Background
Methods
Study designs
Patient subpopulations
Endpoints
Primary endpoints
Secondary endpoints
Statistical analyses
Results
Patients
Efficacy
ACR20 | ACR50 | ACR70 | Change in DAS28-CRP | Change in DAS28-ESR | Change in CDAI | CDAI ≤ 2.8 | CDAI ≥ 58% | HAQ-DI ≥ 0.22 | Change in HAQ-DI* | mTSS** | |
---|---|---|---|---|---|---|---|---|---|---|---|
Age | |||||||||||
MTX-IR combination study | 0.4673 | 0.6419 | 0.8516 | 0.7974 | – | 0.7638 | 0.9784 | 0.4889 | 0.9232 | 0.5847 | 0.5570 |
TNF-IR/INT combination study | 0.4095 | 0.7902 | 0.2886 | 0.4695 | – | 0.6915 | 0.1337 | 0.5813 | 0.8173 | 0.4101 | – |
Monotherapy study | 0.9861 | 0.6249 | 0.8440 | 0.9712 | 0.8819 | 0.5079 | 0.5501 | 0.6872 | 0.3983 | 0.7994 | – |
Sex | |||||||||||
MTX-IR combination study | 0.7934 | 0.7803 | 0.0643 | NC | – | 0.3802 | 0.4315 | 0.3500 | 0.6165 | 0.4633 | 0.5890 |
TNF-IR/INT combination study | 0.6818 | 0.2610 | 0.2086 | 0.4134 | – | 0.5132 | 0.0614 | 0.7993 | 0.2999 | 0.0417 | – |
Monotherapy study | 0.7733 | 0.2587 | 0.0944 | 0.6394 | 0.1953 | 0.6325 | 0.6609 | 0.6818 | 0.8029 | 0.1981 | – |
Race | |||||||||||
MTX-IR combination study | 0.4769 | 0.4827 | 0.3125 | 0.7798 | – | 0.5666 | 0.5479 | 0.3820 | 0.7486 | 0.2893 | 0.6911 |
TNF-IR/INT combination study | 0.0337 | 0.0154 | 0.0529 | 0.3539 | – | 0.3740 | 0.0035 | 0.4085 | 0.1012 | 0.6925 | – |
Monotherapy study | 0.2497 | 0.5923 | 0.9450 | 0.6376 | 0.6242 | 0.8933 | 0.9985 | 0.3730 | 0.1100 | 0.6447 | – |
Region | |||||||||||
MTX-IR combination study | 0.5715 | 0.7835 | 0.7406 | 0.2041 | – | 0.1234 | 0.3924 | 0.4628 | 0.8182 | 0.3900 | 0.4490 |
TNF-IR/INT combination study | 0.7319 | 0.5572 | 0.3057 | 0.9603 | – | 0.9703 | 0.4381 | 0.5830 | 0.5106 | 0.9414 | – |
Monotherapy study | 0.1965 | 0.2636 | 0.5468 | 0.9506 | 0.6213 | 0.8280 | 0.9865 | 0.7148 | 0.1223 | 0.1202 | – |
Weight | |||||||||||
MTX-IR combination study | 0.5261 | 0.6026 | 0.2398 | NC | – | NC | 0.7471 | 0.9225 | 0.4171 | NC | 0.3874 |
TNF-IR/INT combination study | 0.2172 | 0.9392 | 0.0593 | 0.2256 | – | 0.7918 | 0.1423 | 0.5359 | 0.2759 | 0.2538 | – |
Monotherapy study | 0.2376 | 0.4871 | 0.1161 | 0.3297 | 0.2533 | 0.1991 | 0.9981 | 0.5408 | 0.0939 | 0.2366 | – |
BMI | |||||||||||
