Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Some concerns |
Quote: "Patients were blocked randomized individually to one of two treatment arms by means of random computer-generated lists, with an allocation ratio of 1:1, with block sizes of six patients." Quote from protocol: "There will be a centralized randomization at CIGB. The randomization procedure will be carried out by the Supply Group of the Direction of Clinical Investigations at CIGB" Comment: Allocation sequence was concealed. Differences in baseline characteristics (more symptomatic, younger, male patients in the control group) suggests a problem. Quote: "In the control group more symptomatic patients (51.5%) than in the HeberFERON group (40.0%) were present; however this difference was not statistical significant." "Some imbalances existed at enrollment between the groups, including a higher median age in the HeberFERON than in the control group, as well as more patients with higher than 7 days from onset of the symptoms in the HeberFERON group." |
| Deviations from intervention |
High |
Comment: Unblinded study. Important deviations from assigned intervention (3 PCR positive patients in the control arm received the intervention) . No information on co-intervention administration for corticosteroids, antivirals and antibiotics and biologics. Outcome data were analyzed using intention-to-treat analysis. |
| Missing outcome data |
High |
79 randomized, 63 analyzed in ITT population. 60 analyzed in safety population. Data unavailable in >5% of population. Risk assessed to be high for outcomes: Mortality. Incidence of viral negative conversion. Time to viral negative conversion. Incidence of clinical improvement. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Some concerns |
Comment: Mortality, Incidence of viral negative conversion and Time to viral negatvie conversion are observer-reported outcomes not involving judgement. We consider that the assessment of these outcomes cannot possibly be influenced by knowledge of the intervention assignment. Risk assessed to be low for outcomes: Mortality. Incidence of viral negative conversion. Time to viral negative conversion. For the outcome clinical improvement (discharge), we considered it could be influenced by knowledge of the intervention assignment, but it is not likely to have happened in the context of a pandemic. Adverse events and serious adverse events may contain both clinically- and laboratory-detected outcomes, therefore it can be influenced by knowledge of the intervention assignment, but is not likely to. Risk assessed to be some concerns for outcomes: Incidence of clinical improvement. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were available. Risk assessed to be low for the outcomes: Mortality. Incidence of viral negative conversion. Time to viral negative conversion. Incidence of clinical improvement. Adverse events. Serious adverse events. |
| Overall risk of bias |
High |