**1. Introduction**

In March 2020, the World Health Organization (WHO) recognized Coronavirus Disease 2019 (COVID-19) as a public health problem and declared the state of pandemic contamination [1]. Since its detection in late 2019, in China, the newly discovered virus, called SARS-CoV-2 [2] spread rapidly around the world with cases, to date, in 223 countries, with more than 127 million infected individuals and nearly 3 million deaths [3]. The region of Americas concentrates almost half of all diagnosed individuals, with the United States being the most affected country, totaling 30 million cases [3].

SARS-CoV-2 belongs to a family of single-stranded, positive-sense and enveloped RNA viruses, known as *Coronaviridae* [4], has high mutation rate and rapid spread, with multiple mutations having appeared and spread during the pandemic [5, 6]. The transmission of the virus occurs through droplets expelled by a person with the disease or through contact with contaminated surfaces [7].

In general, patients with COVID-19 have fever, cough, myalgia, nausea, diarrhea, reduced smell and taste, as well as mild breathlessness [8]. In the most severe cases, patients can develop Acute Respiratory Distress Syndrome (ARDS), heart failure, shock and renal failure [9]. Elderly, obese and individuals with pre-existing conditions, such as diabetes, hypertension, cardiovascular and pulmonary diseases, cancer, chronic kidney disease, among others, have higher risk of progressing to more critical cases of the disease [10]. In addition to symptoms and severity of the disease, the impact of COVID-19 affects all aspects of our lives, generating financial consequences, insecurity and anxiety [11].

Advances have been made in the knowledge of COVID-19 and in the development of safe and effective vaccines [12]. However, there is still no specific pharmacological protocol approved to prevent and/or reduce contamination by the virus, so that there are countless ongoing researches to find an appropriate treatment [13]. The development of vaccines, convalescent plasma therapies, cell-based and monoclonal antibody therapies are some of the treatments studied worldwide. However, the development of new drugs is a long and expensive process, and the current health emergency has led to the use of existing drugs [14].

The pandemic has induced the global scientific community to focus efforts on COVID-19 [15] and clinical trials represent the gold standard for evidence-based practice [16], as they are important methods for assessing intervention modalities, generating impact on current and future clinical practice [17]. However, attention should be paid to clinical trials with inadequate or low-quality designs, and it is important to analyze their designs on clinical trial registration platforms to identify those that provide the best scientific evidence that can reduce the effects of the COVID-19 pandemic [18].

In view of the fact that SARS-CoV-2 is a virus with characteristics never before studied, with several consequences that go beyond contamination, and in the absence of an approved effective therapy, correctly designed clinical trials are essential for evaluating interventions in order to prevent and contain the spread of the disease. Thus, the guiding issue that supported this chapter was: "Which interventions for use in patients with COVID-19 are being evaluated by American researchers?"

#### **2. Methods**

The database chosen for this study was the Clinical Trials platform (https://clinica ltrials.gov/), which comprises a web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions [19]. In the search strategy, keywords "COVID-19" in the "Condition or Disease" section and "United States" in the "Country" section were used.

No filters were applied, so that all registered clinical trials were analyzed. Data were collected in March 2021 by a single previously trained researcher. Studies with suspended, withdrawn and terminated recruitment status, observational and expanded access studies, and those that did not mention COVID-19 diagnosis and those including healthy patients among their eligibility criteria were excluded.

The following information was collected: study location, number of participants, age groups of subjects (0–17, 18–64, >65), allocation (randomized, non-randomized e n/a), intervention model (single group assignment, sequential assignment,

*Clinical Trials on COVID-19: What is Being Researched in the United States? DOI: http://dx.doi.org/10.5772/intechopen.98494*

crossover assignment, parallel assignment and factorial assignment), masking (blind, double-blind, triple-blind, quadruple-blind and open label), purpose (diagnostic, treatment, prevention, basic science, supportive care, health services research, device feasibility, screening and other), diagnostic criteria for COVID-19 (confirmed, suspect and confirmed or suspect), other eligibility criteria, recruitment status (completed, recruiting, active, not recruiting, not yet recruiting and enrolling by invitation), numbers of arms, type of intervention (dietary supplement, drug, biological, device, diagnostic test, procedure, radiation, behavioral, combination product and other), phase (early phase 1, phase 1, phase 2, phase 3, phase 4, phase 1 and phase 2, phase 2 and phase 3 and n/a), presence of placebo (yes and no), comparison arm (yes and no), and sponsor (university, pharmaceutical/ biotechnology company, research organizations, hospital, health care provider, doctor, united states department of defense and philanthropy).

