








key: cord-294651-iy0h2pyf
authors: Nasrallah, Ali A.; Farran, Sarah H.; Nasrallah, Zainab A.; Chahrour, Mohamad A.; Salhab, Hamza A.; Fares, Mohammad Y.; Khachfe, Hussein H.; Akl, Elie A.
title: A large number of COVID-19 interventional clinical trials were registered soon after the pandemic onset: a descriptive analysis
date: 2020-06-08
journal: J Clin Epidemiol
DOI: 10.1016/j.jclinepi.2020.06.005
sha: 
doc_id: 294651
cord_uid: iy0h2pyf

Abstract Background There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the Coronavirus disease 2019 (COVID-19) pandemic. The number of registered trials related to COVID-19 is increasing by the day. Objectives To describe the characteristics of the currently registered clinical trials related to COVID-19. Methods We searched the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) on May 15, 2020. We included any entry that is related to COVID-19. We abstracted then descriptively analyzed the following characteristics of the registered trials: study design, status, phase, primary endpoints, experimental interventions, and geographic location among other qualifiers. Results We identified 1,308 eligible registered trials. The majority of trials were initially registered with ClinicalTrials.gov (n= 703; 53.7%) and the Chinese Clinical Trial Registry (ChiCTR) (n= 291; 22.2%). The number of participants to be enrolled across these trials was 734,657, with a median of 110 participants per trial. The most-commonly studied intervention category was pharmacologic (n=763; 58.3%), with antiparasitic medications being the most common subcategory. While over half of trials were already recruiting, we identified published peer-reviewed results for only 8 of those trials. Conclusion There is a relatively large number of registered trials but very few results published so far. While our findings suggest an appropriate initial response by the research community, the real challenge will be to get these trials completed, published, and translated into practice and policy.

In December 2019, the Chinese city of Wuhan witnessed the outbreak of a pneumonia of unknown origin [1] . The outbreak was traced back to Wuhan's Seafood Market [2] , and characterized by a strong person-to-person transmission [3] . Subsequently, scientists identified a new strain of Coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the source of the outbreak [4] . SARS-CoV-2 is a novel member of the beta coronavirus family, which includes SARS-CoV, source of an outbreak in 2002, and MERS-CoV, the origin of an outbreak in Saudi Arabia in 2012 [5] .

On 11 th of February 2020, the World Health Organization (WHO) announced Coronavirus disease 2019 (COVID-19) as the name of this new disease [6] . Within three months, COVID-19 outbreak had already affected six continents [7] , and the WHO upgraded its status from epidemic to pandemic on March 11, 2020 [8] . As of May 30 th , 2020 there have been 6,052,315 confirmed cases and 367,288 deaths [9] .

Patients infected with COVID-19 present with a wide spectrum of clinical presentations [10] , ranging from no symptoms to acute respiratory distress syndrome (ARDS) and death [11] . In parallel, with the high infectivity rates of the virus have led to the overstraining of healthcare systems [12] [13] [14] . Supportive management remain the pivot of treatment protocols in the absence of evidence on efficacious antiviral or anti-inflammatory medications [15] .

To date, most recommendations on preventing disease transmission and treating infected patients are based on anecdotal evidence and experts' opinions. Randomized control trials (RCTs) are needed to provide unbiased evidence to guide the clinical care and public health practices aimed to control COVID-19 outbreak [16] . Analyzing the status of clinical trials is a way of describing the current status of research in a scientific field, assessing the direction and magnitude of progress, and identifying potential gaps in interventional research [17] . Thus, this study aimed to describe the characteristics of the currently registered clinical trials related to COVID-19.

We used the WHO International Clinical Trials Registry Platform (ICTRP) database [18] to identify on all COVID-19 clinical trials and retrieve related information. The ICTRP is a network of international clinical trial registers which ensures single-point access and unambiguous identification of trials [18] 

We included all records retrieved on May 15 th , 2020 from the ICTRP that were labeled as one of the following study types: interventional, screening, prevention, treatment. We excluded the following: trials not directly related to treating or preventing COVID-19 disease, noninterventional trials, and the following types of trials; basic science, diagnostic test, epidemiological research, expanded access, health-services, observational, and prognosis.

