• Ping-Tao Tseng, Bing-Syuan Zeng, Chih-Wei Hsu, Trevor Thompson, Brendon Stubbs, Po-Ren Hsueh, Kuan-Pin Su, Yen-Wen Chen, Tien-Yu Chen, Yi-Cheng Wu, Pao-Yen Lin, Andre F Carvalho, Dian-Jeng Li, Ta-Chuan Yeh, Cheuk-Kwan Sun, Yu-Shian Cheng, Yow-Ling Shiue, Chih-Sung Liang, and Yu-Kang Tu.
• Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
• J R Soc Med. 2024 Feb 1; 117 (2): 576857-68.

ObjectivesThe aim of this network meta-analysis (NMA) was to assess whether participants assigned to a placebo and standard of care (SoC) group had different major coronavirus disease 2019 (COVID-19)-related outcomes than those assigned to SoC alone.DesignFrequentist model-based NMA.SettingWe searched for randomised controlled trials (RCTs) of Janus kinase/Bruton tyrosine kinase inhibitors for the management of COVID-19.ParticipantsPatients with COVID-19 infection.Main Outcome MeasuresThe primary outcome was the 28-day all-cause mortality, and secondary outcomes were: (1) use of mechanical ventilation; (2) secondary bacterial infection; (3) acceptability (i.e. drop-out rate); and (4) safety (i.e. serious adverse events). We conducted an NMA using the frequentist model. Effect sizes were estimated using odds ratios (ORs) with 95% confidence intervals (95% CIs).ResultsWe identified 14 eligible RCTs enrolling a total of 13,568 participants with COVID-19. Participants assigned to placebo plus SoC had a significantly higher risk of 28-day all-cause mortality than those receiving SoC alone (OR = 1.39, 95% CI = 1.07-1.79). This finding did not change substantially by subgroup analysis stratified by epidemiology factor, pandemic history progression and statistical methodologic consideration. In addition, none of the treatments investigated were associated with a significantly different risk of secondary bacterial infection, acceptability or safety compared with the SoC group.ConclusionsThis NMA suggested a higher all-cause mortality in patients treated with placebo plus SoC compared with those treated with SoC alone. However, caution is advised in interpreting these results due to the absence of a direct head-to-head comparison. Future research should critically evaluate the necessity of placebo administration in COVID-19 RCTs and consider alternative study designs to minimise potential biases.Trial registration: The current study was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (TSGHIRB No. B-109-29) and registered in PROSPERO (CRD42022376217).

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