key: cord-0910058-4nci3fsi
authors: Mousa, Albeir Y.; Broce, Mike; Lucas, B. Daniel
title: Cardiovascular Disease Novel Coronavirus and the Search for Investigational Therapies
date: 2020-05-17
journal: J Vasc Surg
DOI: 10.1016/j.jvs.2020.04.503
sha: e9717b9cbd4541f78d03f48f2163041675bb0e1a
doc_id: 910058
cord_uid: 4nci3fsi

PURPOSE: The primary purpose of the current study was to investigate and summarize the registered trials that listed COVID-19 as the primary condition. METHODS: We performed a search on ClinicalTrials.gov using the independent search terms COVID-19, SARS, and SARS COV2, and then downloaded the data file on March 23, 2020. All trials were downloaded to a csv file and searched for appropriateness. RESULTS: Fifty-six of 124 (45.2%) registered trials were listed as recruiting. The majority (85, 68.5%) classified their study as interventional, 37 (29.8%) classified as observational and one (0.8%) each classified their study as either expanded access:individual patients | treatment IND/Protocol or expanded access:intermediate-size population | treatment IND/Protocol. There were 67 (54.0%) of the trials that listed drug as the type of study. Immunological and antiviral trials were the greatest, representing approximately 30% and 21%, respectively. When immunological and antiviral drugs were used alone or in combination, they represented 41.9% and 34.4%, respectively. Anti-malarial agents are represented in 7.5% of trials. Approximately 14% of trials involved Traditional Chinese Medicine. The aforementioned study agents used solely or in combination represented approximately 80% of therapeutic approaches to COVID19. CONCLUSION: There was a large and quick response on ClinicalTrials.gov to the COVID-19 outbreak. Many of the registered trials are currently recruiting new patients, while some will begin in the near future. Specific potential experimental therapies, including dosing and monitoring, might be found by reviewing content. Within clinicaltrials.gov, patients, family members, health care professionals and researchers can search and find ongoing and future trials for COVID-19.

were not yet recruiting, 5 (4%) were withdrawn and 5 (4%) 9

were completed. COVID-19 related research trials can be found by anyone on 10 ClinicalTrials.gov. Hubei Province of China. It spread rapidly, resulting in an epidemic throughout China, followed 6 by an increasing number of cases in other countries throughout the world. In February 2020, the 7 World Health Organization referred to the disease as COVID-19 (i.e., Coronavirus disease 8 2019). The virus that causes COVID-19 is structurally related to the virus that causes acute 9 respiratory syndrome (SARS) and has been referred to as (SARS-CoV-2); and once previously, 10 was referred to as 2019-nCoV. 1 It is well established that many virus infections can affect the heart and experts suspect that 4 coronavirus may be no different. Viruses are known to induce inflammation of the myocardium. 5

In a healthy patient this may not lead to an adverse outcome, but in patients with ARDs, 6 coronary artery disease or heart failure the outcomes may be poor. Since many of the patients 7 affected by coronavirus are elderly with comorbidity, they may be at risk for adverse cardiac 8 events. Other comorbidities like smoking, diabetes, hypertension, renal failure, and COPD may 9 also increase the risk of cardiac death in COVID-19. During the SARS and MERS outbreak there 10 was also concern about adverse cardiac events like acute myocarditis, acute MI and rapid onset 11 CHF. In approximately 60% of MERS cases, presence of one or more pre-existing 12 comorbidities resulted in a worse outcome. Some patients were also found to have subclinical 13 diastolic left ventricular impairment. 14 15

The COVID-19 pandemic has gained much attention, while many researchers and scientists have 16 tried to investigate all aspects of the virus, treatment, spread and complications of the disease. 17

With so much main stream media attention given to COVID-19, where can researchers, 18

scientists, health care providers and patients look for a better understanding of available 19 treatments and research options? One good search engine for finding published medical literature 20 from medical journals is more commonly referred to as (PubMed®) and is located at the 21 following link https://www.ncbi.nlm.nih.gov/pubmed/. 16 If one (i.e., researchers, scientists, 22

health care providers or patients) is more interested in the future or what is currently being 23 studied, then (ClinicalTrials.gov) https://clinicaltrials.gov/ 17 is a very good option. 1

