COVID-19 Partnerships: Julio Chirinos and Jordana Cohen, University of Pennsylvania

During the COVID-19 pandemic, ArgoPond provided services to several research teams by leading clinical trial Data and Safety Monitoring Boards (DSMBs) and assisting with other clinical research strategic oversight. We are excited to present a series of interviews with some of these researchers, who effectively conducted clinical trials during a remarkable moment in history. In this blog, we speak with Drs. Julio Chirinos and Jordana Cohen of the University of Pennsylvania Perelman School of Medicine.

The Leaders and Their Research Focus Prior to the Pandemic

Dr. Julio A. Chirinos is a cardiologist and clinical trialist at the University of Pennsylvania who directs the Arterial Hemodynamics and Cardiac Imaging Quantification Laboratory. Trained in Medicine at Santa Maria Catholic University in Arequipa, Peru, he completed his cardiology fellowship at the University of Miami. Julio’s primary interest is in heart failure with preserved ejection fraction (HFpEF).  The most common form of heart failure, it is a condition for which there are no consistently effective pharmacologic treatments.

Dr. Jordana B. Cohen is a nephrologist and epidemiologist at the University of Pennsylvania. Trained in Medicine at Rutgers and in Nephrology at Penn, and having received a Masters of Science in Clinical Epidemiology at Penn, her research expertise is in causal inference modeling and pharmacoepidemiology. Prior to the pandemic, she worked on renin angiotensin system inhibitors and their impact in high-risk patients such as those with diabetes, hypertension, and chronic kidney disease.

Why They Pivoted to a COVID-19 Trial

ACE inhibitors and angiotensin receptor blockers (ACEi/ARB) are among the most widely used medications in the world — millions of people use these drugs for high blood pressure, heart failure, and kidney disease. In late February and early March 2020, as the scope of the COVID-19 outbreak became clear, publications began appearing that raised concerns about the role of ACEi/ARB in COVID-19 because of the shared mechanism centered on ACE2.

ACE2 is normally displayed on the surface of cells in the respiratory tract, kidneys, blood vessels, and heart, and it is also the most important ‘handle’ that SARS-CoV-2 uses to enter cells. There were guesses that ACEi/ARB drugs might enhance cellular invasion by the virus or worsen lung inflammation. Some experts believed ACEi/ARB agents might be protective. As the virus was novel, there were scant clinical data to support either claim. Nevertheless, strongly worded recommendations were written – in particular to halt the use of ACEi/ARB agents in patients currently depending on them. Clinical on-line forums were receiving hundreds of thousands of visits as physicians tried to figure out how to proceed with a ubiquitous class of drugs and a rapidly spreading epidemic.

A schematic of the dual function of angiotensin converting enzyme 2 (ACE2)  in the modulation of angiotensin and as a SARS-CoV-2 cellular entry mechanism.
Interplay between the SARS-CoV-2 spike protein and the renin-angiotensin system via ACE2. (N Engl J Med 2020:1653-1659)

While new opinions were published almost daily, data to back them up did not follow.  Julio remembered, ‘We found ourselves with all this clinical research infrastructure and experience at a time when all of our previous projects had been shut down because of the pandemic. We could either stay home, write grants and analyze data for a year or use our tools to contribute to the pandemic by generating robust clinical evidence rapidly. Clinical trials were not being launched quickly enough, and there was too much reliance on observational data and opinion.”

Jordana also felt strongly that something needed to be done. Messages were accumulating from her chronic kidney disease patients informing her that they, on their own, were stopping their ACEi/ARB medications because of lay press reports about possible risk. As one example of how complex the problem of poor information had become, a major academic medical center in the US, with little clinical evidence to support such a recommendation, sent an email to all their providers instructing them to stop using ACEi/ARBs in patients immediately. Because so many people were going to be so quickly affected, the central question of the REPLACE study was swiftly born: Should physicians continue or discontinue ACEi/ARB drugs in patients admitted to the hospital with COVID-19?

The Trial: Randomized Elimination and Prolongation of ACE Inhibitors and ARBs in Coronavirus 2019 (REPLACE)

The REPLACE trial was by far the fastest the pair had ever implemented. It took only 8 days to evolve from concept to a full protocol ready for institutional review board approval. The trial was simple – among patients receiving ACEi/ARB medications admitted to the hospital for COVID-19, randomize each to either continue or stop receiving that medication. The study began at the University of Pennsylvania, but many additional sites were soon brought on board. By the conclusion of the trial, patients from 20 referral hospitals in the USA, Canada, Mexico, Sweden, Peru, Bolivia, and Argentina had participated.

A significant challenge for most clinical trials in COVID-19 was counterintuitive: finding enough patients. So many clinical trials were being launched in the spring and summer of 2020 that it became difficult for studies to recruit enough patients to arrive at a reliable result. A significant advantage of the REPLACE trial was its use of a new hierarchical endpoint. Designed with Dr. Thomas Hanff, an advanced heart failure and transplant fellow at the University of Pennsylvania, the REPLACE method for measuring patient improvement or worsening allowed more powerful conclusions to be drawn from a smaller number of enrolled patients than would be possible using the World Health Organization (WHO) score or other common trial endpoints during the pandemic. It also incorporated multiple clinical processes, such as death, respiratory and kidney failure, and length of hospitalization.

Ultimately, the REPLACE trial enrolled 152 patients and demonstrated that ACEi/ARB drugs did not impact the overall outcome of patients hospitalized with COVID-19. This important class of cardiovascular- and kidney-protective medications were safe to continue in patients suffering from SARS-CoV-2 infection. The team’s success with the REPLACE trial led them to stand-up a second clinical trial of another common agent, fenofibrate, which is currently enrolling patients in North America, South America and Europe and has received funding from the National Institutes of Health, with additional support from Abbott Pharmaceuticals to increase the number of patients enrolled, and to add new countries and sites to the trial, for a prompt completion. Argo Pond is also providing DSMB support for this trial.

The Biggest Surprises

For Dr. Cohen, the most unexpected part of conducting the trial was the wide fluctuation in the numbers of patients available to be studied over time.  ‘We would alternate between not being able to keep up with the number of patients being enrolled to suddenly needing to add additional hospitals to the effort in order sustain recruitment.’  It was quite different than the illnesses the team was used to working on, in which the availability of new patients was usually steady over time.

For Julio, an important lesson was in how readily, at the beginning of the pandemic, the scientific community appeared to be willing to lower its standard of evidence.  Treatment recommendations, and even some policy, was being set by hunch rather than fact. It reminded him of the early days of the HIV epidemic, when the disease was unfamiliar, spreading quickly, and nothing seemed to be able to stop the progression of the illness.

One positive surprise to the group was the willingness of researchers to collaborate under really tough circumstances.  Multinational teams were rapidly assembled based on pre-existing friendships or even entirely new collaborative relationships.  In a moment of great uncertainty, researcher teams –  patients, caregivers, and scientists – were prepared to risk their lives to generate the information needed to combat the disease.

‘In the end,’ reflected Dr. Cohen, ‘we learned a huge lesson in the importance – and possibility – of gathering data quickly and reliably in a state of emergency.’

Related Publications from the Researchers

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: A prospective, randomised, open-label trial

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) tiral protocol

Clinical and proteomic correlates of plasma ACE2 (angiotension-converting enzyme 2) in human heart failure

Thrombosis in COVID-19

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