A COVID Trial Pitches a Tent in the Great Outdoors

by | Feb 26, 2024 | 2021, all stories 2021

A COVID Trial Pitches a Tent in the Great Outdoors

When you think of advanced clinical trials, you usually don’t think of a tent. But that’s where you’d be wrong—in April 2020, when COVID felt new and every breath was terrifying, a tent was just what the doctor ordered.

Why Not in California?

The idea came to the team very early in the pandemic—so early, in fact, that Upi Singh, MD, division chief and professor of infectious diseases, remembers that it was before social distancing, when a group of doctors including herself and Julie Parsonnet, MD, George DeForest Barnett professor of medicine, started to think outside the box.

Jason Andrews, MD, associate professor of infectious diseases; Bonnie Maldonado, MD, senior associate dean of faculty development and diversity, and Taube professor of global health and infectious diseases; Prasanna Jagannathan, MD, assistant professor of infectious diseases; and Hector Bonilla, MD, clinical associate professor of infectious diseases, were also quickly made part of the team.

Like many others, they realized that COVID trials would need to be set up quickly and that outpatient trials would be ideal because they enable doctors to see and treat patients in a low-touch environment. They decided on a clinical and translational research unit (CTRU) and ended up with the idea for a tent.

As Maldonado explains, some tents had already been set up for COVID testing and were about to be decommissioned, so repurposing them made a lot of sense. “We thought they’d be suitable and safe,” she says.

“Bringing people to the hospital to do COVID research was almost taboo. There was too much anxiety around it back then,” Singh adds. “We were seeing some of the drive-through tents in various places around the country, so we thought, well, why not? We live in California, it’s good weather, we could do it here.”

Turning an Idea Into Reality

Chaitan Khosla, PhD, Wells H. Rauser and Harold M. Petiprin professor of chemical engineering and chemistry, as well as director of the Innovative Medicines Accelerator (IMA), was brought in early too. The IMA, an initiative born out of the long-range-planning mission at Stanford, seeks to help turn research ideas into actual real-world drug trials or programs by, among other things, helping to fund promising early-stage research and form alliances with biotechnology and pharmaceutical companies, governments, and nongovernmental organizations to exchange knowledge and expertise.

In this case, “This was an obvious thing for us to support,” Khosla says. His role was to help with fundraising and operational aspects and to “understand how to bring the vision of the IMA to reality in the context of a disease that occurred after the IMA was created.” And that reality had to happen quickly.

The team talked to leadership, administration, the CTRU, and the people at the IMA, as well as writing to donors for funds, and in a matter of weeks, the tent was up. The idea was raised at the end of March, and April 25, “a sunny Saturday,” Singh remembers, was the first day in the tent.

COVID team members at work in the tent

The CTRU tent under a beautiful sky

Jagannathan was co-principal investigator (PI) of the first trial, the peginterferon lambda, with Singh, and remembers the fast growth of the idea. “Within a few days after the shelter in place began, we began work on the study,” he remembers. “We started as a small group of investigators—Upi, Julie Parsonnet, Jason Andrews, myself—but grew our team rapidly (with almost daily Zoom calls that went into the wee hours of the night).”

Andrews agrees: “In hindsight, it was remarkable how fast things came together! At that time, clinical trials among inpatients were underway, but there was no attention towards the needs of patients who were not yet hospitalized (which at the time comprised about 90% of all COVID patients).” The questions, he says, were: “Could we treat them early, avert serious disease and complications, and prevent hospitalizations? Could we reduce risk of transmission to their families? Everyone was understandably focused on inpatients, but this was the proverbial tip of the iceberg. So we went to work and initiated some of the first outpatient clinical trials for COVID in the country.”

The Early Days

During the tent’s run from April 2020 to January 2021, it hosted six trials for COVID treatment, including peginterferon lambda, camostat, favipiravir, and multiple Regeneron monoclonal antibody trials. The early days were particularly challenging.

For one thing, even just setting up the tent involved a lot of teamwork and creative thinking, not to mention just plain old getting your hands dirty. In the early days, there wasn’t even furniture. Singh bought chairs on Amazon and put them together with fellow faculty and staff members, which she found to be a surprising bonding experience.

“I’m a pretty engaged faculty member,” she says, “but you get to know people differently in a situation like the tent. You’re not just sitting in meetings and having intellectual discussions. You’re seeing who will come help you put chairs together, and you’re having a cup of coffee outdoors when COVID is there and everyone’s scared. You learn about people in a different way.”

Team Treat COVID staff

Parsonnet agrees. “It could be cold sometimes in the tent, and it could be wet and rainy and windy, but it felt like we had this great team—the subjects and the research staff together working to bring something good out of the pandemic. It was innovative, interesting, and exciting; we were out at the forefront.”

