BIG STAKES, BIG STATS: Making sense of COVID-19 trials


PITTWIRE — When we hear about clinical trials, we might picture doctors and patients partnering to test new therapies. What we might not think about are the teams of other professionals and scholars who make those studies happen and figure out what the results mean. In the search for new and better treatments, those roles are critical in normal times. In a pandemic, the work becomes all the more urgent.

Take, for instance, Maria Mori Brooks. In the three decades since she earned her PhD in statistics, the Pitt professor of epidemiology and biostatistics has proved her mettle making sense of the numbers generated by multicenter research collaborations. As codirector of the Graduate School of Public Health’s Epidemiology Data Center, she’s helped dozens of National Institutes of Health–funded scientists design and optimize data collection and management, as well as formulate computing and statistical methods for clinical studies. She also serves as principal investigator for the data coordinating centers of three multicenter investigations.
Still, nothing quite prepared Brooks and her colleagues for their roles since June with ACTIV-4 Antithrombotics, a set of clinical trials funded through Operation Warp Speed. The study is part of the U.S. government’s public-private partnership Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). ACTIV-4 Antithrombotics evaluates how well blood thinners (anticoagulants) work in treating COVID-19 patients.
The trials consortium will yield outcomes from three distinct COVID-19 patient populations—inpatient, outpatient and post-discharge.    
Many COVID-19 deaths are caused by microscopic blood clots.    
Before this pandemic, doctors often gave patients low-dose blood thinners during extended hospitalizations to prevent clots that might form because of reduced physical activity. Given that COVID-19 clotting can cause lung damage, strokes and heart attacks, higher-dose blood thinners seemed like a good idea for people with COVID-19.  
Yet, that was just a hunch. Or a hope. The treatment had not been vetted in clinical trials, so physicians didn’t have any evidence to guide their practice.
“Some people are treating their patients with anticoagulants and some aren’t,” Alison Morris, Pitt’s division chief for pulmonary, allergy and critical care medicine, noted in January. But now, ACTIV-4 Antithrombotics inpatient arm has given doctors some answers. 
The trial randomized participants, with a goal of enrolling 2,000, to receive either high-dose heparin or the standard anticoagulant regimen used as a preventative among hospitalized people.
ACTIV-4 Antithrombotics inpatient arm is one of three collaborating multicenter studies of hospitalized patients—the others are based in the U.K. and Canada—that together span 300 hospitals on four continents, all working in parallel on the blood thinner question.   
A typical multicenter clinical trial team spends years detailing protocols and enrollment plans, garnering approval from institutional review boards and vetting contracts. Patient recruitment, data collection, analytics and the publication of findings often span multiple five-year grant cycles. With ACTIV-4, Antithrombotics, everyone involved has hustled like never before, says epidemiologist Steve Wisniewski (PhD ’94), who leads coordination of the entire ACTIV-4 Antithrombotics effort. 
“The train tracks were being put down as the train was coming down the path,” says Wisniewski, who is Pitt vice provost for budget and analytics and codirector with Brooks of the Epidemiology Data Center. The EDC team works with Berry Consultants, a private firm that analyzes multicenter clinical trial data and has aggregated all of the data from ACTIV-4 Antithrombotics and its partners abroad. 
Brooks is lead statistician for the outpatient protocol, which was initiated in September 2020. For the inpatient protocol, which launched first, she was responsible for presenting preliminary results to the ACTIV-4 Antithrombotics data safety monitoring board (DSMB). DSMBs evaluate issues like study integrity and safety for participants, explains Brooks from behind the closed door of her home office. (Like many families, hers has been schooling and working remotely since March 2020.) 
She’s served on a number of external DSMBs in the last two decades. For the conventional clinical trial, such reviews might occur every six months. 
For the inpatient population, Brooks presented monthly, yielding two major announcements in a matter of months:
In late January, the NIH announced some good news. Among those hospitalized with moderately severe infections, full-dose heparin reduced their need for mechanical ventilation and other life support. The results were convincing enough to close enrollment for the inpatient arm.
This was after the DSMB closed recruitment of critically ill patients in late December; interim analysis suggested that it was futile to give full-dose heparin to these patients—the treatment could even worsen their condition.    
Pitt physicians have taken major roles with ACTIV-4 Antithrombotics, as well: Matthew Neal, the Roberta G. Simmons Associate Professor of Surgery, cochairs the ACTIV-4 Antihrombotics inpatient study; Frank Sciurba, a professor of medicine and education, cochairs the outpatient study and Morris cochairs the ACTIV-4 Antithrombotics post-discharge study.    
Says Morris: “Despite the hopefulness around the vaccine, people are still getting sick and dying. We still really need studies like this to figure out how to treat patients. I don’t think we’re out of the woods at this point.”

Wheels Up

The conventional way to organize clinical trials compares a single treatment to placebo and takes years to generate results. All of the study infrastructure—enrollment protocols, electronic records and analytics—serve that single comparison. It’s as though each airplane flying into a region had its own control tower and airport, and those airports were torn down after passengers disembarked. 
ACTIV-4 Antithrombotics, which evaluates the effectiveness and safety of treating COVID-19 patients with varying types of blood thinners, is a multiplatform adaptive trial. This is the new, high-powered and, frankly, more sensible, way to get answers about treatments. In tandem with the Pitt co-led international REMAP-CAP platform (which has pivoted from pneumonia studies to COVID-19 trials), it uses a single, overarching experimental infrastructure to briskly collect a wide range of clinical and laboratory data. Think of it as an international airport of randomized clinical trials, serving passengers of existing airlines, as well as those still to be founded.    
As additional questions arise regarding blood thinners, ACTIV-4 Antithrombotics will tackle those, too.    
“This group has been outstanding putting together questions, collecting data,” says Keith Hoots, an MD and director of the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. “And it’s going to get better.”  


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