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

Data sources

COVID-evidence includes trials from international registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform [ICTRP]), preprint servers (medRxiv, bioRxiv), PubMed, the WHO COVID-19 literature database, and a listing of all trials with ethical approval in Switzerland⁹.

Identification and selection of trials

Our protocol and details on the search strategies and specific definitions used for COVID-evidence are available on the Open Science Framework (OSF)¹⁰. We searched the relevant data sources using peer-reviewed search strategies developed by information specialists. Results from literature databases and preprint servers were pre-screened by a single reviewer who excluded unsuitable publications (e.g. opinion papers or observational, non-interventional studies). Cases with unclear eligibility were discussed by at least three reviewers until consensus was reached.

We included any planned, ongoing or completed trial that tested any intervention to treat or prevent COVID-19 in humans that was registered or published within the first 100 days of the COVID-19 outbreak, i.e. after the first cases reported to the WHO to 100 days later (January 1 to April 9, 2020). We considered as a trial any study prospectively assigning an intervention¹¹. This included randomized and non-randomized, controlled or non-controlled trials regardless of language, geographical region, or setting. Epidemiological studies or studies of diagnostic test accuracy (without any health-related outcome) were excluded.

Data extraction

For each trial, we extracted dates of registration and publication, design characteristics and details of the population, intervention, comparison, outcomes, geographic region, funding and setting. We categorized drugs and biologicals according to major pharmacological classes and main clinical indications.

A team of 19 reviewers (including clinicians, clinical researchers, clinical pharmacologists, meta-researchers and systematic reviewers) either manually extracted information or verified information that was obtained with automatic data scraping methods. All details on scraping, variable definitions and extraction/verification procedures are available on OSF^10,12. For all trials registered up to April 9, 2020, we extracted data through April 30. The status for each trial was updated on July 6, 2020 (using ClinicalTrials.gov where possible; if not, we used the ICTRP; for trials originally registered in the Chinese Clinical Trial Registry available through ICTRP we used the former if it was more up to date).

When a trial had entries in different data sources, we gave first priority to publications, second to preprints, and third to registries (here, ClinicalTrials.gov was preferred).

Author requests on enrolment

From May 12 to July 3, 2020, we emailed the corresponding investigators of all trials, except discontinued ones, inquiring about their enrolment accrual. Replies were collected up to July 6, 2020.

Statistical analyses

All analyses were descriptive and reported as percentages, medians (interquartile range, IQR) or means. We used Ninox (Ninox Software GmbH, Berlin, Germany; version 2.6), and R (version 3.6).

General characteristics

The 689 trials’ median target sample size was 120 (IQR 60 to 300; Table 1); 40.7% (n=280) planned to enroll fewer than 100 participants, 8.3% (n=57) over 1,000, and 1.6% (n=11) over 5,000 (see Underlying data)¹². 75.8% (n=522) trials were randomized and 59.2% (n=408) did not use blinding (Table 1). Randomized trials were on average three times larger than non-randomized trials (median sample size 150 vs. 50).

Although few trials focused on health-care workers (3.6% [n=25]), they were larger: 96,821 planned health-care workers (median 700 [IQR 400 to 2,486]) versus 155,571 planned patients (median 100 [IQR 50 to 240]) for the inpatient trials (76.2% [n=525]) (Table 1). Overall, 46.4% of the trials intended to use mortality as a primary (n=98) or secondary outcome (n=369; Table 1). Out of the 525 inpatient trials, 55.6% (n=292) planned on reporting mortality as an outcome.

Interventions to treat COVID-19

Out of the 689 trials, 607 (88.1%) assessed treatment interventions (187,209 planned patients); drugs were more frequent (349 trials [57.5%]), encompassing a vast range of substances. The two most common pharmacological classes were antiviral drugs (assessed in 144 trials; e.g. lopinavir/ritonavir [n=45]) and antimalarial drugs (112 trials; e.g. hydroxychloroquine [n=83]). There were 106 trials investigating traditional medicine and 70 exploring highly diverse pharmaceuticals of various classes, e.g. bismuth potassium citrate, ebastine, pirfenidone, dipyridamole and hydrogen peroxidase (Figure 1 and see Extended data)¹². The comparators were predominantly standard of care or no intervention (47.1% [n=286]), placebo (17% [n=103]) or other interventions (18%; [n=109]) (Table 1).

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

Interventions for treatment assessed in more than 25 trial: antiviral drugs were assessed in 144 trials; (e.g. lopinavir/ritonavir [n=45]), antimalarial drugs in 112 trials; (e.g. hydroxychloroquine [n=83]), monoclonal antibodies in 52 trials (e.g. tocilizumab [n=26]), 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 27 trials (e.g. physical activity). More information can be found in the Extended data¹².

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 data¹².

Interventions to prevent COVID-19

Overall, 78 trials (11.3%) focused on prevention (205,841 planned participants), mainly prophylactic drug use (n=41), vaccines (n=14; 9 already started recruitment; see Extended data)¹² and non-pharmaceutical interventions (n=10) (e.g. masks or the use of media and influencers in people’s compliance to hygienic practices). Four trials (0.6%) assessed interventions both for prevention and for treatment. No trial planned to assess benefits or harms of implementing or de-implementing any social distancing or lockdown measures.

Time trends and global shift

The number of trials increased rapidly; on average 0.5 trials per day were registered in January, 8.1 in February, 8.4 in March, and 17.6 in April 2020.

