Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis

Ping-Tao Tseng^{1

2

3

4}, Bing-Syuan Zeng^{1

5}, Trevor Thompson⁶, Brendon Stubbs^{7

8

9}, Po-Ren Hsueh^{10

11}, Kuan-Pin Su^{12

13

14}, Yen-Wen Chen³, Tien-Yu Chen^{15

16}, Yi-Cheng Wu¹⁷, Pao-Yen Lin^{18

19}, Andre F Carvalho²⁰, Chih-Wei Hsu¹⁸, Dian-Jeng Li²¹, Ta-Chuan Yeh¹⁵, Cheuk-Kwan Sun^{22

23}, Yu-Shian Cheng^{2

24}, Yow-Ling Shiue^{5

19}, Chih-Sung Liang^{25

26}, Yu-Kang Tu^{27

28}

Affiliations

¹ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
² Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
³ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
⁴ Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan.
⁵ Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan.
⁶ Centre for Chronic Illness and Ageing, University of Greenwich, London, UK.
⁷ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK.
⁹ Faculty of Health, Social Care Medicine and Education, Anglia Ruskin University, Chelmsford, UK.
¹⁰ Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
¹¹ School of Medicine, China Medical University, Taichung, Taiwan.
¹² College of Medicine, China Medical University, Taichung, Taiwan.
¹³ Mind-Body Interface Laboratory (MBI-Lab), China Medical University and Hospital, Taichung, Taiwan.
¹⁴ An-Nan Hospital, China Medical University, Tainan, Taiwan.
¹⁵ Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
¹⁶ Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁷ Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan.
¹⁸ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁹ Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
²⁰ Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
²¹ Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan.
²² Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
²³ School of Medicine for International Students, College of Medicine, I-Shou University Kaohsiung, Kaohsiung, Taiwan.
²⁴ Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Kaohsiung, Taiwan.
²⁵ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
²⁶ Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan.
²⁷ Institute of Health Data Analytics & Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan.
²⁸ Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.

PMID: 37646204
DOI: 10.1111/pcn.13592

Free article

Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis

Ping-Tao Tseng et al. Psychiatry Clin Neurosci. 2023 Dec.

Free article

. 2023 Dec;77(12):638-645.

doi: 10.1111/pcn.13592. Epub 2023 Sep 27.

Authors

Affiliations

¹ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
² Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
³ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
⁴ Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan.
⁵ Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan.
⁶ Centre for Chronic Illness and Ageing, University of Greenwich, London, UK.
⁷ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK.
⁹ Faculty of Health, Social Care Medicine and Education, Anglia Ruskin University, Chelmsford, UK.
¹⁰ Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
¹¹ School of Medicine, China Medical University, Taichung, Taiwan.
¹² College of Medicine, China Medical University, Taichung, Taiwan.
¹³ Mind-Body Interface Laboratory (MBI-Lab), China Medical University and Hospital, Taichung, Taiwan.
¹⁴ An-Nan Hospital, China Medical University, Tainan, Taiwan.
¹⁵ Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
¹⁶ Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁷ Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan.
¹⁸ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁹ Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
²⁰ Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
²¹ Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan.
²² Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
²³ School of Medicine for International Students, College of Medicine, I-Shou University Kaohsiung, Kaohsiung, Taiwan.
²⁴ Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Kaohsiung, Taiwan.
²⁵ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
²⁶ Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan.
²⁷ Institute of Health Data Analytics & Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan.
²⁸ Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.

PMID: 37646204
DOI: 10.1111/pcn.13592

Abstract

Aim: Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19.

Methods: We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events.

Results: The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar.

Conclusion: These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.

Keywords: COVID-19; coronavirus disease 2019; interleukin 6; network meta-analysis; placebo effect.

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Can placebo effect save your life?
Tani H. Tani H. Psychiatry Clin Neurosci. 2023 Dec;77(12):629. doi: 10.1111/pcn.13600. Psychiatry Clin Neurosci. 2023. PMID: 38062575 No abstract available.

References

1. WHO. WHO Coronavirus (COVID-19) Dashboard. [Cited 10 May 2023.]. Available from https://covid19.who.int/.
1. Collaborators C-EM. Estimating excess mortality due to the COVID-19 pandemic: A systematic analysis of COVID-19-related mortality, 2020-21. Lancet 2022; 399: 1513-1536.
1. Group WHOREAfC-TW, Shankar-Hari M, Vale CL et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA 2021; 326: 499-518.
1. Krause PR, Fleming TR, Longini IM et al. Placebo-controlled trials of Covid-19 vaccines-why we still need them. N. Engl. J. Med. 2021; 384: e2.
1. Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evidence Based Med 2016; 21: 125-127.

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Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis

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Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis

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