Singh likened it to a start-up—at first, the CEO does everything. In the early days, she would get the drug, draw blood, label tubes for the trial, and even recruit patients. She managed the trials and the project while also managing her other work as division chief and her various other projects, including her lab. And team members often worked seven days a week, including the many staff members from the Stanford Center for Clinical Research Center: clinical research coordinators, nurses, lab staff, phlebotomists, and countless others

Singh had never worked like this before. “I’d never done a clinical trial. I’m a basic science parasitologist, I’m not a virologist. I hadn’t done any of that. So,” she laughs, “it was a little unusual.”

Outdoors in a Pandemic

The team faced numerous challenges. For one thing, the administrative and operational work was very difficult. “We were trying to set up a CTRU that could support multiple faculties’ goals and be operated and deployed with the resources of the CTRU in a fair, democratic manner,” Khosla describes, “while also promoting the best possible science. Trying to deliver on the enormous value of what was being envisioned was my biggest challenge.”

For Jagannathan, “One of the biggest challenges of working in that setting was the unknown, the risk we were putting ourselves and our study staff in and the risks we were putting our families in at home.”

Keeping up morale in the tent with Team Treat COVID

In addition, there were challenges with patients. The patients (120 in total for some early trials) had to visit the tent nine times each during the course of the trials, and they were given the drug on the first visit, so there were concerns that they wouldn’t show up again. But they did, to everyone’s relief—the tent’s trials had a 95% retention rate. Over the last year, the team handled more than 3,000 patient visits in the COVID CTRU.

Yet another issue was the weather. There were brutally hot days in the summer, when it was over 100 degrees in the tent, making things difficult for everyone, particularly staff and doctors in full personal protective equipment. During October, Northern California wildfires made the air quality so bad that the tent had to be shut down. For a period of three weeks, Singh remembers, she was checking the air quality website PurpleAir first thing in the morning, and sometimes patient appointments were canceled or the whole operation was moved indoors to the CROWN clinic.

And then, of course, there was the obvious fear of COVID infection. Patients were anxious, and often very ill, and the staff were scared too. One of the nursing staff later confided in Singh that he was convinced he would get COVID at some point from working in the tent, but he figured he was young and he’d be OK.

But that story had a happy ending: There were zero COVID transmissions in the tent. It was a successful experiment in many ways. “We had the first outpatient clinical trials site in the United States, I believe,” Parsonnet says.

Singh agrees: “We were able to show that we could do really high-quality science at the beginning of a pandemic. I presented the idea and the concept at a national infectious diseases meeting in October 2020, and people were shocked that we had already completed an outpatient clinical trial for COVID-19 and that we had been able to do it so quickly.”

A Team Effort

All the members of the team emphasize that across the board, this was a team effort. The tent hosted anywhere from to four to 10 team members at a time, but there were numbers of people in administration and staff working behind the scenes.

And no one wants to forget the patients’ contributions, either. “I knew that patients were upset and scared, but we would enroll somebody in a trial, and we would see them every other day for a month or nine times in the next three weeks,” Singh says. “You got to know them. And they were nervous. Try to remember back to April and May of 2020. Very few people had COVID; people didn’t really know what to do. And patients were so appreciative that we were there, smiling, that we were happy to see them. And we were grateful that they didn’t cancel their visits, and we were there to take care of them. It reminded me why I went to medical school.”

“People who are involved in clinical trials are

often really motivated by doing good for the world.

These people who join these clinical trials are heroes”

“People who are involved in clinical trials are often really motivated by doing good for the world. These people who join these clinical trials are heroes”

Parsonnet agrees: “People who are involved in clinical trials are often really motivated by doing good for the world. These people who join these clinical trials are heroes. They’re doing something that’s a little risky when they’re not feeling well. And remember, these are randomized trials, so they know there’s a 50% chance they’re getting nothing. And they do it anyway. The altruism of all involved made for a really cohesive, wonderful community between the patients and the staff.”

The People

“To me, it’s all about people,” Singh concludes. “The leadership supported us, the people we included who were doing the work worked hard, and then people were just open-minded and innovative.” And the army of staff members carrying out research duties and trial tasks were, as Singh remembers, “the real backbone of the work in the tent.”

In fact, those staff continue to be crucial. Since the tent’s closure in January 2021, the trials have moved from the tent in the Galvez parking lot to the modulars, where a larger clinical research staff is continuing the crucial COVID treatment trials.

Jagannathan was amazed by “how impressive, collegial, and committed our study staff and volunteer physicians were. We would have long days in the tent and then ask our teams to join study calls multiple times a week, going from 7 p.m. until 10 p.m. or later at night. Everyone would participate to get the study off the ground and make sure that we were conducting the study with integrity.”

