Clinical Trials in COVID-19 Management & Prevention: A Meta-epidemiological Study examining methodological quality
Authors: Honarmand Kimia , Penn Jeremy , Agarwal Arnav , Siemieniuk Reed , Brignardello-Petersen Romina , Bartoszko Jessica J , Zeraatkar Dena , Agoritsas Thomas , Burns Karen , Fernando Shannon M. , Foroutan Farid , Ge Long , Lamontagne Francois , Jimenez-Mora Mario A , Murthy Srinivas , Yepes Nuñez Juan Jose , Vandvik Per O , Ye Zhikang , Rochwerg Bram 
Published: November 2020

Background

The coronavirus disease (Covid-19) pandemic has produced a large number of clinical trial reports with unprecedented rapidity, raising concerns about methodological quality and potential for research waste.

Objectives

To describe the characteristics of randomized clinical trials (RCTs) investigating prophylaxis or treatment of Covid-19 infection and examine the effect of trial characteristics on whether the study reported a statistically significant effect on the primary outcome(s).

Study Design

Meta-epidemiological study of Covid-19 treatment and prophylaxis RCTs.

Eligibility criteria

English-language RCTs (peer-reviewed or preprint) that evaluated pharmacologic agents or blood products compared to standard care, placebo, or an active comparator among participants with suspected or confirmed Covid-19 or at risk for Covid-19. We excluded trials of vaccines or traditional herbal medicines.

Information sources

We searched 25 databases in the US Centre for Disease Control Downloadable Database from January 1 to October 21, 2020.

Trial appraisal and synthesis methods

We extracted trial characteristics including number of centres, funding sources (industry versus non-industry), and sample size. We assessed risk of bias (RoB) using the modified Cochrane RoB 2.0 Tool. We used descriptive statistics to summarize trial characteristics and logistic regression to evaluate the association between RoB due to the randomization process, centre status (single vs. multicentre), funding source, and sample size, and statistically significant effect in the primary outcome.

Results

We included 91 RCTs (46,802 participants) evaluating Covid-19 therapeutic drugs (n = 76), blood products (n = 9) or prophylactic drugs (n = 6). Of these, 40 (44%) were single-centre, 23 (25.3%) enrolled < 50 patients, and 28 (30.8%) received industry funding. RoB varied across trials, with high or probably high overall RoB in 75 (82.4%) trials, most frequently due to deviations from the intended protocol (including blinding) and randomization processes. Thirty-eight trials (41.8%) found a statistically significant effect in the primary outcome. RoB due randomization (odds ratio [OR] 3.77, 95% confidence interval [CI], 1.47 to 9.72) and single centre trials (OR 3.15, 95% CI, 1.25 to 7.97) were associated with higher likelihood of finding a statistically significant effect.

Conclusions

There was high variability in RoB amongst Covid-19 trials. RoB attributed to the randomization process and single centre status were associated with a three-fold increase in the odds of finding a statistically significant effect. Researchers, funders, and knowledge users should remain cognizant of the impact of study characteristics, including RoB, on trial results when designing, conducting, and appraising Covid-19 trials.