MTX-IR combination study | 0.0539 | 0.7636 | 0.4607 | 0.0166 | – | 0.1116 | 0.8669 | 0.5427 | 0.3684 | 0.6091 | 0.1167 |
TNF-IR/INT combination study | 0.3219 | 0.5705 | 0.4019 | 0.1699 | – | 0.5089 | 0.4425 | 0.0593 | 0.8816 | 0.4860 | – |
Monotherapy study | 0.0048 | 0.0186 | 0.0117 | 0.0231 | 0.0466 | 0.0239 | 0.0608 | 0.0492 | <0.0001 | 0.0023 | – |
Smoking history | |||||||||||
MTX-IR combination study | 0.8811 | 0.7700 | 0.5258 | NC | – | 0.9072 | 0.4806 | 0.5732 | 0.4258 | 0.1465 | 0.2046 |
TNF-IR/INT combination study | 0.4588 | 0.9214 | 0.3633 | 0.2900 | – | 0.2582 | 0.3958 | 0.1818 | 0.6147 | 0.7203 | – |
Monotherapy study | 0.2545 | 0.4051 | 0.3061 | 0.6974 | 0.3829 | 0.4994 | 0.6053 | 0.7733 | 0.1321 | 0.4093 | – |
Duration RA (</≥ 2 years) | |||||||||||
MTX-IR combination study | 0.5211 | 0.4003 | 0.1108 | 0.3018 | – | 0.0611 | 0.3217 | 0.1550 | 0.3796 | 0.3297 | NC |
TNF-IR/INT combination study | 0.7880 | 0.8392 | 0.0778 | 0.7489 | – | 0.8370 | 0.2069 | 0.9211 | 0.9795 | 0.8628 | – |
Monotherapy study | 0.6300 | 0.8484 | 0.6729 | 0.2816 | 0.4205 | 0.5917 | 0.5604 | 0.9527 | 0.7008 | 0.0512 | – |
Duration RA (</≥ median) | |||||||||||
MTX-IR combination study | 0.8364 | 0.5116 | 0.1697 | 0.7286 | – | 0.7994 | 0.1961 | 0.1578 | 0.9931 | 0.5678 | 0.3215 |
TNF-IR/INT combination study | 0.0516 | 0.1992 | 0.1678 | 0.3154 | – | 0.2261 | 0.2482 | 0.0951 | 0.2263 | 0.1228 | – |
Monotherapy study | 0.2995 | 0.8856 | 0.8174 | 0.2916 | 0.8227 | 0.6843 | 0.4439 | 0.8276 | 0.2054 | 0.3787 | – |
RF | |||||||||||
MTX-IR combination study | 0.1083 | 0.3854 | 0.0564 | 0.0551 | – | 0.6429 | 0.1869 | 0.0766 | 0.0721 | 0.0427 | 0.8194 |
TNF-IR/INT combination study | 0.0012 | 0.0480 | 0.3007 | 0.0887 | – | 0.0528 | 0.2175 | 0.0070 | 0.0996 | 0.0202 | – |
Monotherapy study | 0.0416 | 0.6937 | 0.7953 | 0.2139 | 0.6410 | 0.1476 | 0.4715 | 0.4768 | 0.7497 | 0.7273 | – |
ACPA | |||||||||||
MTX-IR combination study | 0.0010 | 0.0897 | 0.1654 | 0.0012 | – | 0.0024 | 0.4017 | 0.0566 | 0.0490 | 0.0028 | 0.9994 |
TNF-IR/INT combination study | 0.0453 | 0.2511 | 0.8391 | 0.0866 | – | 0.0379 | 0.9770 | 0.0071 | 0.5114 | 0.0929 | – |
Monotherapy study | 0.0028 | 0.9442 | 0.1778 | 0.1462 | 0.4771 | 0.4249 | 0.5984 | 0.5878 | 0.0316 | 0.0337 | – |
Baseline CRP | |||||||||||