Trials were conducted in 42 countries and through international collaborations (Table 1; see Extended data)¹². Half were from China (51.1% [n=352]), which dominated initially (Figure 2); starting March 2020, more trials came from other countries. Trial characteristics were similar across the five most frequent geographical locations (China, USA, France, Spain and international) contributing to 73.3% (n=505) of the global trial research (Table 1). Traditional medicine was assessed in 30.4% of trials from China (n=107) but rarely in other countries.

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.

Larger trials were initiated later. In February, fewer than 8% of trials included more than 500 participants in contrast to 29.6% of trials in March (Figure 3). Later trials more often used blinding, placebo and mortality as primary outcome (Figure 3). Participations of healthcare workers and healthy people also started later. When the proportion of trials from China decreased, so did trials assessing traditional medicine (from 46.9% to 0.9%) while the proportion of trials assessing drugs rose (from 38.1% to 77.2%). Antivirals came under investigation earlier than antimalarials (Figure 1).

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).

Large trials

Out of the 689 trials, 6.7% (n=46) planned to enroll 1,000 to 5,000 participants. Most were randomized (89.1% [n=41]), assessed drugs (80.4%; n=37), and many were not blinded (52.2% [n=24]). Five were cluster-randomized. The top three regions were the United States (21.7%; n=10), France (13% [n=6]) and international collaborations (10.9% [n=5]) (see Extended data)¹².

Eleven (1.6%) trials, registered between February and April 2020, planned to enroll over 5,000 participants (see Extended data)¹². There were 10 randomized (one cluster RCT), eight not blinded and five conducted in multiple countries. These trials tested drugs (n=9), masks (n=1) and traditional medicine (n=1). Three trials are described as platform trials (i.e. WHO Solidarity trial¹³, RECOVERY trial¹⁴ and CROWN-CORONATION trial¹⁵) and use an adaptive design.

Six drug interventions tested in these 11 larger trials (seven for treatment and four for prevention) were simultaneously investigated in at least 10 smaller trials (see Extended data)¹². Overall, 169 trials (143 for treatment, 24 for prevention and two for treatment and prevention) with fewer than 5,000 participants assessed at least one intervention that was also assessed in a larger trial (median sample size 273 [IQR 90 to 700]; 134 had fewer than 1000 participants). For 107 of those (63.5%) the larger trial was registered before. For example, 106 trials with fewer than 5,000 participants tested hydroxychloroquine and 88 of them (83%) were registered after the first large trial testing this drug and 83 (77.6%) assessed hydroxychloroquine as treatment (Figure 4; see Extended data)¹². These 106 trials had a median sample size of 334, but cumulatively, they planned to enroll as many patients as the four larger trials testing hydroxychloroquine (76,617 vs 77,000).

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 106 smaller trials, 83 assessed hydroxychloroquine for treatment, 22 for prevention and one for both treatment and prevention

Outlook

By the end of 2020, 414 trials (60.1%) with a total of 160,107 planned participants were expected to be completed (i.e. last patient, last visit), including 240 drug trials (97,846 participants) and 22 over-1,000 participants trials and five over-5,000 participants trials. For vaccines, five trials expected completion in 2020, five in 2021 and another four between 2022 and 2024 (see Extended data)¹². However, of the 270 trials that planned to start recruiting by the end of February, 190 started (70.4%), but 80 had not (as of July 6, 2020) (see Extended data)¹².

By July 6, 2020, we received enrolment information for 112 out of the 604 trials listed as planned or ongoing (18.7%). Of the 112 trials, 16 had not started recruiting although their start dates were overdue; one was discontinued. Among the 112 trials, 55 had recruited fewer than 20% of the target sample size, 27 between 20-50%, and 30 more than 50% (median recruitment 14.8% [IQR 2.0 to 62.0%]; median duration of recruitment 72 days [IQR 53.5 to 83 days])). Median recruitment was similar in treatment and prevention trials (15.9% (IQR 2 to 61.1%] vs 14.8% [IQR 4.3 to 62.5%]). For 19 trials, investigators mentioned difficulties in recruitment due to a fortunate decrease in the number of COVID-19 cases.

Limitations

Several limitations merit attention. First, unclear reporting in registries might have introduced inaccurate results. Some ambiguously reported items required discussion among several reviewers but were resolved to the best of our ability. Second, we rarely identified protocols or manuscripts, precluding more detailed analyses of trial designs. Third, some control groups receiving “standard of care” interventions were not clearly described, likely some of these included interventions that were or are still under investigation in other trials. Fourth, we may have missed a few cases of duplicate entries across registries or of multiple national parts of an international trial, thus slightly overestimating the number of trials but not affecting the overall interpretation. Fifth, we arbitrarily selected a period of the first 100 days, which is traditionally used to benchmark early outcomes of policies or presidencies. Finally, we do not assess the actual research output from all these early trials. This unprecedentedly fast-moving research body is scattered across data sources and registries without uniform updates. More definitive answers will require more time, but our results allow for the diagnosis of “system cracks”³⁴ that may become symptomatic in this pandemic, such as infrastructure limitations, and also identify best practices.

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Open Science Framework: COVID-evidence: a living database of trials on interventions for COVID-19 / The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days; https://doi.org/10.17605/OSF.IO/PJEM3¹².

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).