95 (*) 45 85 2013-10-30 FU VISIT 1 - 9 39 18 24 21 PART I 105 2013-11-19 FU VISIT 3 - 8 36 24 27 21 PART I ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1924

372*



-18 2014-07-17 SCREENING 8 107 44 (*) 32 80 (*) M 74.3 kg 1 2014-08-04 BASELINE DAY 1 10 96 36 23 71 (*) 25 2014-08-28 WEEK 4 7 104 77 (*) 57 (*) 97 (*) 57 2014-09-29 WEEK 8 7 103 47 (*) 25 102 (*) 88 2014-10-30 WEEK 12 14 120 69 (*) 47 (*) 131 (*) 113 2014-11-24 WEEK 16 8 112 48 (*) 28 115 (*) 138 2014-12-19 WEEK 20 15 108 169 (**) 64 (*) 324 (***) 148 2014-12-29 UNSCHEDULED 10 120 87 (*) 42 (*) 292 (**) 169 2015-01-19 BASELINE WEEK 24 17 118 73 (*) 40 (*) 182 (*) ___________________________________________________________________________________________________________ NOTE: (a) #=On or after the subject switched to alternate MS medication. (b) * >1-1.5xULN, ** >1.5-2xULN, *** >2xULN. The ULN for Bilirubin is 21 umol/L. (c) * >1-=3-5xULN, *** >=5-10xULN, **** >=10-20xULN, ***** >=20xULN. SOURCE: BG12MS/109MS305/PART1/L-BCABN.SAS DATE: 25SEP2015

Page 1925

Table 239: Summary of Blood Chemistry Laboratory Parameters - Change From Baseline by Visit: Studies 109MS301 and 109MS302

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 1 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Number of subjects in safety 771 769 760 1529 351 population Week 4 n 752 730 727 1457 335 Mean 0.42 11.27 14.70 12.98 -0.40 SD 13.948 21.221 30.134 26.100 12.793 Median 0.00 6.00 7.00 7.00 0.00 Min, Max -74.0, 225.0 -140.0, 250.0 -128.0, 325.0 -140.0, 325.0 -66.0, 106.0 Week 8 n 728 699 678 1377 326 Mean 1.93 6.54 7.39 6.96 -0.10 SD 30.578 19.128 18.007 18.583 14.777 Median 0.00 3.00 4.00 4.00 0.00 Min, Max -93.0, 492.0 -180.0, 199.0 -140.0, 119.0 -180.0, 199.0 -113.0, 92.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1926

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 2 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 12 n 718 689 668 1357 322 Mean 1.05 3.83 5.09 4.45 0.12 SD 25.085 14.799 16.949 15.901 19.374 Median 0.00 2.00 3.00 3.00 0.00 Min, Max -66.0, 573.0 -185.0, 119.0 -158.0, 96.0 -185.0, 119.0 -147.0, 129.0 Week 16 n 707 660 646 1306 313 Mean 0.44 3.40 3.33 3.36 0.56 SD 14.334 15.435 16.476 15.952 27.044 Median 0.00 2.00 2.00 2.00 0.00 Min, Max -69.0, 176.0 -183.0, 92.0 -156.0, 124.0 -183.0, 124.0 -155.0, 364.0 Week 20 n 690 641 632 1273 310 Mean -0.40 2.39 2.41 2.40 -1.30 SD 10.940 15.983 15.424 15.702 16.052 Median 0.00 1.00 2.00 2.00 -0.50 Min, Max -75.0, 124.0 -187.0, 158.0 -151.0, 84.0 -187.0, 158.0 -157.0, 59.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1927

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 3 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 24 n 680 655 629 1284 315 Mean 0.13 1.71 2.09 1.90 -0.28 SD 11.866 16.563 16.155 16.359 19.429 Median 0.00 1.00 1.00 1.00 0.00 Min, Max -53.0, 131.0 -187.0, 170.0 -143.0, 95.0 -187.0, 170.0 -165.0, 135.0 Week 28 n 660 621 601 1222 296 Mean 0.23 0.98 1.55 1.26 0.66 SD 13.272 18.736 18.624 18.676 20.794 Median 0.00 1.00 1.00 1.00 0.00 Min, Max -82.0, 122.0 -191.0, 332.0 -141.0, 203.0 -191.0, 332.0 -58.0, 242.0 Week 32 n 641 621 601 1222 298 Mean 0.41 0.61 0.52 0.57 2.07 SD 20.122 13.821 16.513 15.198 25.736 Median -0.50 1.00 1.00 1.00 -1.00 Min, Max -55.0, 398.0 -193.0, 75.0 -155.0, 191.0 -193.0, 191.0 -63.0, 256.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1928

