Managing trial participants with cardiovascular and metabolic disease during COVID-19

This is of particular concern for cardiovascular (CV) and metabolic trials because the subjects recruited are typically older (>50 years) with underlying cardiovascular disease and/or diabetes. Based on current epidemiological data, these are the individuals that may be at higher risk of contracting COVID-19 and portend a worse prognosis (Wang D et al, JAMA 2020;323(11):1061-1069).  Consequently, they may be unwilling or unable to attend study specific visits or procedures due to imposed quarantines, restricted access to healthcare facilities, and limited availability of site staff or even temporary closure of a site. Ensuring the safety of trial subjects is paramount while maintaining study integrity.

Several cardiovascular implications have emerged as our understanding of the COVID-19 pandemic evolves that could have an impact on ongoing cardiometabolic trials. One of them focuses on the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Many participants can be anticipated to be taking an ACE inhibitor or an ARB but might be considering to discontinue these drugs in light of (preclinical) findings that suggests ACE inhibitors and ARBs could potentially increase the risk of COVID-19 infection. Currently, there is no clinical data to support an adverse or beneficial effect with use of these therapies in COVID-19 or persons with CV disease. Although these concerns raise the need for additional research, the American College of Cardiology, American Heart Association and the European Society of Cardiology (Council of Hypertension) recommend continuation of ACE inhibitors/ARBs in accordance with indications for which they have shown benefit. Investigators are urged to discuss this information with their trial participants. Discontinuation of these therapies could impact subject safety, potentially confound endpoint assessments and affect the scientific integrity of the study. 

Reports of elevations in hs-cTnI and natriuretic peptides (NT-pro-BNP or BNP) levels have been observed in patients infected with COVID-19. A rise and fall in troponin (indicating myocardial injury) is common among persons with an acute respiratory illness; elevation in natriuretic peptides is also common (even in the absence of clinical heart failure).  In trials where these biomarkers are routinely being assessed (such as heart failure trials or for cardiac safety assessment), interpretation of clinically significant elevations may be challenging in light of COVID-19.  Changes could be related to infection with the virus (and necessitate appropriate testing) or may reflect exacerbation of an underlying CV condition, based on clinical signs and symptoms and/or electrocardiographic changes. Detailed documentation of decisions in these situations will be necessary.

COVID-19 clinical operations

Keeping your clinical trial on track in an evolving environment. 

Key study endpoints in CV trials often require specialised testing (e.g., invasive procedures, advanced non-invasive cardiac imaging and functional testing, etc.). These tests may only be available in large hospital centers where access may be restricted and the risk for exposure to COVID-19 is heightened. As such, trial participants may be unwilling or unable to undergo the protocol specific procedure(s).  To minimise the potential for missing data, alternative testing sites, which may require certification by core laboratories, may need to be considered, if available. If this is not feasible, it may be necessary to extend the window for the testing procedure, depending on the study specific scientific merits as well as participant burden. These protocol deviations will need to be carefully tracked and documented. Drop out of some sites or subjects may skew the data if the affected subjects may not be representative of the general study population. The handling of missing critical endpoint data due to COVID-19 will need to be discussed in the statistical analysis plan. 

Facilitating continuity of care, ensuring appropriate medical oversight, minimising missed visits/procedures, and provision of investigational product may be challenging during the COVID-19 pandemic. There may be an increase in the use of telephone visits, where allowed by the protocol, or the protocol may need to be amended to permit the use of phone visits. Home health agencies may need to be employed to perform key safety assessments, collect blood for safety laboratory testing and/or administer study drug, depending on the mode of administration. 

Communication with investigators and trial participants is all the more critical during the COVID-19 pandemic. The safety of each trial participant and the risks of continued participation in the study need to be weighed against the potential benefits.  To ensure a prompt response to questions related to the study and COVID-19, we strongly recommend the use of a study specific COVID-19 email address for correspondence. This process can assure that all site questions are rapidly triaged to the appropriate member of the cross functional team and that all team members are aware of the plan of action. 

Learn more about our range of services to keep your clinical trial on track during the COVID-19 pandemic. To speak with one of our cardiovascular and metabolic disease experts, please contact us.