6. ROB table: tocilizumab vs standard care(SC)/placebo. Incidence of serious adverse events.
| Study | 1.Randomisation |
2.Deviations from intervention |
3.Missing outcome data |
4.Measurement of the outcome |
5.Selection of the reported results |
Overall risk of bias |
| Hermine CORIMUNO‐19 2020 | Low | Some concerns 1 | Low | Some concerns 2 | Low | Some concerns |
| Rosas COVACTA 2021 | Low | Low | Low | Low | Low | Low |
| Salama EMPACTA 2020 | Low | Low | Low | Low | Low | Low |
| Salvarani 2020 | Low | Some concerns3 | Low | Some concerns4 | Low | Some concerns |
| Stone 2020 | Low | Low | Low | Low | Low | Low |
| Wang 2020 | Some concerns 5 | Some concerns 6 | Low | Some concerns 7 | Some concerns8 | High |
| Gordon REMAP‐CAP 2021 | Low | Some concerns 9 | Low | Some concerns10 | Low | Some concerns |
| Veiga TOCIBRAS 2021 | Low | Some concerns11 | Low | Some concerns 12 | Low | Some concerns |
1 Quote: “Open‐label study” Comment: unblinded study.
Deviations from intended intervention arising because of the study context: three participants in the treatment group did not receive study drug. Administration of co‐interventions of interest (antivirals, corticosteroids and biologics) were reported. The proportions of participants receiving antivirals and steroids were imbalanced between two arms (> 10% absolute difference between the two arms) for steroids. This deviation could affect the outcome and was not balanced. Nevertheless, this domain was rated as 'Some Concern' as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. Data for the outcome were analysed using intention‐to‐treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
2 Comment: method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study. The outcome contains both clinically‐ and laboratory‐detected events which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic.
3 Quote: "the trial was open label" Comment: unblinded study.
Deviations from intended intervention arising because of the study context: Cross over: 15 (23%) participants in the standard care arm received the study treatment. For 12 (18%) the studied treatment was administered because of clinical worsening as planned in the protocol. Nevertheless, this decision could have been influenced by the trial context. Administration of co‐interventions of interest were reported and not balanced: antivirals (35% vs 47%) and corticosteroids (10% vs 10.6%). These deviations could affect the outcome and were not balanced. Nevertheless, this domain was rated as 'Some Concern' as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. Data for the outcome were analysed using intention‐to‐treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
4 Comment: method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study. The outcome contains both clinically‐ and laboratory‐detected events which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic.
5 Quote: "Randomization numbers were generated using SAS statistical software package (SAS Institute, Cary, USA). A computer‐ generated 1:1 block randomization scheme was used to assign participants to either treatment group or control one. Each consecutively coded participant was randomly enrolled by the sub‐site investigators until the total number of cases allocated to the site was reached." Comment: allocation sequence random. Allocation concealment unclear.
6 Quote: "One case in the control group aggravated on day three after randomization was transferred to the tocilizumab group according to the rules of the study protocol." Comment: unblinded study. Deviations from intended intervention arising because of the study context: One participant cross‐over. No information on administration of any co‐interventions of interest: antivirals, corticosteroids, biologics. Hence, this domain was rated as some concern as not enough information on deviations that arose because of the trial context were reported. Participants were not analysed according to their randomised groups for the outcome. Of note, 1 participant randomised to the control group was analysed in the intervention group. Nevertheless, we considered the analysis to be probably appropriate to estimate the effect of assignment to intervention.
7 Comment: method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study. The outcome may contain both clinically‐ and laboratory‐detected events. Assessment of this outcome can be influenced by knowledge of the intervention assignment but is not likely in the context of a pandemic.
8 The protocol and statistical analysis plan were not available. The registry was available. Serious adverse events were not mentioned in the registry but reported in the paper. No information on whether results were selected from multiple outcome measurements or analyses of the data.
9 Quote: “open‐label” Comment: unblinded study. Deviations from intended intervention arising because of the study context: No participant cross‐over. Administration of co‐interventions of interest: antivirals (Remdesivir, 32.8%) and corticosteroids (> 80%) were administered, but numbers per group were not reported. Hence, this domain was rated as some concern as not enough information on deviations that arose because of the trial context were reported. Data for the outcome were analysed using intention‐to‐treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
10 Comment: method of measuring outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor). Outcome may contain both clinically‐ and laboratory‐detected events which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic.
11 Quote: “open label” trial. Comment: unblinded study.
Deviations from intended intervention arising because of the study context: Cross over: 2/64 (3%) of the control arm received tocilizumab. Co‐interventions of interest (corticosteroids and antivirals), were reported, but no information on another co‐intervention of interest: biologics. Hence, this domain was rated as some concern as not enough information on deviations that arose because of the trial context were reported. Data for the outcome were analysed using intention‐to‐treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention.
12 Comment: method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study. The outcome contains both clinically‐ and laboratory‐detected events which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic