Clinical trials for treatment or prevention of COVID-19 . A review of Clinicaltrials . gov .

Background: Coronavirus disease 2019 (COVID-19) has rapidly progressed into the worst pandemic in recent years. There are currently no approved therapies to treat the disease. Several clinical trials are being conducted to evaluate therapeutic approaches. Methods: We conducted a cross-sectional descriptive study to examine the main characteristics of COVID-19-related clinical interventional trials registered with ClinicalTrials.gov  from January to March 27th, 2020. . Results: We included 519 trials, 57.6% were phase II or III, open-label and randomized trials. Disease treatment was evaluated in 75.5% of trials, while prevention was evaluated in 12.1%. A total of 243 trials were listed as recruiting, and 42.4% were not yet recruiting. Approximately 20% of the analyzed trials are investigating antimalarial agents, while 10.2% are studying the use of convalescent plasma to treat the disease. Antiretrovirals, monoclonal antibodies, the use of stem cells, nitric oxide gases and vaccines are the most commonly evaluated therapies. As of the publication of this review, none of the clinical trials had uploaded results. Conclusions: ClinicalTrials.gov is an important database that contains ongoing research trials on COVID-19This study quantifies the outcomes of COVID-19-related clinical trials.  More than 500 studies have been  analyzed finding that most of these studies are interventional clinical trials  Phase II or III evaluating drugs or biological agents for the prevention or treating COVID-19.


Introduction
The world is currently experiencing a general crisis regarding the healthcare system. SARS-CoV-2 has become a pandemic, and it has affected over 150 countries in a matter of weeks. The inability of many public health systems to address the spread of this disease has become notorious in many countries where the number of individuals with the disease and the number of deaths increase every day.
The clinical characteristics of COVID-19 include pyrexia, radiological signs of acute respiratory distress, reduced or normal white blood cells, lymphopenia, and a failure to resolve complications (e.g., secondary bacterial infections such as bacterial pneumonia) after 3 to 5 days of antibiotic treatment 2 .
The presence of contradictory information on possible treatments for this disease, some of which lacks a scientific foundation, has generated irresponsible actions regarding approached to treat COVID-19 3 .
Randomized controlled trials (RCTs) are the gold standard design for evaluating the efficacy and safety of clinical interventions and are valued for their statistical rigor and low levels of bias 4 .
Regulatory agencies are also contributing to the response to the coronavirus outbreak by providing general recommendations on how to use certain medicines that are still under investigation and guidance on measures that should be taken to stop the spread of the disease 5 .
ClinicalTrials.gov is a clinical trials registry that provides patients, family, health care professionals, investigators, and the general public with information about clinical studies on a wide range of diseases and conditions. This site is supported by the National Library of Medicine (NLM) at the National Institutes of Health (NIH) of the United States of America 6 . This database provides a public list of initiated, ongoing, and completed clinical trials, and it is considered a source of summary result information to complement the medical literature. It is the world's largest clinical trial registry, and it is publicly available and accessible to all citizens 7 .
How should COVID-19 be treated and what treatment options should be made available? Well-designed clinical trials are the answer to this question since they are the only type of study that is capable of assessing the efficacy and safety of new therapeutic approaches for any disease 8,9 .
In 2005, the International Committee of Medical Journal Editors (ICMJE) required that intervention trials be registered prior to the enrollment of the first subject as a prerequisite for publication in scientific journals. The registration of all clinical trials in any of the available public databases guarantees the transparency of research.
The numbers of cases and deaths caused by this pandemic are increasing continuously, demonstrating the need to identify therapeutic options for the disease. Drug repurposing may prove to be the best strategy for the quick development of novel therapeutic options 10 .
There are several drugs that are being evaluated, and some of the trials have yet to be initiated. Infected persons need to be treated with these drugs, but it is also necessary to determine the efficacy and safety profile of the therapies that are being used. There is a need to increase knowledge about the disease and enhance research efforts to find a cure for COVID-19, which will provide a scientific basis to make important decisions in health systems worldwide.
In this cross-sectional study, we aimed to examine the main characteristics of COVID-19-related clinical trials that were registered in ClinicalTrials.gov from January to March 27 th , 2020.

Study design
This is a cross-sectional analysis of all interventional studies that were registered on ClinicalTrials.gov from January to March 27 th , 2020. The database was downloaded on May 15 th , 2020.

Methods
A combination of search terms was used to retrieve interventional trials that examined COVID-19 ("coronavirus," "SARS-CoV-2", COVID-19). All trials were reviewed by two independent reviewers (MF and PG). Data on the design, masking, randomization, primary purpose, interventions, sample size grouping, type of therapeutic approaches and location of the included studies were extracted by the two reviewers (MF and PG) manually. Information about recruitment status, phases of the trials, and funding sources were used the same way the database was established. The search was restricted to interventional trials. The reviewers MF and PG extracted the data and checked each other's work for accuracy. Disagreements between the two reviewers were settled by consensus.