Matching jackets for Team TreatCOVID, Clinical Trials Research Unit

“Everybody understood that this was a moment that was not about ourselves,” Khosla states. “It was essentially a calling. They weren’t doing it to promote their own careers or to feather their own nests. There was a real altruism associated with this whole initiative. I think sometimes you have to be in the depths of a really miserable situation to see people have such noble goals.”

Bonilla was full of praise for each member of the team, calling Singh “the mayor of the village” and citing others’ “warm personalities, great knowledge,” and “incredible support.” “We became a real family,” he adds. “I have never been so happy doing this kind of job.”

“It really was an impressive organizational effort that involved a lot of different people with a variety of talents,” Parsonnet says. She remembers the early days of the tent almost fondly: “It gave us a wonderful feeling of doing something transformative and doing something as a community.”

And Maldonado echoes, “The camaraderie that developed among staff, faculty, and most importantly our participants was surprising and rewarding. We’ve all been in this together!”

If you have any questions about COVID-19 trials at Stanford, please email us at treatcovid@stanford.edu.

Working in the Tent

Jason Andrews, who has worked on many global health initiatives, from a renovated grain shed in Nepal to a renovated truck in Brazil, was a little more familiar with nontraditional medical environments. But, he adds, “it was exciting to find creative ways to extend access to these investigational treatments for COVID to patients who otherwise might not have options.”

He worked regularly in the tent, as well as serving as a co-investigator on several of the studies and principal or co-principal investigator on others, and found the experience invigorating. “There was a real esprit de corps among the CTRU team, particularly in the earliest days,” he remembers. “There was a strong can-do spirit, with all of us finding solutions to overcome obstacles and fulfill our commitment to the patients. It was really fulfilling to be part of a team that was so focused and committed.”

Prasanna Jagannathan also worked regularly in the tent and was familiar with clinical trials (although not in this particular setting.) “As the saying goes,” he says, “in the lambda study, we built the plane (tent) as we flew (occupied) it.” He was part of the early group of staff who worked seven days a week during the tent’s early days, and also served as a co-PI on the first study.

Bonnie Maldonado was no stranger to unique clinical trials, having set them up in small villages in Veracruz and in the highlands of Chiapas, Mexico, among Indigenous Nahuatl and Mayan populations, among many others, but she agrees that there were distinct challenges involved in this work. “Very early on, most of the work was actually being done by our infectious diseases faculty,” Maldonado remembers, “seven days a week, on top of their routine clinical, teaching, and research responsibilities. The biggest challenge so far has been trying to build new programs and clinical trials de novo, from identifying a novel therapeutic to understanding the construction and equipment needed to maintain the COVID CTRU tent and buildings.”

She took her turn as the PI of one of the studies and co-PI of others, working weekly in the tent to enroll and attend patients, and has now moved on to thinking about how to build new strategies for therapeutic studies.

Julie Parsonnet also helped recruit, monitor, and treat patients. She is the PI for the camostat trial and helped design and implement the lambda trials (not to mention her other projects and duties).

Hector Bonilla, who was part of the original team voting for the tent and its location, was invited to be part of the first outpatient trial of lambda. He remembers that the tent “became our second home” and calls the work “the opportunity of a lifetime.” He worked nights (recruiting mainly Spanish speakers for the trial) as well as days (enrolling patients, collecting samples, drawing blood, and answering patient questions, among many other duties). He remembers colleagues doing the same, sharpening their Spanish as the trial went along. “It was a real village,” he concludes, remembering how the work and interactions with colleagues made him “feel proud and respected by each division member.”

Chaitan Khosla, who worked mostly offsite, was “in complete awe of the clinical team in the tent,” he says. “And not just the doctors but also the clinical staff over there—the nurses, the clinical research coordinators, and the other support staff.”

“There is no way we could have done any of this without the staff,” Upi Singh agrees. “They also took a chance early on in the pandemic, trusting that they would be safe. And they very quickly became addicted to the positive impact of the work and the connections with patients.”

COVID-19 Modeling Team at Forefront of Pandemic Projections and Planning

by | Feb 26, 2024 | 2021, all stories 2021

COVID-19 Modeling Team at Forefront of Pandemic Projections and Planning

COVID-19 Modeling Team at Forefront of Pandemic Projections and Planning

Just weeks after the World Health Organization declared the coronavirus a global pandemic in March 2020, a team of Stanford Health Policy faculty and researchers scrambled to launch a modeling framework to investigate the epidemiology of COVID-19 and to evaluate policy responses.

A year later, the Stanford-CIDE Coronavirus Simulation Model (SC-COSMO) remains at the forefront of dozens of projection models in the United States and Mexico, while helping the state of California and its prison system, hospitals, and health care providers plan for and mitigate the impact of the pandemic. As of May 2021, the SC-COSMO team’s work has resulted in a half dozen studies published in medical journals and open data sites.