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 4 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 36 n 651 626 614 1240 306 Mean -0.17 0.73 0.91 0.82 0.80 SD 10.535 14.509 14.365 14.432 18.739 Median 0.00 1.00 1.00 1.00 -0.50 Min, Max -72.0, 64.0 -189.0, 99.0 -155.0, 74.0 -189.0, 99.0 -77.0, 142.0 Week 40 n 628 605 597 1202 294 Mean 0.99 0.79 -0.17 0.32 0.83 SD 20.301 18.449 14.315 16.526 29.314 Median 0.00 0.00 0.00 0.00 -1.00 Min, Max -77.0, 297.0 -185.0, 283.0 -155.0, 73.0 -185.0, 283.0 -63.0, 425.0 Week 44 n 606 584 590 1174 295 Mean 1.76 -0.04 0.69 0.33 0.13 SD 36.802 13.299 17.034 15.289 32.421 Median -1.00 0.00 1.00 0.00 -1.00 Min, Max -80.0, 769.0 -188.0, 61.0 -148.0, 179.0 -188.0, 179.0 -63.0, 500.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1929

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 5 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 48 n 598 598 602 1200 295 Mean -0.14 0.35 1.36 0.86 0.80 SD 11.778 14.934 17.591 16.322 26.319 Median 0.00 0.00 1.00 1.00 -1.00 Min, Max -68.0, 116.0 -191.0, 177.0 -159.0, 176.0 -191.0, 177.0 -67.0, 382.0 Week 52 n 557 575 570 1145 286 Mean -0.56 -0.01 1.34 0.66 0.99 SD 10.674 15.062 22.639 19.215 24.697 Median 0.00 0.00 1.00 0.00 -1.00 Min, Max -66.0, 65.0 -187.0, 135.0 -157.0, 377.0 -187.0, 377.0 -71.0, 254.0 Week 56 n 565 557 562 1119 282 Mean 0.09 0.16 0.35 0.26 0.02 SD 14.517 13.745 16.110 14.973 17.227 Median 0.00 0.00 0.00 0.00 0.00 Min, Max -70.0, 167.0 -189.0, 87.0 -157.0, 102.0 -189.0, 102.0 -75.0, 138.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1930

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 6 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 60 n 559 576 585 1161 287 Mean 0.75 0.10 0.74 0.42 -1.18 SD 15.996 15.295 16.306 15.809 12.668 Median 0.00 0.00 1.00 0.00 0.00 Min, Max -50.0, 176.0 -191.0, 161.0 -156.0, 106.0 -191.0, 161.0 -58.0, 91.0 Week 64 n 538 562 548 1110 267 Mean 0.48 2.17 0.07 1.14 -2.03 SD 26.920 54.629 16.154 40.490 12.003 Median -1.00 0.00 0.00 0.00 -1.00 Min, Max -79.0, 569.0 -188.0, 1250.0 -150.0, 155.0 -188.0, 1250.0 -66.0, 45.0 Week 68 n 524 551 547 1098 276 Mean 2.14 -0.42 -0.53 -0.47 -1.60 SD 32.412 13.851 15.135 14.499 11.306 Median 0.00 0.00 0.00 0.00 -1.00 Min, Max -75.0, 443.0 -188.0, 84.0 -151.0, 61.0 -188.0, 84.0 -53.0, 69.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1931

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 7 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 72 n 521 564 564 1128 274 Mean -0.05 -0.14 0.04 -0.05 -0.32 SD 11.482 13.611 15.281 14.464 14.152 Median 0.00 0.00 1.00 0.00 0.00 Min, Max -51.0, 134.0 -192.0, 75.0 -150.0, 113.0 -192.0, 113.0 -67.0, 86.0 Week 76 n 507 544 543 1087 265 Mean -0.21 -0.08 -0.28 -0.18 -1.98 SD 11.698 13.693 15.318 14.521 11.486 Median -1.00 0.00 0.00 0.00 -1.00 Min, Max -51.0, 115.0 -182.0, 73.0 -158.0, 85.0 -182.0, 85.0 -65.0, 41.0 Week 80 n 505 533 530 1063 265 Mean -0.73 0.06 0.13 0.10 -1.46 SD 11.308 12.447 15.329 13.952 12.614 Median -1.00 0.00 0.00 0.00 -1.00 Min, Max -74.0, 115.0 -76.0, 99.0 -149.0, 74.0 -149.0, 99.0 -70.0, 64.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1932