Amendments from Version 1
We added reviewers main observations. In the methods section we eliminated the paragraph regarding the creation of new variables from the extracted data according to the reviewer comments. We also clarified one inclusion criteria regarding dates. We added initials of the names of the independent reviewers in brackets. We also added a phrase regarding funding sources of the trials according to clinicaltrial.gov definitions. We changed conclusions of the manuscript. We include two new references.

Inclusion criteria
1. Trials investigating an intervention(s) on humans related to COVID-19

Study in any phase
3. Registered or published in ClinicalTrials.gov prior to March 27th, 2020.

Variables
Most of the information regarding the design of the studies was in the same column in the original downloaded database; for the purposes of our analysis, elements of the design were separated into different variables within the database, and no additional form was used. We extracted the information in the same way as it is reflected in ClinicalTrials.gov: (see ClinicalTrials.gov data elements definitions): Clinical trials were classified according to phase (I, I/II, III, II/III, III, or IV), type of intervention models (single group assignment, parallel assignment, and sequential assignment), type of allocation (randomized allocation, nonrandomized and not applicable in case there was only one group of treatment), and type of masking (open label, single-blind masking, double-blind masking, triple-blind masking and quadruple-blind masking).
Other characteristics of interest included primary purpose (basic science, treatment, supportive care, screening, diagnosis, prevention, health research services and others) and intervention type (drug, biological, behavioral, medical devices, diagnostic or other).
Recruitment status was also recorded (not yet recruiting: the study has not started recruiting participants; recruiting: the study is currently recruiting participants; not recruiting: the study is ongoing, and participants are receiving an intervention or being examined, but potential participants are not currently being recruited or enrolled; terminated: the study has stopped early and will not start again; completed: the study has ended normally, and participants are no longer being examined or treated; withdrawn: the study stopped early, before enrolling its first participant; or unknown: a study on ClinicalTrials.gov whose last known status was recruiting, not yet recruiting, or active, not recruiting but that has passed its completion date and the status has not been verified within the past 2 years), We included trials with participants of all ages and genders. We classified trials according to the estimated number of participants and categorized them as follows: up to 100, 101-500, 501-1000, + 1000 participants. We used the traditional development phases approach for the size of trials.
We also recorded the funding source for the trial. This describes the organization that provides funding or support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting. Organizations listed as sponsors and collaborators for a study are considered the funders of the study. Classification of funding sources was the same used by clinicaltrial.gov.

Statistical analysis
Data were extracted directly from the ClinicalTrials.gov database, which contains information for all registry records, and we downloaded a file in comma-separated values (.csv) format (see underlying data: (https://osf.io/28jh7/) 11 ). We performed a descriptive analysis of COVID-19-related clinical trials registered in the database downloaded on May 15 th , 2020.
Descriptive statistics were used to summarize the trial characteristics: categorical variables are reported as frequencies and percentages, while enrollment rate is reported as the median and IQR. All the data were analyzed using SPSS 24.0.

Characteristics of COVID-19 trials
Among the 339,723 studies registered in the database, 829 were COVID-19-related trials, 519 of which were interventional studies (62.6%), making them eligible for inclusion in our study ( Figure 1). Funding/status of the studies/age of participants The funding characteristics for all interventional trials are displayed in Table 2 11 . The most common source of funding was the pharmaceutical industry (12.3%).
As of May 2020, 243 of 519 trials were recruiting subjects, while 42.4% had their status as ''not yet recruiting''. Only ten of the trials were completed, and 25 were enrolling by invitation. A total of 0.6% were suspended trials, and 1.0% were withdrawn trials. Most of the studies (87.1%) included subjects who were 18 years and older (Table 2 11 ).

Starting date
The median number of trials registered over time was 58 trials per month from January to April 2020. Figure 2 shows the increasing rate of trials posted on this website. During the first days of May, the number of trials registered was 128.
Most of the trials found in this review are scheduled to end in 2020.

Sample size (enrollment)
To assess the enrollment of participants in clinical trials, the authors recategorized this variable into four groups. It was observed that 42.6% of trials had up to 100 participants, and 39.5% had 101-500 participants (Figure 3). The median enrollment was 144 participants (IQR 350).

Type of therapeutic approaches
Among the included studies, 22.8% were investigating antimalarial agents, while 10.8% were investigating the use of convalescent plasma. Other therapeutics under evaluation included new vaccines (2.6%) as well as monoclonal antibodies, interferons and antiretrovirals (Table 3 11 ).

Gender
Among the included studies, 98.8% comprised both sexes, while 1.2% recruited only female participants.

