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Design | Phase IIIb/IV randomized, open-label, non-inferiority, postauthorization safety endpoint-driven study |
Primary objective | Evaluate the safety of tofacitinib at 2 doses (5 mg BID and 10 mg BID) compared with a TNFi in patients with RA who were 50 years of age or older and had at least 1 additional CV risk factor |
Coprimary endpoints | Adjudicated MACEa and adjudicated malignancies (excluding NMSC) |
Statistical plan | Determine whether the upper limit of the 95% CI for the primary comparison of the combined tofacitinib doses compared to TNFi exceeded the pre-specified non-inferiority criterion of 1.8 |
Regulatory update | Pfizer continues to work with the EMA and other regulatory agencies to update XELJANZ labeling in their respective markets based on their ongoing review of the complete ORAL Surveillance results |
Treated patients (N=4362) |
|
Female, n (%) | 3410 (78.2) |
Median age, years (range) | 60.0 (50.0-88.0) |
Mean disease duration, years (SD) | 10.4 (9.1) |
Mean BMI, kg/m2 (SD) | 29.8 (6.5) |
Current/ex-smokers, n (%) | 2103 (48.2) |
Selected comorbidities, n (%) | |
History of CHD | 497 (11.4) |
History of diabetes mellitus | 759 (17.4) |
History of hypertension | 2878 (66.0) |
History of extra-articular disease | 1605 (36.8) |
Tofacitinib 5 mg BID |
Tofacitinib 10 mg BID (includes patients switched to 5 mg BID dose per Feb 2019 protocol amendment) |
Tofacitinib Doses Combined | TNFi | |
Adjudicated MACE | ||||
No. of pts with first event/total no. (%) | 47/1455 (3.2) | 51/1456 (3.5) | 98/2911 (3.4) | 37/1451 (2.5) |
No. of patient-years | 5166.32 | 4871.96 | 10,038.28 | 5045.27 |
Incidence rate per 100 patient-year (95% CI) | 0.91 (0.67, 1.21) |
1.05 (0.78, 1.38) |
0.98 (0.79, 1.19) |
0.73 (0.52, 1.01) |
Hazard ratio for tofacitinib vs TNFi (95% CI)d |
1.24 (0.81, 1.91) |
1.43 (0.94, 2.18) |
1.33 (0.91, 1.94)a |
|
Noninferiority margin for primary comparison (criterion not met; 1.94>1.8) | ||||
NNH (over 5-year period) vs TNFie | 113 | 64 | ||
Adjudicated malignancies (excluding NMSC) | ||||
No. of pts with first event/total no. (%) | 62/1455 (4.3) | 60/1456 (4.1) | 122/2911 (4.2) | 42/1451 (2.9) |
No. of patient-years | 5491.48 | 5311.71 | 10,803.19 | 5482.30 |
Incidence rate per 100 patient-year (95% CI) | 1.13 (0.87, 1.45) |
1.13 (0.86, 1.45) |
1.13 (0.94, 1.35) |
0.77 (0.55, 1.04) |
Hazard ratio for tofacitinib vs TNFi (95% CI)d |
1.47 (1.00, 2.18) |
1.48 (1.00, 2.19) |
1.48 (1.04, 2.09)a |
|
Noninferiority margin for primary comparison (criterion not met; 2.09>1.8) | ||||
NNH (over 5-year period) vs TNFie | 55 | 55 |
Tofacitinib 5 mg BID |
Tofacitinib 10 mg BID (N=1456) (includes patients switched to 5 mg BID per Feb 2019 protocol amendment) |
TNFi (N=1451) | |
Serious AE, n (%) | 351 (24.1) | 306 (21.1) | 306 (21.1) |
AEs of special interest, n (%) | |||
Serious infection | 141 (9.7) 1.17 (0.92, 1.50) |
169 (11.6) 1.48 (1.17, 1.87) |
