Outcomes
TNF-α
ADVERSE EVENTS, ADVERSE EVENT, TUMOUR NECROSIS, HYPERSENSITIVITY
Outcomes were assessed on day 29 after randomization. The stage 1 was principally designed to specify the optimal dose and primary endpoints for stage 2, and no formal hypothesis testing was performed. We designed multiple pre-specified clinical endpoints for stage 1, including response rate on day 29, mortality on day 29, and proportion of patients alive and discharged without supplemental oxygen on day 29. The response was defined as a sustained clinical improvement of a two-point reduction on a six-point ordinal scale without subsequent worsening on day 29. The viral load of SARS-CoV-2 and cytokines/chemokines related to the inflammatory and immune status were analysed in a central laboratory, as described in the Supplementary Materials. Briefly, the viral load in nasopharyngeal swab samples was measured by quantitative reverse transcription (RT)-PCR using three pairs of unique primers for the ORF1ab, N protein, and S protein genes. The viral copy number was determined using the quantification cycle (Cq) data for the N protein gene only. Negative SARS-CoV-2 nucleic acid was defined as all three gene targets below the limit of quantitation (Cqs > 37). To assess the levels of cytokines and chemokines, venous blood samples were collected. The concentrations of a series of cytokines/chemokines, including tumour necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 1 receptor antagonist (IL-1ra), IL-2, IL-2Rα, IL-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-17A, IL-12p70, monocyte chemoattractant protein 1 (MCP-1), C-X-C motif chemokine 10 (IP-10), and macrophage inflammatory protein 1-beta (MIP-1β) were analysed. The statistical analysis plan for viral load and cytokines/chemokines was defined as the average change from baseline (day 1) to day 29.For safety assessment, data from physical examination, clinical laboratory examinations, electrocardiograph (ECG) examination, vital signs, Treatment Emergent Adverse Events (TEAE), serious adverse events (SAE), adverse events of special interest, higher hypersensitivity, and infusion-related reactions were collected by day 29.