MTX-IR combination study | 0.9068 | 0.5979 | 0.6065 | 0.0537 | – | 0.2589 | 0.4199 | 0.3974 | 0.3455 | 0.2497 | 0.0221 |
TNF-IR/INT combination study | 0.0948 | 0.3845 | 0.6999 | 0.8008 | – | 0.8900 | 0.4386 | 0.1774 | 0.0159 | 0.6836 | – |
Monotherapy study | 0.0314 | 0.0759 | 0.0101 | 0.0074 | 0.0055 | 0.0152 | 0.5015 | 0.1328 | 0.0570 | 0.0006 | – |
Baseline ESR | |||||||||||
Monotherapy study | 0.5073 | 0.8452 | 0.9318 | 0.7010 | 0.1295 | 0.5070 | 0.0123 | 0.9278 | 0.2552 | 0.6488 | – |
Baseline SDAI | |||||||||||
MTX-IR combination study | 0.5963 | 0.5269 | 0.4816 | 0.1452 | – | 0.0399 | 0.9009 | 0.7552 | 0.6002 | 0.5804 | 0.7226 |
TNF-IR/INT combination study | 0.5986 | 0.9399 | 0.5674 | NC | – | NC | 0.4333 | 0.1970 | 0.2160 | NC | – |
Prior bDMARD | |||||||||||
MTX-IR combination study | 0.8583 | 0.5175 | 0.1973 | 0.9345 | – | 0.8793 | 0.2421 | 0.2202 | 0.8858 | 0.6812 | 0.2246 |
Prior anti-TNFs | |||||||||||
TNF-IR/INT combination study | 0.1215 | 0.2340 | 0.0925 | 0.2052 | – | 0.2210 | 0.1916 | 0.2797 | 0.2853 | 0.3850 | – |
Prior csDMARDs | |||||||||||
MTX-IR combination study | 0.4208 | 0.4886 | 0.6909 | 0.3946 | – | 0.1183 | 0.8905 | 0.2846 | 0.9064 | 0.9111 | 0.3586 |
TNF-IR/INT combination study | 0.4941 | 0.6441 | 0.3744 | 0.3431 | – | 0.1108 | 0.6155 | 0.8227 | 0.2881 | 0.7416 | – |
Monotherapy study | 0.7935 | 0.2370 | 0.6967 | 0.8694 | 0.3740 | 0.5514 | 0.5602 | 0.5459 | 0.3767 | 0.9655 | – |
Background csDMARDs | |||||||||||
TNF-IR/INT combination study | 0.3194 | 0.6946 | 0.3646 | 0.1658 | – | 0.5573 | 0.2718 | 0.3391 | 0.5595 | 0.8590 | – |
MTX history | |||||||||||
Monotherapy study | 0.5540 | 0.3982 | 0.3313 | 0.2163 | 0.2163 | 0.2583 | 0.6631 | 0.1498 | 0.3692 | 0.6913 | – |
Glucocorticoid use | |||||||||||
MTX-IR combination study | 0.5072 | 0.6390 | 0.8555 | 0.3366 | – | 0.3784 | 0.7197 | 0.8891 | 0.1751 | 0.7058 | 0.9422 |
TNF-IR/INT combination study | 0.2751 | 0.9400 | 0.8334 | 0.6142 | – | 0.6061 | 0.0656 | 0.5640 | 0.0994 | 0.8873 | – |
Monotherapy study | 0.0907 | 0.1650 | 0.9422 | 0.0663 | 0.0414 | 0.0195 | 0.4352 | 0.0025 | 0.0962 | 0.7536 | – |
Age and sex
Race and region
Weight and BMI
Baseline autoantibody status
Safety