“The pandemic has continued to evolve, as have the policy questions and available interventions,” says Jeremy Goldhaber-Fiebert, PhD, associate professor of medicine at Stanford Health Policy (SHP). “Basic questions about how quickly the virus would spread in diverse populations were followed by urgent planning for hospital capacity during the surges and then nonpharmaceutical interventions and social distancing questions.”

Jeremy Goldhaber-Fiebert, PhD

Goldhaber-Fiebert is one of the principal investigators of the SC-COSMO project, along with Fernando Alarid-Escudero, assistant professor at the Center for Research and Teaching in Economics in Mexico, and Jason Andrews, MD, associate professor of infectious diseases at Stanford Medicine. Other SHP faculty, among two dozen investigators on the team, are Joshua Salomon, PhD, and David Studdert, LLB, ScD, MPH, both Stanford Health Policy professors of medicine. Studdert is also a professor of law at Stanford Law School.

“We have had to consider the timing and magnitude of subsequent epidemic waves, what fraction of the population may have acquired natural immunity, and what waning immunity might mean. The team has risen to the challenge time after time,” Goldhaber-Fiebert says.

In the summer and fall of 2020, the team focused on school re-openings and how to prevent and control outbreaks in state prisons. Since then, they have been looking at questions regarding vaccination rollout and scale-up, especially in the context of the viral variants that may be threatening yet another surge. Other key analyses have focused on the geographic, socioeconomic, and race and ethnic disparities in COVID-19 risk, access, and outcomes.

“The vaccination rollout effort suggests that prioritizing interventions based on both individual characteristics and geographic concentration of risk might help to achieve better outcomes in terms of reducing illness and mortality overall, and reducing disparities,” says Salomon, a senior fellow at the Freeman Spogli Institute for International Studies who heads up the Stanford Prevention Policy Modeling Lab.

The Prisons and Jails Project

One of the team’s first projects was working with county jails and the California Department of Corrections and Rehabilitation to reduce the spread of COVID-19 among the incarcerated.

“Incarcerated people are a particularly vulnerable group: They reside in close proximity, making it difficult or impossible to employ the same disease control measures that are being used in the general population,” says Goldhaber-Fiebert, who co-leads the prison project with Andrews and Studdert.

Andrews describes the work in jails and some of its important milestones.

“We partnered locally with county jails in San Mateo and Santa Clara and with California’s prison system,” he says, noting that Stanford students Yiran Liu, who is pursuing her PhD in cancer biology, and Chris LeBoa, an undergraduate human biology major, led a study of infection rates and prevention measures in the jails.

Jason Andrews, MD

“Incarcerated individuals are heavily impacted by certain measures being taken to prevent spread,” Andrews says. “For example, many of them have had their court dates delayed, they haven’t been able to see their family members in person, and their classes have been suspended. These measures are all taken to protect health, but their impact on mental health and well-being may be underappreciated.”

Goldhaber-Fiebert says that the work in the jails allowed the team to address COVID-19 challenges on a larger scale, using data on more than 100,000 men and women incarcerated in California state prisons. Two other Stanford students, Tess Ryckman, a PhD candidate in health policy, and Elizabeth Chin, a PhD candidate in bioinformatics, led the work to analyze these data, create high-resolution models of transmission, and simulate the effects of prevention interventions, including vaccination.

Shortly after the prison project was launched, some 44,000 people in U.S. prisons had tested positive for COVID-19, according to the Marshall Project. That figured skyrocketed to 396,265 by May of 2021, with 2,886 deaths.

Through a $1 million gift from the Horowitz Family Foundation, Stanford Medicine established a COVID-19 Emergency Response Fund to support research and prevention strategies to slow and eventually stop the spread of COVID-19 infection in California prisons and jails.

The Golden State

Another major SC-COSMO project is providing the state of California with county-level COVID-19 estimates for such things as infection counts, detected cases, and projections of future needs for hospital beds. SC-COSMO modeling is featured in the California COVID Assessment Tool, or CalCAT, which provides assessments of the short-term forecasts of COVID-19 trends and presents scenarios of the course of the disease across the 58 counties in the Golden State.

Instead of relying on one or two projection models—as some countries and U.S. states did when the pandemic first hit—the CalCAT tool incorporates COVID-19 estimates from a number of respected organizations, including Stanford, UCLA, MIT, Johns Hopkins University, and Imperial College London. The Stanford team provided more than 10 rounds of projections for the state from June through December 2020.

“It’s like using the wisdom of the crowd,” says Goldhaber-Fiebert. “Instead of hanging your hat on one model, you’re looking at a range of predictions to help you plan and forecast—and leveraging the whole community of researchers and analysts who are working on this problem.”

