Table 3.
Treatment‐emergent AEs (any cause) and AEs of interest throughout the entire study period (months 0–24)a
| Tofacitinib 5 mg twice daily | Tofacitinib 10 mg twice daily | Placebo switching to tofacitinib 5 mg twice daily | Placebo switching to tofacitinib 10 mg twice daily | |
|---|---|---|---|---|
| Treatment‐emergent AEs (any cause) | ||||
| No. of evaluable patients | 321 | 316 | 81 | 79 |
| Duration of treatment, mean (median) days | 572 (709) | 600 (711) | 580 (714) | 569 (714) |
| Total no. of patient‐years of exposure | 508 | 525 | 129 | 124 |
| Number of AEs | 1,510 | 1,562 | 315 | 290 |
| Patients with AEs, no. (%) | 279 (86.9) | 275 (87.0) | 63 (77.8) | 57 (72.2) |
| Crude exposure‐adjusted incidence rate/100 patient‐years (95% CI) | 169 (150.4–190.2) | 167 (148.6–188.2) | 116 (90.8–148.8) | 110 (85.2–143.1) |
| Patients with SAEs, no. (%) | 86 (26.8) | 78 (24.7) | 19 (23.5) | 20 (25.3) |
| Discontinuations due to AEs, no. (%) | 55 (17.1) | 47 (14.9) | 9 (11.1) | 13 (16.5) |
| Deaths, no. (%)b | ||||
| All | 7 (2.2) | 3 (0.9) | 2 (2.5) | 0 (0.0) |
| While receiving study treatmentc | 4 (1.2) | 1 (0.3) | 1 (1.2) | 0 (0.0) |
| Liver enzyme testsd | ||||
| No. of evaluable patients | 318 | 315 | 81 | 78 |
| ALT ≥1× ULN | 143 (45.0) | 151 (47.9) | 22 (27.2) | 36 (46.2) |
| ALT ≥3× ULN | 19 (6.0) | 21 (6.7) | 2 (2.5) | 6 (7.7) |
| AST ≥1× ULN | 134 (42.1) | 148 (47.0) | 27 (33.3) | 32 (41.0) |
| AST ≥3× ULN | 10 (3.1) | 9 (2.9) | 2 (2.5) | 2 (2.6) |
| Total bilirubin ≥1× ULN | 17 (5.3) | 23 (7.3) | 6 (7.4) | 6 (7.7) |
| Total bilirubin ≥3× ULN | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| AEs of interest | ||||
| No. of evaluable patients | 321 | 316 | 81 | 79 |
| Serious infections, no. (%) | 24 (7.5) | 19 (6.0) | 2 (2.5) | 5 (6.3) |
| Crude exposure‐adjusted incidence rate/100 patient‐years (95% CI) | 4.8 (3.2–7.1) | 3.6 (2.3–5.7) | 1.5 (0.4–6.2) | 4.1 (1.7–9.7) |
| Patients with malignancies, no. (%)e | 14 (4.4)f | 10 (3.2)g | 1 (1.2) | 1 (1.3) |
| Excluding nonmelanoma skin cancere | 6 (1.9) | 7 (2.2) | 1 (1.2) | 0 (0.0) |
| Nonmelanoma skin cancer | 8 (2.5) | 3 (0.9) | 0 (0.0) | 1 (1.3) |
| Cardiovascular events, no. (%)e | 9 (2.8) | 9 (2.9) | 2 (2.5)h | 0 (0.0) |
| TB, no. (%)i | 0 (0.0) | 2 (0.6) | 0 (0.0) | 1 (1.3) |
| Herpes zoster, no. (%)j | ||||
| All | 24 (7.5) | 32 (10.1) | 4 (4.9) | 7 (8.9) |
| Disseminated | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) |
| GI perforation, no. (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Lymphopenia, no. (%) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) |
| Thrombocytopenia, no (%) | 1 (0.3) | 3 (0.9) | 0 (0.0) | 0 (0.0) |
| Neutropenia, no. (%)d, k | ||||
| No. of evaluable patients | 316 | 309 | 79 | 77 |
| Mild (≥1.5 to <2 × 103 cells/μl) | 41 (13.0) | 44 (14.2) | 8 (10.1) | 12 (15.6) |
| Moderate to severe (≥0.5 to <1.5 × 103 cells/μl) | 11 (3.5) | 18 (5.8) | 2 (2.5) | 4 (5.2) |
| Life‐threatening (<0.5 × 103 cells/μl) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Decrease in hemoglobin, no. (%)d, k | ||||
| No. of evaluable patients | 316 | 309 | 79 | 77 |
| Mild or moderate (decrease of ≥1 gm/dl to ≤2 gm/dl) | 71 (22.5) | 77 (24.9) | 21 (26.6) | 22 (28.6) |
| Severe (decrease of >2 gm/dl to <3 gm/dl or absolute value >7 gm/dl but <8 gm/dl) | 13 (4.1) | 17 (5.5) | 4 (5.1) | 5 (6.5) |
| Life‐threatening (decrease of ≥3 gm/dl or absolute value ≤7 gm/dl) | 7 (2.2) | 8 (2.6) | 1 (1.3) | 2 (2.6) |
Except where indicated otherwise, values are the number (%). All patients received background methotrexate, including those in the placebo groups. Mean changes from baseline over time in hemoglobin level, platelet, neutrophil, and lymphocyte counts, and, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine levels are shown in Supplementary Figure 4 (available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40803/abstract). Changes in ALT and AST are without regard to baseline. 95% CI = 95% confidence interval; SAE = serious adverse event; ULN = upper limit of normal; GI = gastrointestinal.
There was a total of 12 deaths that were adjudicated to be either related or unrelated to study treatment. Three patients died after withdrawing from the study due to AEs considered related to treatment (adult respiratory distress syndrome and viral pneumonia in 1 patient in the tofacitinib 5 mg sequence, metastatic lung cancer in 1 patient in the tofacitinib 5 mg sequence, and acute renal failure in 1 patient in the placebo switching to tofacitinib 5 mg sequence). Two patients died after withdrawing from the study due to non–treatment‐related AEs (multiorgan failure in 1 patient in the tofacitinib 5 mg sequence and chronic obstructive pulmonary disease in 1 patient in the tofacitinib 10 mg sequence). One patient who was randomized to receive tofacitinib 10 mg died before receiving study medication.
In the group receiving tofacitinib 5 mg twice daily, 1 patient each died of pneumonia, probable acute myocardial infarction, cardiac arrest and respiratory arrest, and heart failure. One patient in the tofacitinib 10 mg twice daily group died due to glycerin swab aspiration. One patient who received placebo and then switched to tofacitinib 5 mg twice daily died due to acute renal failure, cardiac arrest, and other AEs.
Based on a value in the specified range being reported for ≥1 sample.
Adjudicated in a blinded manner by a Safety End Point Adjudication Committee.
One patient experienced both an event of nonmelanoma skin cancer (basal cell carcinoma) and a malignancy (prostate cancer).
One patient experienced 2 events of nonmelanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) and a malignancy (melanoma in situ); these events were reported 5 years after the end of the study and were not included in the final study report.
Both events occurred during treatment with tofacitinib.
Includes cases of disseminated and lymph node tuberculosis (TB).
Includes disseminated, ophthalmic herpes zoster.
Decrease from baseline.