n/N (%) | Combination therapy with MTX in MTX-IR patients 52 weeks | Combination therapy with csDMARDs in TNF-IR/INT patients 24 weeks | Monotherapy in MTX-IR/INT patients 24 weeks | |||||
---|---|---|---|---|---|---|---|---|
Placebo | Sarilumab 150 mg q2w | Sarilumab 200 mg q2w | Placebo | Sarilumab 150 mg q2w | Sarilumab 200 mg q2w | Adalimumab 40 mg q2w | Sarilumab 200 mg q2w | |
TEAEs | ||||||||
Patients aged < 65 years | 217/356 (61.0) | 268/360 (74.4) | 267/345 (77.4) | 76/152 (50.0) | 99/150 (66.0) | 102/154 (66.2) | 105/144 (72.9) | 113/158 (71.5) |
Patients aged ≥ 65 years | 29/41 (70.7) | 32/41 (78.0) | 45/51 (88.2) | 14/29 (48.3) | 20/31 (64.5) | 18/30 (60.0) | 36/40 (90.0) | 14/26 (53.8) |
Serious AEs | ||||||||
Patients aged < 65 years | 17/356 (4.8) | 31/360 (8.6) | 33/345 (9.6) | 4/152 (2.6) | 6/150 (4.0) | 6/154 (3.9) | 7/144 (4.9) | 7/158 (4.4) |
Patients aged ≥ 65 years | 4/41 (9.8) | 6/41 (14.6) | 12/51 (23.5) | 2/29 (6.9) | 0/31 (0.0) | 4/30 (13.3) | 11/40 (27.5) | 3/26 (11.5) |
AE leading to death | ||||||||
Patients aged < 65 years | 2/356 (0.6) | 1/360 (0.3) | 1/345 (0.3) | 1/152 (0.7) | 0/150 (0.0) | 0/154 (0.0) | 1/144 (0.7) | 1/158 (0.6) |
Patients aged ≥ 65 years | 0/41 (0.0) | 1/41 (2.4) | 0/51 (0.0) | 0/29 (0.0) | 0/31 (0.0) | 0/30 (0.0) | 0/40 (0.0) | 0/26 (0.0) |
AE leading to discontinuation | ||||||||
Patients aged < 65 years | 17/356 (4.8) | 44/360 (12.2) | 42/345 (12.2) | 6/152 (3.9) | 11/150 (7.3) | 13/154 (8.4) | 10/144 (6.9) | 10/158 (6.3) |
Patients aged ≥ 65 years | 5/41 (12.2) | 8/41 (19.5) | 12/51 (23.5) | 2/29 (6.9) | 3/31 (9.7) | 4/30 (13.3) | 4/40 (10.0) | 3/26 (11.5) |
Infections | ||||||||
Patients aged < 65 years | 112/356 (31.5) | 149/360 (41.4) | 133/345 (38.6) | 43/152 (28.3) | 35/150 (23.3) | 45/154 (29.2) | 49/144 (34.0) | 54/158 (34.2) |
Patients aged ≥ 65 years | 15/41 (36.6) | 19/41 (46.3) | 26/51 (51.0) | 5/29 (17.2) | 5/31 (16.1) | 11/30 (36.7) | 15/40 (37.5) | 4/26 (15.4) |
Serious infections | ||||||||
Patients aged < 65 years | 9/356 (2.5) | 7/360 (1.9) | 13/345 (3.8) | 1/152 (0.7) | 1/150 (0.7) | 2/154 (1.3) | 2/144 (1.4) | 2/158 (1.3) |
Patients aged ≥ 65 years | 1/41 (2.4) | 4/41 (9.8) | 2/51 (3.9) | 1/29 (3.4) | 0/31 (0.0) | 0/30 (0.0) | 1/40 (2.5) | 0/26 (0.0) |
Opportunistic infections | ||||||||
