key: cord-0780553-qiyoamek
authors: Varshney, Anubodh S.; Wang, David E.; Bhatt, Ankeet S.; Blood, Alexander; Sharkawi, Musa A.; Siddiqi, Hasan K.; Vaduganathan, Muthiah; Monteleone, Peter P.; Patel, Manesh R.; Jones, W. Schuyler; Lopes, Renato D.; Mehra, Mandeep R.; Bhatt, Deepak L.; Kochar, Ajar
title: Characteristics of Clinical Trials Evaluating Cardiovascular Therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: A Cross Sectional Analysis
date: 2020-10-26
journal: Am Heart J
DOI: 10.1016/j.ahj.2020.10.065
sha: bb29a4ea381dd5b335fbf385a222dd67e4698035
doc_id: 780553
cord_uid: qiyoamek

BACKGROUND: Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. METHODS: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. RESULTS: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n=37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n=16), renin-angiotensin-aldosterone system-related therapies (12.3%; n=14), and colchicine (8.8%; n=10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n=5) and 9.6% (n=11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n=100), enrollment of less than 1000 participants (86.8%; n=99), single site implementation (55.3%; n=63), and had a primary outcome of mortality or a composite including mortality (56.1%; n=64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n=93). At the time of database query, 28.9% (n=33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n=78). Most lead sponsors were located in North America (43.9%; n=50) or Europe (36.0%; n=41). CONCLUSIONS: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

The coronavirus disease 2019 (COVID- 19) pandemic, which has affected over 27 million individuals and caused over 899,000 deaths globally as of September 10, 2020 1 , has motivated a laudable global effort to rapidly evaluate novel and established therapies that may improve outcomes in COVID-19 patients. At present, a limited number of therapies have been shown to improve clinical outcomes in patients infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) via randomized controlled trial (RCT) data 2,3 . Cardiovascular (CV) disease is widely prevalent and remains the leading cause of mortality globally 4 . Patients with CV comorbidities are more likely to have severe illness and in-hospital mortality 5, 6, 7 . Moreover, hospitalized COVID-19 patients who develop acute cardiac injury, manifesting as elevation in troponin level, constitute a cohort with a particularly poor prognosis 5, 7, 8 . These clinical observations are corroborated by evidence of various CV pathophysiologic mechanisms in COVID-19 patients 9, 10, 11 . Additionally, both the renin-angiotensin-aldosterone system (RAAS) 12 and thromboinflammation 13 are implicated in COVID-19 pathogenesis. Collectively, these findings highlight a potential prominent role for CV therapies in the management of COVID-19. However, the characteristics of ongoing trials evaluating CV therapies for treatment of COVID-19 are not well described, and have implications for the clinical, investigative, and policy communities, as well as funding agencies.

We therefore evaluated registered clinical trials of established CV therapies related to COVID-19 using the ClinicalTrials.gov database, which was established to improve monitoring and conduct of research studies 14 .

The ClinicalTrials.gov database was queried on August 7, 2020 using the search terms "COVID-19", "SARS-CoV-2", "2019-nCoV", "severe acute respiratory syndrome coronavirus 2", and "2019 novel coronavirus" (found at: https://clinicaltrials.gov/ct2/results?cond=COVID- 19) for interventional studies. Studies in the following standardized, ClinicalTrials.gov-generated intervention categories were reviewed: "Anti-Arrhythmia Agents", "Anticoagulants", "Antihypertensive Agents", "Cardiotonic Agents", "Channel Blockers", "Colchicine", "Fibrinolytic Agents", "Hypoglycemic Agents", "Lipid Regulating Agents", "Natriuretic Agents", "Platelet Aggregation Inhibitors", and "Vasodilator Agents". Studies evaluating established cardiovascular drugs (e.g., antithrombotics, RAAS related therapies, nitric oxide) or other fibrinolytics (defibrotide) were included. Given the longstanding role of colchicine in the treatment of pericarditis 15 and recent evidence demonstrating its benefit in patients with myocardial infarction 16 and chronic coronary artery disease 17 , it was considered a CV therapy.