Latino populations throughout California have higher average levels of exposure risk due to occupation and housing characteristics. Areas with high exposure risk tend to have higher case rates but below average testing rates

The team looked at more than 1,900 California county and state-level public health orders related to the virus from January 2020 through February 2021 and made the data publicly available as well as MedRxiv, an open-source medical research website for pre-peer-reviewed studies and public comment. They also developed a data visualization tool that allows users to easily visualize and compare information within and across counties.

“Stanford’s new health order data set helps California officials understand the course of COVID and plan the ongoing response,” says Ryan McCorvie, a statistician working for the California Department of Public Health’s COVID-19 modeling group. “Analysis of the detailed local response in each county can help policy makers across the state judge outcomes effectively.”

Partners in Mexico

The Stanford members of the SC-COSMO team also collaborate with their partners in Mexico, working on strategies to mitigate the pandemic by collecting, synthesizing, and openly sharing the most relevant and useful data, while adapting the SC-COSMO model to the Mexican context.

“Having real-world impact requires conducting high-quality analytic work as well as engagement with policy makers and communicating findings in understandable ways to the media and the public,” says Alarid-Escudero. The team in Mexico has helped inform COVID-19 policy making in several states, including Hidalgo and Aguascalientes, providing analyses of data on cases, hospitalizations, and deaths, as well as projections.

“We are motivated because timely and rigorous

science can be used to protect people’s health

and well-being, especially those who are often

neglected or are at greatest risk”

“We are motivated because timely and rigorous

science can be used to protect people’s health

and well-being, especially those who are often

neglected or are at greatest risk”

“We also communicated our findings from modeling analyses focused on end-of-year holiday social gatherings, distancing, and implications for school reopening for the 20 million people living in the Mexico City Metropolitan area,” Alarid-Escudero says. “Shortly, we will be launching an interactive tool with model projections for all of the states of Mexico.”

Team members who led this work include Andrea Luviano, Valeria Gracia, and Yadira Peralta.

“For the team, this past year’s focus on COVID-19 has been very productive but also extremely intense,” says Goldhaber-Fiebert. “We are motivated because timely and rigorous science can be used to protect people’s health and well-being, especially those who are often neglected or are at greatest risk. While we hope the pandemic will soon recede and with it the pace of COVID-19-specific work, we have developed long-term collaborations, tools, and research programs around infectious disease modeling, health in incarcerated populations, and disparities in health equity that will carry on for years to come.”

Stanford Student Collaborations

——————–

Marissa Reitsma

Anneke Claypool

The SC-COSMO project has allowed Stanford students to use the modeling and data analytic tools to shed light on important questions about the pandemic.

Marissa Reitsma, a PhD candidate in health policy, for example, used five years of the American Community Survey of the Census Bureau to map out areas with a high proportion of people at increased risk of being exposed to COVID-19 due to their occupation and housing characteristics. She and her colleagues published their findings in the Journal of General Internal Medicine. Their study found that communities of color may be most susceptible to low vaccine coverage due to long-standing disparities in health care, mistrust fueled by a history of exploitation in clinical trials, and other structural risk factors.

“This study provides hard numbers to what has been acknowledged in public discourse,” Reitsma says. “We hope our study motivates equity-focused policies like support for safe self-isolation, cash assistance, and paid sick leave for low-income individuals that need to quarantine.”

Reitsma also worked with Anneke Claypool, a PhD candidate in management science and engineering, focusing on the fact that Black and Hispanic populations are being hit harder than most by the pandemic due to a variety of socioeconomic and economic reasons. The two students won an early-career grant from the Stanford Center for Population Health Sciences to analyze multiple streams of data, which they are using to evaluate the effects of different interventions and policies in order to identify the most important drivers of racial disparities. They believe their results will help decision makers prioritize effective interventions. Their work has been focused on approaches to vaccine access and acceptance to improve population health.

It’s Been a Busy Year for Hospital Medicine

by | Feb 26, 2024 | 2021, all stories 2021

It’s Been a Busy Year for Hospital Medicine

Hospitalists are always on the frontlines caring for patients with many types of illnesses. COVID-19 broke the mold, significantly increasing the number of hospitalized patients and thus the work for the hospitalists. But it also created some opportunities they were able to take advantage of.

For one thing, according to clinical professor Neera Ahuja, MD, chief of the hospital medicine division, “hospitalists have become experts in the care of COVID-19 patients. It’s almost protocolized. We have protocols around quarantining, around discharge. We know what meds to start, when to start them, when patients are turning the corner and improving. It’s almost like a checklist. We start with ‘Do they need oxygen? Do they have enough oxygen that they now need steroids? Have we started remdesivir? Do they need IV fluids?’ and so on.

“We have become very comfortable using personal protective equipment when we see any patient in the hospital because we know the risk of COVID-19 is there,” she continues. “We have to wear masks when we see patients, so it’s impossible for them to see our facial expressions. When we’re at the bedside, showing compassion has had to change a bit.”

