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

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.

Coronavirus disease 2019 (COVID-19) is caused by the SARS-CoV-2 betacoronavirus. COVID-19 shares 79% sequence identity with SARS-CoV, the virus that caused a major outbreak in 2002–2003¹.

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 treatment².

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-19³.

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 bias⁴.

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 disease⁵.

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 America⁶.

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 citizens⁷.

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 options¹⁰.

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.

Methods

Results

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).

Figure 1. Flowchart of the review.

Phase II and Phase III studies were the most common (30.1% and 18.1%, respectively). Parallel assignment design was the most common study design (77.8%). Most clinical trials were open-label (59.7%) and randomized (75.5%). Disease treatment trials accounted for 75.5% of the eligible trials. Approximately 60% of the studies were evaluating drugs (Table 1¹¹).

Table 1. Main attributes of COVID-19 trials.

	No.	%
Phase
Early Phase 1	8	1.5
Phase 1	22	4.2
Phase 1/Phase 2	24	4.6
Phase 2	156	30.1
Phase 2/Phase 3	49	9.4
Phase 3	94	18.1
Phase 4	31	5.9
Not applicable	135	26.0
Design
Parallel assignment	404	77.8
Single group assignment	85	16.4
Sequential assignment	20	3.9
Factorial	3	.6
Crossover	7	1.3
Masking
Open-label	310	59.7
Single-blind	47	9.1
Double-blind	49	9.4
Triple-blind	34	6.6
Quadruple-blind	79	15.2
Randomization
Randomized	392	75.5
Nonrandomized	53	10.2
Not applicable	74	14.3
Primary Purpose
Treatment	392	75.5
Prevention	63	12.1
Supportive care	20	3.9
Diagnostic	14	2.7
Health services research	8	1.5
Screening	4	0.8
Basic science	4	0.8
Other	14	2.7
Intervention
Drug	311	59.9
Biological	79	15.2
Diagnostic test	15	2.9
Behavioral	16	3.1
Device	24	4.6
Procedure	11	2.1
Dietary supplement	8	1.5
Other	55	10.7
Total	519	100.0

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.

Figure 2. Rate of registered clinical trials according months of the year 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).

Figure 3. Enrollment by sample size groups.

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 Platform¹².

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 the efficacy and safety profile of any new treatment or for a new medical indication. The number of registered trials was high, 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 groups¹⁵. According to the FDA, therapies that are under investigation to treat COVID-19 should only be examined in randomized controlled trials¹⁵.

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 effects that have been observed in past endeavors to treat intense viral illnesses with chloroquine¹⁶.

A systematic review of the use of chloroquine concluded that there is sufficient evidence of its effectiveness and safety for other indications, which justifies the clinical research on the use of chloroquine to treat patients with COVID-19¹⁷.

Currently, the use of the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or the ethical approval of clinical trials are of vital importance, as stated by the World Health Organization^17,18.

We found that the second most commonly used treatment was convalescent plasma, which is examined in 10.3% of the included studies. Using plasma for convalescent patients has been successfully used for the treatment of several viral diseases during different outbreaks, such as the 2003 SARS-CoV-1 epidemic, the 2009–2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic¹⁹. Patients accepting this treatment showed benefits approximately 1 week later, suggesting that high titer levels can be used to effectively neutralize the virus, avoid inflammatory responses and improve symptomatology without severe adverse events²⁰. Information from China has shown that this therapy brings clinical and radiological improvement, decreases viral loads and increases survival times²¹.

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-19¹⁷.

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 studies²².

Remdesivir has also demonstrated its efficacy in inhibiting coronaviruses such as SARS-CoV and MERS-CoV in vitro²³. 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%, respectively¹⁷.

The World Health Organization (WHO), the Surviving Sepsis Campaign Guide and the CDC have stated that there is no current evidence to recommend a specific antiviral treatment for patients with confirmed COVID-19, and such evidence can only derive from a controlled clinical trial^18,24.

In a study of available scientific information, a group of scientists from Universidad Nacional de La Plata, Argentina, concluded that no studies have provided high-quality evidence for the use of hydroxychloroquine, chloroquine, or lopinavir/ritonavir to treat patients with COVID-19²⁵.

Regarding the use of nitric oxide, The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19-induced pneumonia. Instead, they suggest the use of this treatment only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies²⁴.

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 stages²⁶

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 guidance²⁷ 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.

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.

Data availability