119 (8.2) — |
Adjudicated opportunistic infectionc | 39 (2.7) 1.82 (1.07, 3.09) |
44 (3.0) 2.17 (1.29, 3.66) |
21 (1.4) — |
All herpes zosterd (non-serious/serious) |
180 (12.4) 3.28 (2.44, 4.41) |
178 (12.2) 3.39 (2.52, 4.55) |
58 (4.0) — |
Adjudicated hepatic event | 46 (3.2) 1.29 (0.83, 2.00) |
72 (4.9) 2.14 (1.43, 3.21) |
35 (2.4) — |
Adjudicated NMSC | 31 (2.1) 1.90 (1.04, 3.47) |
33 (2.3) 2.16 (1.19, 3.92) |
16 (1.1) — |
Adjudicated pulmonary embolism | 9 (0.6) 2.93 (0.79, 10.83) | 24 (1.6) 8.26 (2.49, 27.43) |
3 (0.2) — |
Adjudicated deep vein thrombosis | 11 (0.8) 1.54 (0.60, 3.97) |
15 (1.0) 2.21 (0.90, 5.43) |
7 (0.5) — |
Adjudicated venous thromboembolism | 17 (1.2) 1.66 (0.76, 3.63) | 34 (2.3) 3.52 (1.74, 7.12) |
10 (0.7) — |
Adjudicated death from any cause |
26 (1.8) 1.49 (0.81, 2.74) | 39 (2.7) 2.37 (1.34, 4.18) |
17 (1.2) — |
Most common adverse reactions in the first | ||
---|---|---|
XELJANZ® 5 mg BID (n=1336) |
Placebo (n=809) |
|
Upper respiratory tract infection | 4% | 3% |
Headache | 4% | 2% |
Diarrhea | 4% | 2% |
Nasopharyngitis | 4% | 3% |
Adverse events (AEs)[all-cause] and serious adverse events (SAEs) in patients receiving XELJANZ over more than 9 years4 | ||
---|---|---|
All XELJANZb (n=4481) 16,291 pt-yrs | XELJANZ 5 mg BID (n=1123) 4683 pt-yrs | |
Patients with AEs (any cause), n (%) | 4036 (90.1) | 1015 (90.4) |
Discontinuation due to AEs, n (%) | 1120 (25.0) | 315 (28.0) |
SAEs, patients with events/100 pt-yrs (95% CI) | 9.0 (8.6, 9.5) | 8.2 (7.3, 9.1) |
Characteristics | RA | All XELJANZ® Dosesa,b (N=7964) |
Mean age, years | 52.6 |
≥65 at baseline, n (%) | 1270 (15.9) |
Female, n (%) | 6522 (81.9) |
BMI (kg/m2), mean | 27.1 |
Disease duration (years), mean (range) | 8.1 (0.00-65.7) |
CRP (mg/L). median (Q1-Q3) | 9.2 (3.8-22.8) |
Current/ past smokers, n (%) | 2754 (34.6) |
Prior therapy. n (%) | |
Methotrexate | 6657 (83.6) |
Non-bDMARD(non-methotrexate) | 3739 (46.9) |
TNFi | 1245 (15.6) |
Non-TNFi bDMARD | 414 (5.2) |
Concomitant corticosteroids, n (%) | 4254 (53.4) |
Incidence rates, patients with events/100 pt-yrs (95% CI) for safety events of interest5,6,c | |
---|---|
RA | All XELJANZ® Dosesb,c (N=7964) 23,497 pt-yrs |
|
Serious infections | 2.5 (2.3, 2.7) |
HZ (nonserious and serious) | 3.6 (3.3, 3.8) |
TBf | 0.2 (0.1, 0.2) |
Opportunistic infections (excluding TB)f | 0.4 (0.3, 05) |
Malignancies (excluding NMSC)f | 0.7 (06, 0.9) |
NMSCf | 0.6 (0.5, 0.7) |
Lymphoma/lymphoproliferative disordersf | 0.1 (0.0, 0.1) |
MACEf,g | 0.4 (0.3, 0.5) |
VTE | 0.25 (0.19, 0.33) |
DVT | 0.2 (0.1, 0.2) |
PE | 0.1 (0.1, 0.2) |
ATE | 0.35 (0.28, 0.44) |
Gastrointestinal perforationf | 0.1 (0.1, 0.2) |
Hvilke laboratorieverdier som bør overvåkes ved behandling med XELJANZ
Finn ut mer om erfaringer ved bruk av XELJANZ innen RA, PsA, AS, UC og JIA
Pfizer AS, Org.nr 915 213 596
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PP-BCP-NOR-0001 juni 2023
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