Neera Ahuja, MD

Tracking the COVID-19 Numbers

Clinical assistant professor of hospital medicine William Collins, MD, carved out a useful data-driven path during spring 2020. As COVID-19 began to grow in numbers, he says, “we were trying to understand all the different ways that we could gather data about our patients and then streamline it. I’ve been working with professor of biomedical informatics Manisha Desai, PhD, and Yingjie Weng, MHS,and the Quantitative Sciences Unit to regularly update how many patients we’ve seen, their demographics, length of stay, and if they are having to come back into the hospital soon after discharge.”

They have also focused on preventing additional illness and addressing long-term follow-up. Collins details those efforts: “We have also looked at how we should use anticoagulation to prevent thrombotic events in COVID-19 patients, who appear to be at higher risk for deep vein thromboses and pulmonary emboli. I was part of a national, NIH-sponsored clinical trial looking at what’s the best strategy for preventing clots in COVID-19 patients. We’re also looking at longer-term symptoms in COVID-19 patients, which seems to be a big area in the coming year. As we move past the pandemic stage, there are going to be a lot of people who are profoundly affected by COVID-19. There’s a big push to understand how to best serve those patients.”

Introducing Point-of-Care Ultrasound for COVID-19 Patients

Creative initiatives sometimes follow emergencies. One that Ahuja is particularly proud of is using bedside ultrasound for COVID-19 patients, following a national trial led by clinical assistant professor of hospital medicine Andre Kumar, MD, MEd.

Ahuja explains that “patients with COVID-19 would have to get X-rays and CT scans, especially when our numbers were very high and we weren’t sure what was happening. Kumar hypothesized that it would be easier to bring a portable ultrasound to the bedside and diagnose COVID-19 pneumonia that way. Sure enough, ultrasound has shown specific findings in the lungs in patients with COVID-19. Through March 2021, Kumar was finalizing his findings and working on the publication. There were some limitations: You have to have someone trained in ultrasound do the procedure and be exposed to COVID-19 patients. But it saved patients from radiation and could be done more conveniently than bringing a COVID-19 patient down to radiology.”

COVID Surge Team Staffing

Even before the first cases arrived in the U.S., clinical associate professor Jeffrey Chi, MD, started thinking about how to manage the division’s personnel needs during a surge. “We were hearing stories of hospitals abroad being overwhelmed,” he said. “We thought about how to anticipate what patient volumes would be like and if we would have the staffing we need. The hospital service was already quite busy pre-COVID-19. When the pandemic arrived, our faculty stepped up and everyone sacrificed, adding many additional weeks of service on top of their existing schedules.”

“When the pandemic arrived, our faculty stepped up and everyone

 sacrificed, adding many additional weeks of service on top of their

existing schedules”

“When the pandemic arrived, our faculty stepped up and everyone

 sacrificed, adding many additional weeks of service on top of their

existing schedules”

Sacrifice came with the unusual territory, Chi explains. “We are a young division. Many of us have children under the age of 6. In fact, four or five more were born during COVID-19. Faculty were self-isolating from families at home. Everyone was completely overwhelmed but recognized that these were unique circumstances and part of the job to help our community. Staffing needs could change with little notice and at times we were operating at 120% of our normal capacity. Without extra available faculty, the existing staff were asked to work more, sometimes as much as three weeks without a day off. Thankfully, other divisions and departments like gastroenterology, oncology, and neurology were able to help out by taking additional patients to offload our service to allow more capacity for the COVID-19 patients.”

The surge team finally shut down in late February 2021.

Keeping the Train Running

Chi pointed to the contribution that the medical residents have made during the pandemic. Associate residency program director and clinical associate professor Poonam Hosamani, MD, as Chi says, “was instrumental in getting buy-in from the residents to mobilize when they were needed.”

Hosamani talks about what the residents did: “I cannot highlight enough all of the amazing work that residents did caring for COVID-19 patients; they kept the train running. After we created the COVID-19 surge team for the internal medicine wards in December 2020, the residents did an amazing job creating workflows for that team. They created tons of materials about how to care for COVID-19 patients for those rotating through, then others added to those materials as they had a rotation with COVID-19 patients.”

Poonam Hosamani, MD (second from right)

It was important for medical students, with whom hospital medicine has a very strong presence in the preclinical years, to be able to continue their education despite COVID-19. Hosamani says that “the curriculum was quickly revised to teach communication skills to early students remotely through a telemedicine lens because they couldn’t have the usual encounters with standardized patients.

Students were able to apply these skills to clinical encounters in our free clinics that they staff, as well as in shadowing encounters with providers in the community.”