ClinicalTrials.gov is an internet-based registry that provides easy access to a whole host of 2 publicly and privately funded clinical studies. Patients, family members, health care 3 professionals, researchers or anyone else can search and find on-going and completed trials on 4 almost any illness or condition. It is maintained by the National Library of Medicine (NLM) at 5 the National Institutes of Health (NIH). Studies are registered before they begin, and list an 6 approximate start date with the status of the study (e.g., not yet recruiting, recruiting, etc.) 7 throughout the course of the study. The primary purpose of the current study was to investigate 8 and summarize the registered trials that listed COVID-19 as the primary condition, while 9

highlighting the importance of the registry to clinicians and patients as a source of therapeutic 10 options. 11 12 Methods 13 14 We performed a search on ClinicalTrials.gov using the independent search terms COVID-19, 15 SARS, and SARS COV2, and then downloaded the data file on March 23, 2020. All trials were 16 downloaded to a csv file and searched for appropriateness. There were 125 listed trials, and one 17 trial for hypertension that was placed on-hold due to COVID 19 was excluded. Thus, this left 18 124 trials for analysis. The file was imported into SPSS 19 18 and basic descriptive statistics were 19

performed. Trial characteristics such as trial status, intervention, trial phase and classification 20 were summarized and were placed into tables for easy comparison. In addition, the anticipated 21 start date for the trials was used to create a summary graph of the number of studies that expected to start within each month and plotted over time. The current study was designed and 1 conducted in such a manner as to apply to known good clinical practice guidelines. Table I as not applicable. There were 23 (18.5%) listed as phase 2 trials and 13 (10.5%) listed as Phase 11

3. There were 8 (6.5%) that listed Phase 1, 8 (6.5%) listed a combination of Phase 2|Phase 3 and 12 8 (6.5%) that listed Phase 4. Three (2.4%) were listed as a combination of Phase 1|Phase 2, and 13 two (1.6%) listed as Early Phase 1. (See Table II Table IV ) 22

Immunological and antiviral trials were the most common among the therapeutic trials (30% and 1 21%, respectively). Immunological and antiviral when used alone or in combination, represented 2 41.9% and 34.4%, respectively. Anti-malarial agents are represented in 7.5% of 3 trials. Approximately 14% of trials involved Traditional Chinese Medicine. The aforementioned 4 study agents used solely or in combination represented approximately 80% of therapeutic 5 approaches to COVID19. (See Table V interventional. This serves as some evidence that the researchers associated with these trials are 1 seeking to understand and treat the COVID-19 disease. 2 3 As has been highlighted in the lay media, immunological and antiviral approaches to are the bulk of clinical trial investigations (approximately 75% of listed trials). Several existing 5 and experimental monoclonal antibodies and antivirals were among the listed trials. Indeed, the 6 approved, but off-label, use of these agents have been inserted into local treatment algorithms. 7 8 Despite the highly publicized use of antimalarials for COVID-19, we found only 7.5% of trials 9

including one of these agents. We would propose that the practice of using an antimalarial for 10 the treatment of COVID-19 is happening off-label, likely as a "first line" treatment. Therefore, 11

we would not expect to see a large number of these trials listed. However, this is somewhat 12 unfortunate, recognizing that more substantive efficacy and safety data are needed regarding the 13 relative efficacy of this class of agents. 14 15

With the general acceptance of the virus originating in Wuhan, China, it was not surprising that 16 14% of the trials involved Traditional Chinese Medicine. While agents such as the traditional 17

Chinese medicine formula Fuzheng Huaya are not approved for medical use in the US by the 18 Food and Drug Administration, they may provide alternative treatments for COVID -19, 19 especially in the context of a research trial. Presently, fuzheng huaya has shown promise in the 20 treatment of viral hepatitis, 19 while huaier has demonstrated immunomodulatory effects. 20 21

Although clinicaltrials.gov was inherently useful to our caring for patients with COVID-19, there 1 are many additional complications which may surface for a vascular surgeon. As a result of the 2 pathogenesis of the disease 21 , there is the likely increase in thromboembolic conditions such as 3 acute limb ischemia, acute deep venous thrombosis, and pulmonary emboli (PE). 4

Anticoagulation must be considered. Furthermore, vascular interventions will be performed to 5

standard, but with extra precautions (PPE, negative pressure rooms, etc.). If indicated, lysis for 6 PE may be done in the prone position secondary to severe respiratory compromise. Acute 7 kidney injury will require acute placement of dialysis access in the popliteal vein if the patient is 8 in the prone position. Unfortunately, with these and many more evolving scenarios, surgeons 9 will have to proceed without level 1 evidence from ongoing clinical trials. 10 11

As COVID-19 was emerging as a pandemic, clinicaltrials.gov proved to be a useful tool to not 12 only identify clinical trial opportunities for patients, but also as a stimulus for reviewing off-label 13 options for affected patients. Out of the US-based clinical trials listed, our medical center is 14 assessing four of the trials as potential options for our patient base. Listed trials provide 15 appropriate contact information, and we encourage readers to access this resource as a 16 contemporaneous avenue for their patients. There was a large and quick response on ClinicalTrials.gov to the COVID-19 outbreak. Many of 21 the registered trials are currently recruiting new patients, while some will begin in the near 22 future. Specific potential experimental therapies, including dosing and monitoring, might be 23 

Within clinicaltrials.gov, patients, family members, health care 1 professionals and researchers can search and find ongoing and future trials for COVID-19

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