The database search was then reviewed for studies evaluating extracorporeal membrane oxygenation (ECMO), and these studies were also included for analysis. Trials evaluating CV therapies in combination with non-CV therapies were also included, as these often represent large, network-based, platform trials. Studies evaluating anti-microbial (e.g., hydroxychloroquine, remdesivir), convalescent plasma, non-colchicine anti-inflammatory (e.g., methylprednisolone, tocilizumab), experimental, or other therapies without established CV therapies were excluded, as were studies that were withdrawn or terminated. Three investigators (ASV, DEW, AK) independently reviewed studies for eligibility to ensure all included trials involved evaluation of established CV therapies. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. 

The initial ClinicalTrials.gov query yielded 2,935 registered studies related to COVID-19 registered on or before August 7, 2020. Of these, 1,645 (56.0%) had an interventional study design. Among interventional studies, 114 (6.9%) involved established CV therapies (Figure 1 ).

A total of 10 therapeutic categories were represented among trials of CV therapies related to COVID-19 (Figure 2) . Trials evaluating antithrombotics were the most common (32.5%; J o u r n a l P r e -p r o o f Journal Pre-proof 37/114), followed pulmonary vasodilators (14.0%; 16/114), RAAS-related therapies (12.3%; 14/114), and colchicine (8.8%; 10/114). Multiple CV therapies will be assessed in 4.4% (5/114) of studies, and 9.6% (11/114) will evaluated CV therapies in combination with non-CV therapies. Detailed trial characteristics are presented in Table 1 

ClinicalTrials.gov has the following notable findings: 1) a minority of interventional studies related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies or CV specific outcomes; 2) most studies are planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions; and 3) are estimated to complete after December 2020. Given that the CV system is strongly implicated in COVID-19 J o u r n a l P r e -p r o o f Journal Pre-proof pathogenesis and patients with CV comorbidities have increased risk for adverse outcomes with COVID-19, these findings have the potential to inform future investigations of possible COVID-19 therapies. This analysis also provides a quantitative basis for the need for thoughtful application of trial results to clinical practice and policy development by considering important trial design characteristics and limitations.

Approximately 7% of registered clinical trials related to COVID-19 sought to evaluate CoV-2 enters epithelial cells via angiotensin-converting enzyme 2 (ACE2), leads to subsequent downregulation of ACE2 expression 22 , and serum angiotensin II levels have been shown to correlate with SARS-CoV-2 viral load and severity of respiratory failure 23 , the focus on these therapies among CV drugs is appropriate. Severe COVID-19 is also characterized by abnormalities in hemostatic markers 24 and potentially endotheliitis 11 . As such, it is apt that most registered studies are designed to evaluate antithrombotic strategies in COVID-19 patients.

Colchicine, which reduces levels of inflammatory mediators 25 that are correlated with worse outcomes in COVID-19 patients 7 , is also appropriately being evaluated. Despite the known endothelial-stabilizing, anti-inflammatory, and beneficial CV effects of statins 26 , there are few trials evaluating the potential role of these commonly used and generally well-tolerated drugs in COVID-19 patients.

This analysis also demonstrates that registered CV therapeutic trials are limited in scale and generalizability. Of note, multiple distinct trials seek to evaluate the same therapy, but have differing primary outcomes. Most trials were open label, a placebo control arm was present in less than one quarter, and about 10% of trials had no control group. Such designs may introduce systematic biases 27 and results from these trials should be interpreted in the appropriate context before clinical application. Despite widespread COVID-19 prevalence and multiple studies examining the same or similar therapies, most studies aimed to enroll less than 1000 patients and were planned to be single-center.

Findings from this analysis also delineate the timeline of when potentially beneficial CV therapies for COVID-19 may be identified and underscore the need for measured approaches to public policy changes that take into account the time required for meaningful clinical evidence to be generated. While almost all studies in the analytic cohort were scheduled to begin enrollment J o u r n a l P r e -p r o o f Journal Pre-proof before August 2020, it is noteworthy that almost one-third of studies were not yet recruiting at the time of the database query. Additionally, over two-thirds of studies are estimated to be completed after December 2020.