Patients aged < 65 years | 2/356 (0.6) | 2/360 (0.6) | 3/345 (0.9) | 1/152 (0.7) | 0/150 (0.0) | 2/154 (1.3) | 0/144 (0.0) | 1/158 (0.6) |
Patients aged ≥ 65 years | 0/41 (0.0) | 0/41 (0.0) | 1/51 (2.0) | 0/29 (0.0) | 0/31 (0.0) | 0/30 (0.0) | 1/40 (2.5) | 0/26 (0.0) |
Tuberculosis | ||||||||
Patients aged < 65 years | 0/356 (0.0) | 0/360 (0.0) | 0/345 (0.0) | 0/152 (0.0) | 0/150 (0.0) | 0/154 (0.0) | 0/26 (0.0) | 1/158 (0.6) |
Patients aged ≥ 65 years | 0/41 (0.0) | 0/41 (0.0) | 0/51 (0.0) | 0/29 (0.0) | 0/31 (0.0) | 0/30 (0.0) | 1/40 (2.5) | 0/26 (0.0) |
ANC < 1.5 × 109/L* | ||||||||
Patients aged < 65 years | 5/356 (1.4) | 66/360 (18.3) | 81/345 (23.5) | 1/152 (0.7) | 24/150 (16.0) | 32/154 (20.8) | 31/144 (21.5) | 52/158 (32.9) |
Patients aged ≥ 65 years | 1/41 (2.4) | 7/41 (17.1) | 12/51 (23.5) | 1/29 (3.4) | 7/31 (22.6) | 10/30 (33.3) | 9/40 (22.5) | 10/26 (38.5) |
ANC ≥ 0.5–1 × 109/L (grade 3) | ||||||||
Patients aged < 65 years | 0 (0.0) | 16 (4.4) | 26 (7.5) | 0 (0.0) | 9 (6.0) | 11 (7.1) | 15 (10.4) | 23 (14.6) |
Patients aged ≥ 65 years | 0 (0.0) | 3 (7.3) | 3 (5.9) | 1 (3.4) | 1 (3.2) | 5 (16.7) | 3 (7.5) | 4 (15.4) |
ANC < 0.5 × 109/L (grade 4) | ||||||||
Patients aged < 65 years | 0 (0.0) | 4 (1.1) | 1 (0.3) | 0 (0.0) | 2 (1.3) | 1 (0.6) | 0 (0.0) | 0 (0.0) |
Patients aged ≥ 65 years | 0 (0.0) | 0 (0.0) | 1 (2.0) | 0 (0.0) | 2 (6.5) | 1 (3.3) | 0 (0.0) | 3 (11.5) |
Platelets < 50 × 109/L | ||||||||
Patients aged < 65 years | 0/356 (0.0) | 0/360 (0.0) | 2/345 (0.6) | 0/152 (0.0) | 0/150 (0.0) | 1/154 (0.6) | 0/144 (0.0) | 1/158 (0.6) |
Patients aged ≥ 65 years | 0/41 (0.0) | 0/41 (0.0) | 0/51 (0.0) | 0/29 (0.0) | 0/31 (0.0) | 0/30 (0.0) | 0/40 (0.0) | 0/26 (0.0) |
ALT > 3 to ≤ 5× ULN | ||||||||
Patients aged < 65 years | 7/356 (2.0) | 24/360 (6.7) | 24/345 (7.0) | 2/152 (1.3) | 4/150 (2.7) | 6/154 (3.9) | 8/144 (5.6) | 9/158 (5.7) |
Patients aged ≥ 65 years | 1/41 (2.4) | 1/41 (2.4) | 0/51 (0.0) | 0/29 (0.0) | 0/31 (0.0) | 1/30 (3.3) | 1/40 (2.5) | 0/26 (0.0) |
ALT > 5 to ≤ 10× ULN | ||||||||
Patients aged < 65 years | 1/356 (0.3) | 9/360 (2.5) | 9/345 (2.6) | 0/152 (0.0) | 0/150 (0.0) | 0/154 (0.0) | 2/144 (1.4) | 3/158 (1.9) |
Patients aged ≥ 65 years | 0/41 (0.0) | 0/41 (0.0) | 0/51 (0.0) | 0/29 (0.0) | 0/31 (0.0) | 0/30 (0.0) | 0/40 (0.0) | 0/26 (0.0) |