Types of intervention were classified according to the WHO's Anatomical Therapeutic Chemical Classification System [20]. In cases where they are not included in the WHO's ATC, information present on the companies' websites was used.

Data were tabulated and analyzed using the Microsoft Excel 2016 for Windows software (Microsoft Press, Redmond, WA, USA) and descriptively presented.

#### **3. Results**

In total, 5,129 records involving COVID-19 were found and, after the search strategy, 1,182 (23%) corresponded to clinical trials developed in the United States. Of these, eight studies that were suspended, 22 that had been withdrawn, 25 terminated, 325 observational studies, 18 expanded access, 37 that did not include COVID-19 diagnosis and, finally, 251 clinical trials using healthy patients were excluded. At the end, 496 studies met the eligibility criteria and were selected.

The geographic distribution of studies highlights the state of California as the main place for carrying out these surveys (155 studies), followed by Florida (124 studies), Texas (121 e studies), Nova York (115 studies), Illionois (86 studies), Massachusetts (81 studies), Pennsylvania (78 studies), North Carolina (75 studies), Washington and Ohio (73 studies each), Michigan (71 studies), Maryland (70 studies), Georgia (66 studies), Louisiana (64 studies), New Jersey (56 studies), Virginia and Arizona (50 studies each), Minnesota (45 studies), Colorado (39 studies), Alabama (38 studies), Tennessee (35 studies), Missouri (33 studies), Connecticut (30 studies), Utah (29 studies), Oregon (28 studies), South Carolina and Kansas (27 studies), Kentucky (25 studies), New Mexico and Nebraska (22 studies each), Indiana and Iowa (21 studies), Wisconsin and Mississippi (20 studies each), Arkansas (16 studies), Idaho and Rhode Island (14 studies), Oklahoma (11 studies), West Virginia (10 studies), Maine and South Dakota (9 studies each), Hawaii and Montana (7 studies each), Vermont (3 studies), and Alaska and Delaware (1 studies each).

The number of participants ranged from 1 to 10,000 individuals. Most clinical trials analyzed involved adults and older adults, with higher percentage in the age group of 18–64 years (48.6%), while surveys that recruited children and adolescents represented only 2.9%.

Regarding the allocation of participants, only 26 studies (5.2%) were not characterized as randomized. The most frequent intervention model is the parallel (75.6%). Regarding the type of masking, the open study model (38.7%) is the most prevalent, followed by the double-blind model (21.4%), while single-blind studies corresponded to only 4.4%. Studies with therapeutic purposes were carried out in the majority (88.3%) and there is predominance of those who consider proven and positive COVID-19 diagnosis (89.1%) as an inclusion criterion (**Table 1**).



#### *Clinical Trials on COVID-19: What is Being Researched in the United States? DOI: http://dx.doi.org/10.5772/intechopen.98494*

#### *Science-Based Approaches to Respond to COVID and Other Public Health Threats*


#### **Table 1.**

*Characteristics of the sample and study design of clinical trials.*

Other eligibility criteria used by researchers were the inclusion of individuals with associated risk factors (28 studies), including cancer (4 studies), type 1 or type 2 diabetes mellitus (3 studies) and heart diseases (1 study).

Regarding recruitment status, at the time of data collection, 59.5% of clinical trials were recruiting participants and 13.7% were active, but not recruiting. Regarding the number of arms, most studies use the two-arm test (67.3%). Most clinical trials research a new drug (64.8%), are in phase 2 (43.2%), 55.2% use placebo and 54.5% use comparison arm. As for sponsors, pharmaceutical/biotechnology companies (35.4%) and universities (29.4%) are those that most invest in clinical trials (**Table 1**).

Regarding the identification and classification of drugs, biological interventions, dietary supplements, combined products and some other interventions, 434 clinical trials use interventions in monotherapy and 67 make use of combinations. In monotherapy, most trials assess immunosuppressants (49 studies), followed by COVID-19 Convalescent Plasma (40 studies), antivirals (32 studies), anticancer (30 studies), antithrombotic (24 studies), anti-inflammatory agents (16 studies), antifibrinolytics (14 studies), antimalarials (13 studies), immunostimulants (7 studies), expectorants (6 studies), antibacterials (5 studies), antiparasitic and corticosteroids (4 studies each), antidepressants (3 studies), sex hormones and modulators of the genital system (2 studies) and antiprotozoals (1 study) (**Tables 2** and **4**). Clinical trials using combinations use antivirals /immunosuppressants (9 studies), antimalarials /antibiotics (6 studies), antithrombotic agents (4 studies) and antivirals/corticosteroids (**Tables 3** and **4**).