The vast majority of lead sponsors of studies analyzed were from either Europe or North America, which is consistent with reported COVID-19 disease prevalence globally 28 . However, lack of adequate testing in low income countries may under-estimate the true prevalence of COVID-19 in many regions of the world. Resource-limited countries are particularly vulnerable to devastating ramifications from spread of SARS-CoV-2 29 , and studies conducted in Europe and North America may have limited generalizability to these regions based on differences in population prevalence of co-morbidities, environmental factors, and healthcare infrastructure.

Therefore, planned RCTs should seek to enroll patients in low income countries when feasible and trials should be established to inform care specifically in these regions. Lastly, if beneficial CV therapies are identified for COVID-19 patients, a global supply chain that could facilitate rapid production, distribution, and utilization of such treatments should be expediently established to maximize therapy access and effectiveness. RCT execution. This approach may help diminish inefficient trial redundancy. For instance, this analysis found ten registered RCTs evaluating colchicine in hospitalized patients with COVID-19. None of these trials have the same primary outcome, and in aggregate they will likely provide mechanistic insights on the potential role of colchicine in COVID-19 treatment but are unlikely to convincingly establish a therapeutic stance. In the context of a clinical trials network or collaboratory, these RCTs could still be permitted to function independently, but could have established a priori an agreement to pool patient-level data upon trial conclusion and assess clinically meaningful outcomes. Such a strategy could facilitate more efficient evidence generation that influences clinical care and patient outcomes on the rapid time scale necessary. Fourth, although lead sponsor types were tabulated from trial-specific entries, ClinicalTrials.gov does not require detailed reporting of trial funding sources. Given that the majority of lead sponsors were academic medical centers, many of which receive financial support from government entities, this may have led to underappreciation of government funding sources.

Fifth, while lead sponsor location is available from ClinicalTrials.gov, not all study entries included detailed information regarding trial sites. Therefore, the geographic distribution of lead sponsor locations may not necessarily reflect the locations of study enrollment and implementation. In addition, the presence of one study location was interpreted as a trial being single site unless a study entry specifically indicated a trial was multi-center. However, it is possible that some trials may be multi-center despite listing only a single study location. Lastly, while interventional studies involving pharmacologic and device therapies are registered, certain J o u r n a l P r e -p r o o f types of interventional studies, including health system research studies, implementation science studies, and quality improvement research, may not require ClinicalTrials.gov registration. Thus, these types of studies may be underreported in our analysis.

The unprecedented COVID-19 pandemic has led to an impressive, rapid initiation of numerous clinical trials evaluating potential COVID-19 therapies. Despite a significant role of the CV system in COVID-19 pathophysiology and outcomes, a minority of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Most trials are planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Trial results should be applied to clinical practice and policy development by considering important study limitations and design characteristics. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

VA CART Research and Publications Committee (Chair)

Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology

Baim Institute for Clinical Research, Roivant (paid to Brigham and Women's Hospital) and Triple Gene

COVID-19 situation reports

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies

Endothelial cell infection and endotheliitis in COVID-19

Thromboinflammation and the hypercoagulability of COVID-19

Design and implementation of a national clinical trials registry

Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Colchicine in Patients with Chronic Coronary Disease

ST-Segment Elevation in Patients with Covid-19 -A Case Series

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)

COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum

Pleiotropic Effects of Statins on the Cardiovascular System

Blinding in randomised trials: hiding who got what

Johns Hopkins Coronavirus Resource Center

Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study

Evidence from Pragmatic Trials during Routine Care -Slouching toward a Learning Health System

Registry-based randomized clinical trials--a new clinical trial paradigm

New Approaches to Conducting Randomized Controlled Trials

Adaptive Designs for Clinical Trials

Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial

HERO Research

Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine -Full Text View -ClinicalTrials

COVID-19: An Unintended Force for Medical Revolution?

Why Should I Register and Submit Results? -ClinicalTrials.gov

Geographic prevalence of COVID-19 cases as of August 7, 2020 (data from WHO COVID-19 Situation Report). B. Geographic prevalence of lead sponsors of trials of cardiovascular therapies related to COVID-19 registered on ClinicalTrials