Students were eventually able to have bedside time with patients during COVID-19. Hosamani credits Chi and clinical associate professor Jason Hom, MD, with “spearheading retaining that critical part of our curriculum. It was a heroic effort and took a lot of hard work to get students to be able to see patients in person,” she says.

Keeping Staff Members Involved Remotely

As is the case for all divisions, hospital medicine staff have been working remotely. Division chief Ahuja recognizes the drawbacks of this situation, in large part because, she says, “they don’t see their faculty physicians anymore. My division manager, Elsie Wang, has really been creative in terms of keeping them engaged.”

Wang points out that staff had previously become familiar with using collaboration platforms like Slack, Jabber, and Zoom. “I used our daily Zoom team huddles to share any updates I had learned in the course of the previous day. One thing that I tried to do for the staff beyond being transparent and sharing information was trying to engage them in different ways. I tried to encourage creativity with a little bit of a surprise each morning: During our huddles we would do scavenger hunts, acrostic poems about COVID-19, and drew inspiration from the Stanford Medicine shield to create our own to share. We basically tried to flex a different muscle.” Staff also helped faculty transition to the online environment and put some thought into transitioning orientations online. “It was a complete team effort,” Wang says. “A stretch project.”

Jumping Into Clinical Trials

To Ahuja, initiating clinical trial work seemed like the right thing to do despite being in the middle of COVID-19. She explains, “We thought: Let’s study what we do and do what we study. Professor of pediatrics Kari Nadeau, MD, PhD, was a brilliant part of our decision to get involved in clinical research. She is hospital medicine’s senior director of clinical research.”

They started out with a series of trials aimed at COVID-19. Ahuja describes their early trials: “We started in March 2020 with the National Institute of Allergy and Infectious Diseases–funded Adapted COVID-19 Treatment Trial (ACTT). ACCT-1 got remdesivir approved by the FDA. It was a real privilege to study that drug. I was the Stanford site’s principal investigator. ACTT-2 brought us baricitinib, a drug that was used in rheumatoid arthritis that showed promise in COVID-19, and we’re doing deeper studies of it in ACTT-4. ACTT-3 brought us interferon beta, and we’re not sure that is going to be efficacious after all. There are several other studies that our division has done and is doing for hospitalized COVID-19 patients.”

Clinical associate professor Nidhi Rohatgi, MD, MS, takes up the story of hospital medicine’s clinical trials at Stanford Hospital: “We had strong support from multidepartmental collaborators across Stanford Medicine. Professor of cardiovascular medicine Ken Mahaffey, MD, and the Stanford Center for Clinical Research (SCCR) were instrumental in helping us with our clinical trials. I enrolled the first patient for ACTT-1 in March 2020 when we were just learning about COVID-19.” She is site principal investigator for an ongoing trial “finding more therapeutic options for COVID-19, especially as new strains of the virus are appearing. We hope to reach a point where we have enough therapeutics that will lower the mortality rate.”

ValleyCare Gets Involved in Clinical Trials

When hospital medicine first launched their clinical trial efforts,they realized that one-third of their division was at Stanford Health Care – ValleyCare, and they decided to see if they could launch their trials there as well.

Clinical assistant professor of hospital medicine Evelyn Ling, MD, MS, led the ValleyCare launch. “We had no experience with clinical trials. It was a collaborative effort with Kari Nadeau and SCCR. Everyone—pharmacy, labs, nursing—was so eager to work with us. It was awesome to be a part of the remdesivir trial, now standard of care for COVID-19 patients.”

Ling foresees bringing non-COVID-19 trials to ValleyCare soon, as well as observational studies and chart reviews.

Introducing AI to Enhance Important Patient Care Planning

According to Ahuja, several members of her division have been working on various modalities of clinical medicine with AI (artificial intelligence). “One question we addressed is whether we can predict early on which patients are going to die within six months in order to introduce the idea of palliative care or hospice to them sooner, with the goal of optimizing their quality of life near the end of life. We’re looking at predictive features in the electronic medical record such as age, associated comorbidities, the number of visits to the ER or admissions to the hospital, and how severe the progression of their disease has been.”

Clinical assistant professor Ron Li, MD, is leading the AI projects along with clinical assistant professor Samantha Wang, MD; assistant professor Jonathan Chen, MD, PhD; and clinical professor Lisa Shieh, MD, PhD. Professor of biomedical informatics Nigam Shah, MBBS, PhD, and clinical associate professor of primary care and population health Winnie Teuteberg, MD, collaborated on the advance care planning project. A second AI project, as described by Li, “tries to identify patients at risk of having to go to the ICU or having an acute event in the next six to 18 hours. The goal is to decrease the rate of unexpected mortality in the hospital.”

Both of these AI projects are resulting in basic redesigns of workflows and clinical teams, making teams less hierarchical, more collaborative, and more democratized. Li says that they “are showing that we can creatively use a machine learning model to make a prediction and redesign a workflow and a team that solves a pretty important problem.”