We exported for each record all the variables reported by ICTRP (See appendix A). We included the following variables for our analysis: study ID, source register unique identifier, original registry, public title, primary sponsor, location (country and region), recruitment status, age range, gender, target size, study design, phase, publication (yes/no, count, and URL), intervention (category, subcategory, and name), primary outcomes, registration date, enrollment date, retrospective label, and trial URL.

Using the source register unique identifier numbers, we verified the data exported from the ICTRP datafile and collected any missing data. Then, two investigators (AAN and HHK) categorized in duplicate and independently the intervention variables into detailed subcategories, as shown in appendix B. Similarly, they categorized outcomes into the following types: mortality, morbidity, patient-reported, surrogate, composite, and other.

In addition, we searched for publications related to the eligible trials. We used the source register unique identifier to search for peer-reviewed publications related to the eligible trials (on PubMed, Medline, Embase, and Scopus), and for pre-print articles (on medRxiv and OSF) [19, 20] . Two investigators (HHK and ZAN) reviewed potentially relevant peer-reviewed publications and pre-print articles independently to confirm their relatedness to the eligible trials.

The complete COVID-19 file retrieved from ICTRP database included a total of 2,487 records.

We excluded 1,179 records for the following reasons: non-interventional trials (n=1,050); cancelled/withdrawn/suspended/terminated/retracted trials (n=44), not directly related to COVID-19 (n=67), duplicate records (n=13), not found in source registry (n=5).

As a result, 1,308 records met our eligibility criteria. Figure 1 1 shows the time distributions of the cumulative number of registered trials with the cumulative number of confirmed cases of COVID-19 [21] . While the former follows an exponential growth pattern, the latter follows an arithmetic growth pattern. case [1] . It is worth mentioning that seven trials started between the years of 2015 and 2019, respectively, and adjusted their protocols and eligibility criteria to include COVID-19 patients. Table 1 : Characteristics of registered trials stratfitied by phase, and across phases (N=1308) Table 2 : Characteristics of assessed interventions stratified across phases (N=1308) Table 3 provide a re-categorization of the types of primay outcomes assessed in the eligible trials. Overall, the majority of trials planned to include morbidity outcomes as primary outcomes (n=704; 53.8%). The next types by order of frequency were surrogate outcomes (n=611; 46.7%), mortality (n=319; 24.4%), and composite outcomes (n=129; 9.9%). Of these trials, 346 (26.5%) had surrogate only outcomes, 351 (26.8%) had morbidity-only outcomes, while 147 trials (11.2%) had both. Only one study did not report any primary outcomes. Table 3 : Types of primay outcomes in the eligible trials stratified by phase

Male 1 3 0 1 1 0 0 2 0 8 <1 Female 0 0 0 1 0 1 0 0 0 2 <1

We have described the characteristics of 1308 currently registered clinical trials related to COVID-19. The trials were planned in 66 countries, with the majority in China. The median number of participants per trial was 110, with only 10% of trials being phase 4. 58% of the trials were recruiting or ongoing, and 3.7% were completed. We only found 8 peer-reviewed original articles reporting results for the eligible trials. We also found 14 preprints of trial results.

Pharmacologic interventions were the most-studied category, with antiparasitic drugs, alone or in combination, being the most studied subcategory. The majority of trials included morbidity outcomes as primary outcomes.

Our study was based on trials registered in the WHO International Clinical Trials Registry Platform (ICTRP), which allows single-point access and unambiguous identification of trials [18] . Also, we used duplicate and independently approach to categorizing interventions and outcomes. A major limitation of our study is that the pool of COVID-19 registered trials is rapidly growing, hence the data would need to be periodically updated. Moreover, some registered trials may have incorrect, missing or outdated information [22] . This shift in geographical location reflects the change of the geographical focus of the pandemic itself to Europe and United States. The number of trials also remarkably increased in Iran, which is now the third largest country of origin for registered trials (9.6%). The previous focus of trials was on Traditional Chinese Medicine, which is somehow expected given that the pandemic started in China. The current focus is on antiparasitic drugs, immunomodulators, and antivirals.

