The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

Abstract

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

Keywords: COVID-19; clinical research agenda; hydroxychloroquine.

Figure 1.. Number of trials assessing the different intervention categories.

Interventions for treatment assessed in more than 25 trial: antiviral drugs were assessed in 141 trials; (e.g. lopinavir/ritonavir [n=45]), antimalarial drugs in 111 trials; (e.g. hydroxychloroquine [n=84]), monoclonal antibodies in 51 trials (e.g. tocilizumab [n=25]), traditional medicine in 106 trials, other drug intervention in 70 trials, nonspecific anti-inflammatory/immunosuppressive drugs in 42 trials (e.g. colchicine [n=4]), antibiotic/anti-parasitic drugs in 34 trials (e.g. azithromycin [n=28]), biologicals in 80 trials (e.g. convalescent plasma [n=27]), procedures in 28 trials (e.g. renal replacement therapy [n=4]), other non-drug interventions in 267 trials (e.g. physical activity). More information can be found in the Extended data . The first column represents the proportion of all trials that were of the specified type. The second column represents the proportion of all trials registered that week that were of the specified type (i.e. within week, between trial types). The third column represents the distribution of when trials of this type were registered (i.e. within trial type, between week), and can be interpreted as either a percentage or count (not specified). A trial might assess more than one intervention category and detail for prevention and treatment trials are given in the extended data .

Figure 2.

Cumulative number of registered trials over time ( a) by continent, and ( b) for countries with at least 10 registrations (excluding China). Four trials not shown were registered in 2019 or earlier, with a study design subsequently adapted to address COVID-19 (EUCTR2015-002340-14-NL; NCT03680274; NCT03331445; and NCT03808922). For 18 trials the registration date was unknown.

Figure 3.

Proportion of trials stratified according to ( a) sample size, ( b) type of participants, ( c) type of control, ( d) type of blinding, ( e) purpose of the trial, and ( f) use of mortality as outcome. The first column represents the proportion of all trials that were of the specified type. The second column represents the proportion of all trials registered that week that were of the specified type (i.e. within week, between trial types). The third column represents the distribution of when trials of this type were registered (i.e. within trial type, between week), and can be interpreted as either a percentage or count (not specified).

Figure 4.. The 110 Trials assessing hydroxychloroquine for COVID-19 registered in the first 100 days of the pandemic.

The dashed lines represent the registration of the four trials planning to enroll over 5,000 participants; two were registered on April 2, 2020. Out of the four trials planning on enrolling over 5,000 participants, two assessed hydroxychloroquine for treatment and two for prevention. Out of the 104 smaller trials, 82 assessed hydroxychloroquine for treatment, 21 for prevention and one for both treatment and prevention