Safety variables of special interest.
| Variables | Placebo-4mg (6 studies, to Week 24) | 2 mg-4 mg-extended, 4 studies | All-bari-RA | ||
|---|---|---|---|---|---|
| Placebo | Baricitinib, 4 mg | Baricitinib, 2 mg | Baricitinib, 4 mg | ||
| Exposure | |||||
| No. patients | 1070 | 997 | 479 | 479 | 3492a |
| Total patient-yrs | 393.8 | 409.4 | 554.5 | 604.1 | 6636.7 |
| No. patients with ≥ 52 weeks treatment, n (%) | — | — | 172 (35.9) | 230 (48.0) | 2723 (78.0) |
| No. patients with ≥ 104 weeks treatment, n (%) | — | — | 123 (25.7) | 103 (21.5) | 1867 (53.5) |
| Longest exposure, days | 235 | 211 | 1276 | 1991 | 2019 |
| ≥ AE, n (EAIR) | |||||
| Any TEAE | 659 (167.3) | 695 (169.8) | 376 (67.8) | 414 (68.5) | 2941 (44.3) |
| SAE, including death | 50 (12.7) | 53 (12.9) | 57 (10.1) | 81 (13.2) | 611 (9.0) |
| Temporary interruption because of AE | 89 (23.0) | 109 (27.1) | 98 (17.7) | 111 (18.4) | 864 (13.1)b |
| Permanent discontinuation because of AE | 35 (8.9) | 47 (11.5) | 37 (6.6) | 55 (8.9) | 393 (5.8) |
| Death, n (IR)c | 2 (0.49) | 3 (0.72) | 1 (0.18) | 3 (0.49) | 22 (0.33) |
| Malignancy, n (IR) | |||||
| Malignancy, excluding NMSC | 2 (0.5) | 2 (0.5) | 3 (0.5)d | 8 (1.3)d | 52 (0.8) |
| 7 (0.7)RAN | 9 (0.9)RAN | ||||
| Lymphoma | 0 | 0 | 0 | 1 (0.09) | 6 (0.09) |
| NMSC | 1 (0.2) | 3 (0.7) | 2 (0.4) | 6 (1.0) | 24 (0.4) |
| Infections, n (IR) | |||||
| TE infectionse | 299 (75.9) | 362 (88.4)* | 223 (40.2) | 263 (43.5) | 1986 (29.9) |
| Serious infection | 17 (4.2) | 16 (3.8) | 18 (3.3) | 29 (4.8) | 194 (2.9) |
| Herpes zoster | 4 (1.0) | 18 (4.3)* | 15 (2.7) | 23 (3.8) | 212 (3.2) |
| Tuberculosis | 0 | 1 (0.24) | 0 | 6 (0.57) | 10 (0.15) |
| Infection leading to deathe | 2 (0.49) | 1 (0.24) | 0 | 1 (0.16) | 5 (0.07) |
| Adverse CV events of special interest, n (IR) | |||||
| MACEf | 2 (0.6) | 3 (0.8) | 1 (0.2) | 2 (0.4) | 31 (0.5) |
| MI | 1 (0.3) | 1 (0.3) | 1 (0.2) | 1 (0.2) | 14 (0.2) |
| CV death | 1 (0.3) | 2 (0.5) | 0 | 1 (0.2) | 8 (0.1) |
| Stroke | 1 (0.3) | 1 (0.3) | 0 | 1 (0.2) | 13 (0.2) |
| DVT/PEe, g | 0 | 5 (1.2) | 3 (0.5) | 4 (0.6) | 31 (0.5) |
| DVTe | 0 | 2 (0.5) | 3 (0.5) | 2 (0.3) | 20 (0.3) |
| PEe | 0 | 3 (0.7) | 1 (0.2) | 2 (0.3) | 16 (0.2) |
| GI disorder, n (EAIR) | |||||
| GI perforations | 0 | 0 | 0 | 1 (0.20) | 3 (0.05) |
↵* p < 0.05 for baricitinib 4 mg vs placebo. P value from Cochran-Mantel-Haenszel percentage test stratified by study. EAIR were calculated as the number of unique patients with an event per 100 patient-years (PY) of overall exposure time. Incidence rates were calculated as the number of unique patients with an event per 100 PY of observation time.
↵a All-bari-RA include patients who switched from placebo, ADA, or MTX to baricitinib. Thus, it is a larger group than the sum of the 2-mg and 4-mg groups.
↵b Some studies did not collect temporary interruption of study drug.
↵c Three deaths occurred among placebo-treated patients (2 infection, 1 stroke/CNS hemorrhage). One of the patients died 2 months after completing the 24-week placebo-controlled period, so that death is not included in the table. This patient never took the active study drug. Four deaths occurred among active-comparator–treated patients (1 ADA-treated patient from infection, 3 MTX-treated patients, 1 PE, 1 pulmonary fibrosis, 1 unwitnessed death), and 22 deaths occurred among baricitinib-treated patients [2 baricitinib 2 mg (1 natural causes, 1 noninfectious acute respiratory failure); 10 baricitinib ≥ 4 mg (3 malignancy, 2 infections, 1 PE, 1 stroke/CNS hemorrhage, 1 MI/CAD, 1 non-CNS hemorrhage, 1 coagulopathy); and 10 patients after switch/rescue to baricitinib 4 mg or entry to LTE period (3 MI/CAD, 3 infection, 1 stroke/CNS hemorrhage, 1 malignancy, 1 noninfectious acute respiratory failure, 1 unwitnessed death)].
↵d See Supplementary Table 2 for case summaries from the 2 mg-4 mg-extended analysis set.
↵RAN In the “as-randomized” analysis for malignancy excluding NMSC, all data were attributed to the initial randomized treatment group disregarding rescue or dose changes. The PY of observation times with the as-randomized analysis were 1055 and 1064 years for 2-mg and 4-mg groups, respectively, and 564 and 615 years for 2 and 4 mg, as-treated analysis.
↵e Used exposure-adjusted incidence rates events/100 PY (patient exposure not censored at the event).
↵f Potential CV AE from the phase III trials and LTE, identified by investigators or according to a predefined list of event terms, were adjudicated by an independent, external Clinical Endpoint Committee, which remained blinded to treatment assignments.
↵g MedDRA-preferred terms of “deep vein thrombosis”/“pulmonary embolism” were analyzed without adjudication. After the September 2016 data cutoff, a followup medical review identified an additional event of DVT (termed thrombophlebitis) in the baricitinib 4-mg group during the placebo-controlled period. That event is not included in this table. EAIR: exposure-adjusted incidence rates; AE: adverse event; CV: cardiovascular; DVT: deep vein thrombosis; GI: gastrointestinal; NMSC: nonmelanoma skin cancer; MACE: major adverse cardiovascular events; MI: myocardial infarction; PE: pulmonary embolism; SAE: serious AE; TE: treatment-emergent; CAD: coronary artery disease; CNS: central nervous system; RA: rheumatoid arthritis; LTE: longterm extension; ADA: adalimumab; MTX: methotrexate; MedDRA: Medical Dictionary for Regulatory Activities.