Study results
None of the included trials have posted any results.

Discussion
This study provides a review of COVID-19-related clinical trials registered with ClinicalTrials.gov during the first five months of 2020. We examine the characteristics of the trials, including their design, location, funding characteristics, recruitment status, age of participants, gender of participants and study sample size. A living protocol has been publish and the intention is to examined COVID-19-related trials registered in the WHO International Clinical Trials Registry Platform 12 .
Phase II and Phase III were the most common study phases. Almost all the included trials included participants of both sexes, the minority was in only in women but not related to specific populations; most of them included adults and older adults and aged between 18 and 99 years old.
More than 75% of the studies we analyzed were randomized trials, which are considered the gold standard for evaluating  most likely due to the efforts of many countries to combat this novel disease for which there is currently no treatment. The response to the COVID-19 pandemic from the community, particularly from researchers, has been excellent, but it is necessary to ensure the rights, safety and wellbeing of subjects. Well-designed clinical trials are important for guaranteeing these rights.
A large proportion of studies (42.6%) enrolled 100 or fewer patients, but these studies are in the early phases of development, and thus, we are not concerned that these studies are underpowered or have a high risk of type II errors (signification level), which would lead to inappropriate conclusions regarding the effectiveness of a therapeutic approach 13,14 .
Overall, most trials focused on the treatment of the disease. This indicates that the possible therapeutic benefits of these interventions include reducing the number of fatal events due to the disease.
As indicated by the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA) has not approved any drugs for treating COVID-19 that have demonstrated an adequate safety profile and adequate efficacy in randomized clinical trials with control groups 15 . According to the FDA, therapies that are under investigation to treat COVID-19 should only be examined in randomized controlled trials 15 .
Among the included studies, approximately 22% are evaluating antimalarial drugs such as chloroquine and hydroxychloroquine. Available evidence regarding the use of chloroquine in COVID-19 patients is limited, so there is still very low confidence in its efficacy for treating COVID-19. The use of chloroquine in the treatment of SARS-CoV-2 should be analyzed in light of both its promise and the potential adverse  Several studies have evaluated multiple drugs with in vitro antiviral activity against SARS-CoV-2 and/or immunomodulatory effects that may have clinical benefit. We found that the use of lopinavir combined with ritonavir in the majority of cases was very frequent. The combination of these two drugs and other antiviral agents in the early stages of COVID-19 infection might hold promise for treating COVID-19 17 .
Favipiravir was evaluated in 1.3% of the registered trials. This drug is considered a broad-spectrum antiviral that shows promise in the treatment of influenza virus infections, particularly due to the apparent lack resistant mutations against the drug in cell culture or animal studies 22 .
Remdesivir has also demonstrated its efficacy in inhibiting coronaviruses such as SARS-CoV and MERS-CoV in vitro 23 . The use of remdesivir has been shown to limit the mortality rate of seriously ill patients needing invasive ventilation and patients who did not need invasive ventilation by 18% and 5%, respectively 17 . There are also a few studies that are evaluating vaccines (2.6%); additionally, there are many pharmaceutical companies developing new vaccines, but many of these evaluations are still in the preclinical stages 26 There are challenges in conducting clinical research on COVID-19, and these challenges are impacting the health systems around the world. There is good clinical guidance 27 on how sponsors should adjust the management of clinical trials and participants during the COVID-19 pandemic. These guidelines must be followed to ensure that clinical trials are performed according national and international standards during this pandemic.

Strengths
This is a descriptive assessment of the current information regarding COVID-19 clinical trials registered in the ClinicalTrials.gov registry until March 2020. This database is updated frequently, is very user-friendly and provides transparency regarding the type, design, distribution, and funding of clinical trials.

Limitations
This study has some limitations. ClinicalTrials.gov does not include all the COVID-19 clinical trials registered and performed around the world. This study focuses on only one database; ClinicalTrials.gov is certainly one of the most important sources of information, but many others also provide valuable information. WHO's ICTRP is not very friendly database for quantitative analysis that is why is was not explored to describe clinical trials that are registered in this platform.

Conclusions
The efficacy and safety profile of many different therapeutic measures for patients infected by COVID-19 are being investigated. More than 500 studies have been registered within ClinicalTrials.gov. Most of these studies are interventional clinical trials evaluating drugs or biological agents. These trials have already started and are evaluating different therapeutic approaches for COVID-19 treatment. It is necessary to discover new classes of medicines.

Open Peer Review
Reviewer Expertise: Trial registration and transparency, research integrity downloaded on May 15th, 2020" and finally the results say "During the first days of May, the number of trials registered was 128". Please clarify any timing restriction used as exclusion criteria and the exact date of data collection.
registration seems to be subsequent to data collection. If so, the authors should not refer to it as underlying data.