Table 2.
Adverse events through day 60 (safety population).
| Tocilizumab N = 295 | Placebo N = 143 | |
|---|---|---|
| Adverse events, n | 949 | 433 |
| Patients with ≥1 adverse event, n (%) | 240 (81·4) | 118 (82·5) |
| Percentage difference (95% CI) | −1·2 (−8·4, 7·0) | |
| Serious adverse events, n | 192 | 122 |
| Patients with ≥1 serious adverse event, n (%)* | 116 (39·3) | 64 (44·8) |
| Percentage difference (95% CI) | −5·4 (−15·2, 4·3) | |
| Deaths, n (%)† | 72 (24·4) | 36 (25·2) |
| Percentage difference (95% CI) | −0·8 (−9·7, 7·5) | |
| Patients with ≥1 adverse event of special interest, n (%), percentage difference (95% CI) | ||
| Infections | 127 (43·1) | 63 (44·1) |
| −1·0 (−10·9, 8·7) | ||
| Serious infections‡ | 71 (24·1) | 42 (29·4) |
| −5·3 (−14·4, 3·3) | ||
| Opportunistic infections§ | 1 (0·3) | 3 (2·1) |
| −1·8 (−5·7, 0·3) | ||
| Bleeding events | 47 (15·9) | 18 (12·6) |
| 3·3 (−4·1, 9·8) | ||
| Serious bleeding events | 13 (4·4) | 5 (3·5) |
| 0·9 (−3·9, 4·5) | ||
| Hypersensitivity¶ | 19 (6·4) | 4 (2·8) |
| 3·6 (−1·1, 7·5) | ||
| Anaphylactic reaction according to Sampson's criteria | 0 | 1 (0·7) |
| – | ||
| Hepatic events | 7 (2·4) | 3 (2·1) |
| 0·3 (−3·8, 3·1) | ||
| Malignancies | 1 (0·3) | 0 |
| – | ||
| Medically confirmed malignancies | 1 (0·3) | 0 |
| – | ||
| Stroke | 3 (1·0) | 4 (2·8) |
| −1·8 (−6·0, 0·8) | ||
| Myocardial infarction | 4 (1·4) | 2 (1·4) |
| −0·04 (−3·7, 2·3) | ||
| Gastrointestinal perforation | 1 (0·3) | 2 (1·4) |
| −1·1 (−4·6, 0·8) | ||
| Laboratory abnormalities | ||
| Patients with non-missing baseline ALT assessment and ≥1 post baseline ALT assessment, n ALT level ≥ grade 3, n (%)⁎⁎ Grade 3 Grade 4 |
280 17 (6·1) 13 (4·6) 4 (1·4) |
140 6 (4·3) 5 (3·6) 1 (0·7) |
| Neutrophil count > LLN at baseline, n Neutrophil count ≥ grade 3, n (%)†† Grade 3 Grade 4 |
245 12 (4·9) 9 (3·7) 3 (1·2) |
115 1 (0·9) 1 (0·9) 0 |
| Platelet count >LLN at baseline, n Platelet count ≥ grade 3, n (%)†† Grade 3 Grade 4 |
258 10 (3·9) 7 (2·7) 3 (1·2) |
122 1 (0·8) 1 (0·8) 0 |
| Concurrent elevation of ALT or AST level >3 × ULN and total bilirubin level >2 × ULN, n (%) | 6 (2·0) | 7 (4·9) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease-19; LLN, lower limit of normal; MedDRA, Medical Dictionary for Regulatory Activities; ULN, upper limit of normal.
Excluding infections, other serious adverse events by MedDRA system organ class that were reported in ≥5% of patients (in either treatment arm) included respiratory, thoracic, and mediastinal disorders (tocilizumab, 23 patients [7·8%]; placebo, 21 patients, [14·7%]) and cardiac disorders (tocilizumab, 16 patients [5·4%]; placebo, 9 patients [6·3%]).
The most common reason for death was COVID-19 pneumonia (36 of 72 deaths in the tocilizumab arm and 20 of 36 deaths in the placebo arm).
Excluding COVID-19 and COVID-19 pneumonia, eight serious infections occurred after day 28, four (urinary tract infection, bacterial sepsis, bacteremia, empyema) in the tocilizumab arm and four (septic shock, staphylococcal pneumonia, osteomyelitis, Pneumocystis jirovecii pneumonia) in the placebo arm.
Candida sepsis in the tocilizumab arm and one event each of Candida sepsis, Pneumocystis jirovecii pneumonia, and respiratory moniliasis in the placebo arm.
Hypersensitivity reactions include all events that occurred during or within 24 h after the infusion of tocilizumab or placebo and that were assessed by the investigator as not unrelated to the infused treatment regardless of whether they were clinically consistent with hypersensitivity.
Percentages based on the number of patients with non-missing baseline assessment and ≥1 post baseline assessment.
Percentages based on the number of patients with levels >LLN for neutrophil and platelet counts at baseline.
The 95% CIs for the percentage differences were estimated using the Newcombe method.
No medically confirmed gastrointestinal perforation or demyelinating adverse events were reported.