During the COVID-19 pandemic, breakthrough news from Chinese hospitals regarding the effectiveness of hydroxychloroquine in COVID-19 patients drew significant attention to the drug [24] . It was especially made the subject of public attention after a cohort study in France found the use of hydroxychloroquine with azithromycin effective and free of side-effects in patients if used early after diagnosis [25] . Chloroquine and its reportedly less toxic derivative, Hydroxychloroquine [26] , used alone or in combination with Azithromycin, are now part of clinical practice for the management of COVID-19 in more than 10 countries including China, Iran, and Italy [27]. On March 28, 2020, the US Food and Drug Administration also approved hydroxychloroquine for emergency use authorization in treating COVID-19 patients [28] . The increasingly widespread use of the drug brings important considerations regarding evidence supporting its use.

As of May 31, 2020, the results of four clinical trials and one prospective observational study on the use of hydroxychloroquine in COVID-19 were published. Three found it superior to conventional treatment [25, 29, 30] , while the others did not observe significant difference between groups [31, 32] . One target trial emulation of 181 patients did not find evidence supporting the use of Hydroxychloroquine for COVID-19 related hypoxic pneumonia [33] . With no long-term follow-up, small sample sizes, multiple methodological flaws, and conflicting results, these published trials do not offer enough high-quality evidence to adequately support guideline recommendatios [34] .

We found 218 registered trials investigating the use of hydroxychloroquine in COVID-19 patients for either treatment or prophylaxis. The majority are either in phase 3 (n=88), or phase 2 (n=52), and most are conducted in Europe (n=76). Only three of these trials had published results [29, 30, 32] . With the known side effect profile of the drug, including cardiomyopathy and arrhythmias [34] and its suggested ability to induce renal and liver impairment [35] , the inclusion of hydroxychloroquine in clinical practice remains questionable until strong and convincing evidence can be generated.

Other therapeutic agents under study included anti-virals, immunomodulators, and biological agents. These include many drugs previoulsy used for the treatment of other infectious pathogens. One example is umifenovir (brand name Arbidol), an antiviral agent used in Russia and China for treating influenza infection, but not approved by the U.S. Food and Drug Administration (FDA) [36] . Another example is Oseltamivir, an FDA-approved drug for the treatment of influenza A and B [37] .

Remdesivir is an anti-viral agent that has recently received considerable attention. The Adaptive COVID-19 Treatment Trial (ACTT), a phase 3 trial involving 1063 participants lead by the National Institute of Allergy and Infectious Diseases , found that patients treated with Remdesivir had significantly faster recovery and lower mortality compared to placebo [38] . In light of the optimistic results, Remdesivir was announced as the new standard of care for COVID-19 patients in the US on April 19, 2020 [39] . Available results by another, although smaller, clinical trial lead by Gilead sciences did not a significant difference in outcomes between 5 and 10 days of treatment with Remdesivir [40] .

Ongoing trials investigating vaccines for COVID-19 are very important, as vaccination is the sustainable solution for counteracting this public health threat [41] . Traditionally, vaccine development is a lengthy process faced by multiple challenges including unknown virus immunogenic profile, vaccine safety, and participants recruitment/adherence [42] . In times of pandemics, additional challenges appear, such as difficulty randomizing populations in high mortality situations, overburdening ethics and regulatory authorities, as well as the absence of large-scale manufacturing for any novel platform technology [43] . Although promising results are available for one trial investigating the adenovirus type 5 (Ad5) vectored COVID-19 vaccine [44] , and most of the 37 identified trials on COVID-19 vaccines are in phase 1 and/or 2, the much-awaited vaccine is not expected to be available before at least 1 year to 18 months [45] .

The selection of primary outcomes reflects how researchers define meaningful evidence for the success of an intervention. However, the selection of outcomes has to insure adequate validity of their measurments and their generalizability for translation in clinical practice or health policies [46] . We found that pharmacologic and biological interventional trials addressed mainly morbidity and surrogate outcomes more frequently than composite, mortality or patient-reported outcomes. Trials targeting psychological interventions or physical therapy measured patientrelated outcomes, an expected finding. We found that 20% of registered trials addressed surrogate outcomes exclusively. In general, it is unclear to what degree surrogate outcome correlates with clinically meaningful effects, like those targeted by clinical outcomes [31] .

However, surrogate outcomes are used in accelerated approval pathways during epidemics or increases in life-threatening diseases, as they allow measurement of intervention effects with smaller sample sizes and shorter trial durations [47] .