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 8 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 84 n 513 550 551 1101 271 Mean 0.38 0.02 -0.33 -0.16 -2.21 SD 13.386 14.804 14.813 14.803 11.082 Median 0.00 0.00 0.00 0.00 -1.00 Min, Max -72.0, 145.0 -190.0, 94.0 -149.0, 62.0 -190.0, 94.0 -72.0, 28.0 Week 88 n 499 531 529 1060 259 Mean 0.05 -0.15 0.03 -0.06 -2.34 SD 11.771 16.173 17.041 16.604 12.814 Median 0.00 -1.00 0.00 0.00 -1.00 Min, Max -49.0, 96.0 -191.0, 136.0 -155.0, 138.0 -191.0, 138.0 -70.0, 65.0 Week 92 n 486 518 516 1034 257 Mean 0.29 -0.54 -0.48 -0.51 -2.00 SD 17.799 15.004 16.274 15.643 12.324 Median -1.00 -1.00 0.00 0.00 -1.00 Min, Max -59.0, 291.0 -195.0, 80.0 -157.0, 93.0 -195.0, 93.0 -69.0, 66.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1933

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 9 of 163 Lab test: ALT/SGPT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 96 n 484 531 517 1048 260 Mean 0.51 0.01 -0.81 -0.40 -1.50 SD 13.456 16.057 15.205 15.640 14.725 Median 0.00 0.00 0.00 0.00 0.00 Min, Max -66.0, 122.0 -192.0, 156.0 -158.0, 56.0 -192.0, 156.0 -104.0, 96.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1934

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 10 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Number of subjects in safety 771 769 760 1529 351 population Week 4 n 746 726 722 1448 334 Mean -0.02 4.77 6.03 5.40 -0.07 SD 7.152 11.905 15.761 13.971 6.989 Median 0.00 3.00 3.00 3.00 0.00 Min, Max -38.0, 103.0 -46.0, 160.0 -88.0, 143.0 -88.0, 160.0 -34.0, 48.0 Week 8 n 723 695 675 1370 324 Mean 0.69 2.32 2.95 2.63 0.23 SD 17.398 9.312 9.980 9.649 7.444 Median 0.00 1.00 2.00 2.00 0.00 Min, Max -48.0, 361.0 -56.0, 90.0 -90.0, 72.0 -90.0, 90.0 -38.0, 62.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1935

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 11 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 12 n 712 686 666 1352 320 Mean 0.07 1.03 1.70 1.36 0.01 SD 11.392 7.324 9.098 8.249 9.462 Median 0.00 1.00 1.00 1.00 0.00 Min, Max -31.0, 250.0 -54.0, 42.0 -84.0, 51.0 -84.0, 51.0 -54.0, 68.0 Week 16 n 702 659 645 1304 309 Mean -0.06 0.84 1.28 1.06 0.74 SD 7.662 7.763 15.901 12.468 18.686 Median 0.00 0.00 1.00 1.00 0.00 Min, Max -29.0, 74.0 -59.0, 42.0 -84.0, 340.0 -84.0, 340.0 -59.0, 295.0 Week 20 n 685 638 624 1262 308 Mean -0.98 0.46 0.54 0.50 -0.81 SD 5.649 8.734 7.678 8.226 7.998 Median -1.00 0.00 0.00 0.00 -1.00 Min, Max -34.0, 48.0 -59.0, 96.0 -67.0, 47.0 -67.0, 96.0 -57.0, 59.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1936

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 12 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 24 n 677 653 620 1273 311 Mean -0.60 0.16 0.27 0.21 0.95 SD 6.508 8.393 8.858 8.620 17.650 Median -1.00 0.00 0.00 0.00 0.00 Min, Max -31.0, 58.0 -58.0, 114.0 -88.0, 81.0 -88.0, 114.0 -62.0, 258.0 Week 28 n 657 613 595 1208 295 Mean -0.31 0.22 -0.35 -0.06 0.38 SD 10.123 16.255 10.195 13.609 9.322 Median -1.00 0.00 0.00 0.00 0.00 Min, Max -35.0, 191.0 -60.0, 368.0 -88.0, 146.0 -88.0, 368.0 -30.0, 109.0 Week 32 n 633 615 599 1214 295 Mean 0.53 -0.33 -0.57 -0.45 0.88 SD 31.456 7.205 8.536 7.887 12.803 Median -1.00 0.00 0.00 0.00 0.00 Min, Max -33.0, 774.0 -61.0, 60.0 -77.0, 68.0 -77.0, 68.0 -30.0, 148.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1937

