Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality

Kimia Honarmand; Jeremy Penn; Arnav Agarwal; Reed Siemieniuk; Romina Brignardello-Petersen; Jessica J Bartoszko; Dena Zeraatkar; Thomas Agoritsas; Karen Burns; Shannon M Fernando; Farid Foroutan; Long Ge; Francois Lamontagne; Mario A Jimenez-Mora; Srinivas Murthy; Juan Jose Yepes-Nuñez; Per O Vandvik; Zhikang Ye; Bram Rochwerg

doi:10.1016/j.jclinepi.2021.07.002

Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality

J Clin Epidemiol. 2021 Nov:139:68-79. doi: 10.1016/j.jclinepi.2021.07.002. Epub 2021 Jul 15.

Authors

Kimia Honarmand¹, Jeremy Penn², Arnav Agarwal³, Reed Siemieniuk⁴, Romina Brignardello-Petersen⁴, Jessica J Bartoszko⁴, Dena Zeraatkar⁵, Thomas Agoritsas⁶, Karen Burns⁷, Shannon M Fernando⁸, Farid Foroutan⁹, Long Ge¹⁰, Francois Lamontagne¹¹, Mario A Jimenez-Mora¹², Srinivas Murthy¹³, Juan Jose Yepes-Nuñez¹⁴, Per O Vandvik¹⁵, Zhikang Ye⁴, Bram Rochwerg¹⁶

Affiliations

¹ Division of Critical Care, Department of Medicine, Western University, 1151 Richmond Street London, Ontario, N6A 3K7, Canada. Electronic address: kimia.honarmand@medportal.ca.
² Faculty of Health Sciences, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada.
³ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, University of Toronto, 27 King's College Circle, Toronto, Ontario, M5S 1A1, Canada.
⁴ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada.
⁵ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Biomedical Informatics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA, 02115, USA.
⁶ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Division General Internal Medicine, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4 1205, Geneva, Switzerland.
⁷ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Unity Health Toronto, St. Michael's Hospital, Li Ka Shing Knowledge Institute, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada.
⁸ Division of Critical Care, Department of Medicine, University of Ottawa, 75 Laurier Ave. E, Ottawa, Ontario, K1N 6N5, Canada.
⁹ Ted Rogers Centre for Heart Research, University Health Network, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada.
¹⁰ Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, 222 Tianshui S Rd, Chengguan District, Lanzhou, Gansu, China.
¹¹ Department of Medicine and Centre de recherche du CHU de Sherbrooke, 12e Avenue N Porte 6, Sherbrooke, Quebec, J1H 5N4, Canada.
¹² School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia.
¹³ Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada.
¹⁴ School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia; Pulmonology Service, Internal Medicine Section, Fundación Santa Fe de Bogotá University Hospital, Cra. 7b (#)12390, Bogotá D.C, Colombia.
¹⁵ Department of Health and Society, Faculty of Medicine, University of Oslo, Problemveien 7, 0315, Oslo, Norway.
¹⁶ Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada.

Abstract

Objective: To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect.

Study design: We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect.

Results: We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect.

Conclusions: There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs.

Registration: CRD42020192095.

Keywords: Clinical trials, Randomized controlled trials; Covid-19; Meta-epidemiology; Methodological quality; Risk of bias; Systematic review.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

COVID-19 / epidemiology
COVID-19 / prevention & control*
Epidemiologic Studies
Humans
Randomized Controlled Trials as Topic / methods*
Research Design / standards*