We identified no completed trials, and only 5 peer-reviewed articles were available. the most likely cause is the recency of the events that triggered the trials of interest. While peer review can be a lengthy process, peer-review platforms are making changes to optimize their assessments, for example by directly posting their reviews to preprint servers [48] .

There is no available evidence to date that appropriately guides recommendations for the prevention and treatment of COVID-19. Those guiding health policies and clinical practice may therefore have to rely on a limited number of trial results, or indirect evidence derived from other diseases. There is a need for evidence-based interventions to mitigate the global humanitarian and economic sequelae of the pandemic. Registration of ongoing trials is essential for researchers to coordinate efforts, but more importantly to optimize the methods of those trials and ensure the transparency of their methods. The case of hydroxychloroquine illustrates very well how the medical community adopted a promising but still unproven intervention, in spite of the supporting evidence being inadequate, and that trials are still ongoing. This could be explained by the lack of effective medications in the face of high mortality rate. Still, the medication comes with a significant side effects and harms. Therefore, it is imperative to have a living process to keep the evidence uptodate as the results of trials start coming out [49] , and then feeding them into living recommendations [50] . Tracking registered trials would improve the efficiency of those living processes.

Future research can focus on improving trial recruitment process, and generating results in the most expeditious way possible. In the face of ongoing challenges, collaborative international efforts may be the key to success. There is also need to explore how to make trial outcomes available to decision makers, including guideline developers in a timely fashion. Future research on trial registration in this field will need to explore its dynamics over the time given the large number of trials being registered. For example, it would be interesting to explore whether and how the country where the trial is being conducted changes with the change of the countries most badly affected. Similarly, it will be important to explore how the categories of interventions and outcomes change over time.

None to declare. 

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

A new emerging zoonotic virus of concern: the 2019 novel Coronavirus (COVID-19)

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

<em>Severe acute respiratory syndrome-related coronavirus</em>: The species and its viruses -a statement of the Coronavirus Study Group

Journal of experimental stroke & translational medicine

Naming the coronavirus disease (COVID-19) and the virus that causes it

A Bibliometric Analysis of COVID-19 Research Activity: A Call for Increased Output

Coronavirus disease 2019 (COVID-19) Situation Report -51, in Coronavirus disease (COVID-2019) situation reports. 2020, World Health Organization: World Health Organization

An interactive web-based dashboard to track COVID-19 in real time

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine

The response of Milan's Emergency Medical System to the COVID-19 outbreak in Italy

Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response

How will country-based mitigation measures influence the course of the COVID-19 epidemic? The Lancet

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

Randomized controlled trials: part 17 of a series on evaluation of scientific publications

Status of the pediatric clinical trials enterprise: an analysis of the US ClinicalTrials.gov registry

International Clinical Trials Registry Platform (ICTRP)

Our World in Data

Exploring qualitative methods reported in registered trials and their yields (EQUITY): Systematic review

Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Coronavirus (COVID-19) Update: Daily Roundup

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv

Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial

Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review

Liver and Kidney Injuries in COVID-19 and Their Effects on Drug Therapy; a Letter to Editor. Archives of academic emergency medicine

Arbidol as a broad-spectrum antiviral: an update

Oseltamivir for influenza infection in children: risks and benefits

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Emory helps lead research on drug to treat COVID-19 patients

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

The effect of control strategies to reduce social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study

The current challenges for vaccine development

Developing Covid-19 Vaccines at Pandemic Speed

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet

How will country-based mitigation measures influence the course of the COVID-19 epidemic?

Choosing primary endpoints for clinical trials of health care interventions

Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward

Living systematic review: 1. Introduction-the why, what, when, and how

Living systematic reviews: 4. Living guideline recommendations

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Key findings:• 1,308 eligible trials related to COVID-19 were registered up to May 15 th , 2020• Trials were planned in 66 countries, with the majority in Europe• While more than half of the trials were already recruiting, eight had peer-reviewed publications What this adds to what is known • The research community has shown a good response to the pandemic in terms of initiating trials.

• The ultimate test will be whether the research community will be able to generate the needed evidence to guide the management of the pandemic.• Efforts should focus on completing the trials and publishing them in a timely fashion.

None to declare.