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 13 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 36 n 645 618 612 1230 305 Mean -0.54 -0.46 -0.50 -0.48 0.42 SD 5.669 8.131 8.458 8.292 8.509 Median 0.00 0.00 0.00 0.00 0.00 Min, Max -34.0, 44.0 -59.0, 107.0 -77.0, 78.0 -77.0, 107.0 -34.0, 76.0 Week 40 n 623 601 593 1194 292 Mean -0.36 -0.51 -1.06 -0.78 0.37 SD 8.836 8.664 7.972 8.328 13.316 Median 0.00 -1.00 -1.00 -1.00 -1.00 Min, Max -33.0, 136.0 -59.0, 116.0 -86.0, 34.0 -86.0, 116.0 -29.0, 179.0 Week 44 n 602 579 587 1166 293 Mean 0.09 -0.98 -0.07 -0.52 0.28 SD 16.892 6.393 23.403 17.204 14.774 Median -1.00 -1.00 -1.00 -1.00 0.00 Min, Max -32.0, 367.0 -57.0, 30.0 -86.0, 530.0 -86.0, 530.0 -35.0, 216.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1938

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 14 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 48 n 593 595 599 1194 294 Mean -0.64 -0.86 -0.43 -0.65 0.35 SD 6.584 7.140 8.799 8.015 10.380 Median -1.00 -1.00 -1.00 -1.00 0.00 Min, Max -29.0, 65.0 -62.0, 49.0 -86.0, 55.0 -86.0, 55.0 -33.0, 121.0 Week 52 n 553 572 570 1142 285 Mean -0.46 -1.03 -0.31 -0.67 0.80 SD 10.453 7.328 11.993 9.936 15.192 Median -1.00 -1.00 -1.00 -1.00 0.00 Min, Max -26.0, 207.0 -58.0, 76.0 -84.0, 192.0 -84.0, 192.0 -38.0, 209.0 Week 56 n 557 553 559 1112 280 Mean -0.19 -0.82 -0.90 -0.86 0.51 SD 15.730 7.296 8.538 7.941 9.357 Median -1.00 0.00 -1.00 -1.00 0.00 Min, Max -27.0, 332.0 -62.0, 70.0 -85.0, 36.0 -85.0, 70.0 -38.0, 90.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched to alternative MS medications are excluded. Baseline is defined as the latest available value prior to or on the date of first exposure to study treatment. SOURCE: BG12MS/JAPAN/ISS/T-LB-BC-CHG-A.SAS DATE: 02DEC2015

Page 1939

Summary of blood chemistry laboratory parameters - change from baseline by visit: Studies 109MS301 and 109MS302 Page 15 of 163 Lab test: AST/SGOT (U/L) _______________________________________________________________________________________________________________________ BG00012 BG00012 Total Placebo 240 mg BID 240 mg TID BG00012 GA _______________________________________________________________________________________________________________________ Week 60 n 553 569 579 1148 286 Mean -0.21 -0.84 -0.59 -0.71 -0.35 SD 8.003 8.371 7.799 8.085 6.365 Median -1.00 -1.00 -1.00 -1.00 0.00 Min, Max -27.0, 65.0 -60.0, 115.0 -70.0, 61.0 -70.0, 115.0 -27.0, 37.0 Week 64 n 533 560 544 1104 267 Mean -0.29 0.68 -1.27 -0.28 -0.92 SD 12.395 34.675 7.820 25.306 6.446 Median -1.00 0.00 -1.00 0.00 0.00 Min, Max -32.0, 242.0 -62.0, 799.0 -78.0, 49.0 -78.0, 799.0 -35.0, 21.0 Week 68 n 521 545 544 1089 273 Mean 1.21 -1.25 -1.34 -1.29 -0.69 SD 22.998 7.460 7.806 7.632 6.115 Median 0.00 -1.00 -1.00 -1.00 -1.00 Min, Max -30.0, 316.0 -62.0, 59.0 -70.0, 23.0 -70.0, 59.0 -30.0, 28.0 _______________________________________________________________________________________________________________________ NOTE: Data after subjects switched

Documents

Page 1919 3 × ULN at Any Post-Baseline Visits · 2017-02-17 · Table 238: Listing of Subjects Li ver Function Tests (ALT, AST) 3 × ULN at Any Post-Baseline Visits Part I (Placebo-Controlled