Lisa Shieh, MD, PhD, and colleagues

A Few Notable Contributors to the Greater Good

Ahuja recognizes the important contributions of three additional members of the division of hospital medicine that go beyond the division’s clinical and research efforts. She says this about them: “Clinical associate professor Errol Ozdalga, MD, has led Medicine Grand Rounds via Zoom every week during COVID-19 and in the process has increased attendance to record levels. Two of our faculty have significant new roles with Stanford Hospital and Stanford ValleyCare: Niraj Seghal, MD, is new to our division, a clinical professor, senior associate dean, and Stanford Hospital’s chief medical officer; clinical associate professor David Svec, MD, MBA, is ValleyCare’s recently appointed chief medical officer.”

Clearly it’s been a busy and rewarding year in hospital medicine.

Infectious Diseases and Hospital Medicine Act Swiftly to Launch Clinical Trials for Remdesivir

by | Feb 26, 2024 | 2021, all stories 2021

Infectious Diseases and Hospital Medicine Act Swiftly to Launch Clinical Trials for Remdesivir

Less than two months after the World Health Organization characterized COVID-19 as a pandemic, the U.S. Food and Drug Administration (FDA) approved emergency use of remdesivir for the treatment of the virulent disease. Later, the FDA gave full approval to remdesivir, which remains the standard of care for hospitalized patients with COVID-19.

Clinical trials, which took place at Stanford and dozens of other sites, yielded convincing data that led to the FDA’s emergency use authorization.

Department of Medicine researchers began recruiting participants for the trials in early March 2020. One pair of trials was sponsored by Gilead Sciences, a company based in Foster City, California, that makes the drug. The other was by the National Institutes of Health (NIH) and one of its institutes, the National Institute of Allergy and Infectious Diseases (NIAID).

The Gilead Trials

Aruna Subramanian, MD, clinical professor of infectious diseases, was the principal investigator of the Gilead trials at Stanford. Subramanian was joined by co-principal investigator Philip Grant, MD, assistant professor of infectious diseases, who helped enroll 46 participants at Stanford and execute these studies. Results were published in the New England Journal of Medicine and the Journal of the American Medical Association.

In results reported April 29, Gilead announced that a five-day treatment course with remdesivir was potentially as effective as 10 days of treatment in its trial of severely ill patients. Later that same day, the NIH reported that early data from its remdesivir trial indicated that the drug helps to accelerate the time to recovery in severely ill patients.

On June 1, results from the remdesivir trial for people with moderate disease stated that a five-day treatment course of remdesivir resulted in a significant clinical improvement over standard of care.

Subramanian says the results from both trials were reassuring to her, both as a scientist and as a doctor who treats patients in the hospital with COVID-19.

“To at least have something that we can potentially use as a treatment for this virus was very assuring,” she says. “In the early course of the pandemic, we were all so scared and disheartened by patients going downhill and needing to be on a ventilator for so long. To see that even those people could potentially be turned around was very encouraging.”

“To at least have something that we can potentially use as a treatment for this virus was very assuring”

Philip Grant, MD (left) and Aruna Subramanian, MD (right)

“To at least have something that we can potentially use as a treatment for this virus was very assuring”

Philip Grant, MD (left) and Aruna Subramanian, MD (right)

The NIH Trial

The process of setting up an infrastructure for clinical trials, slow-moving and deeply complicated under normal circumstances, was accelerated with the outbreak of COVID-19. A team of researchers needs to be assembled, patients need to be recruited, and sites need to be established.

But in a matter of weeks, the division of hospital medicine organized an infrastructure at both Stanford Hospital and Stanford Health Care – ValleyCare and implemented Phase 1 of their first trial—to explore the effectiveness of remdesivir—with impressive results.

Neera Ahuja, MD, chief of the division of hospital medicine, was the principal investigator for the global NIH/NIAID Adaptive COVID-19 Treatment Trial (ACTT) at Stanford. The work was greatly facilitated by Kari Nadeau, MD, PhD, the Naddisy Foundation Endowed Professor of Medicine and Pediatrics and hospital medicine’s senior director of clinical research.

Stanford Hospital and SHC – ValleyCare were among the more than 65 sites around the world hosting the ACTT, a randomized, double-blind, placebo-controlled study that included 1,063 patients for its first phase.

Ahuja and Nadeau worked with clinical associate professor Nidhi Rohatgi, MD, MS; associate professor Sharon Chinthrajah, MD; and clinical assistant professor Rita Pandya, MD, to enroll patients quickly at the Stanford Hospital location. At the other location, David Svec, MD, MBA, clinical associate professor of medicine and chief medical officer at SHC – ValleyCare, was instrumental to the process, along with Minjoung Go, MD, clinical assistant professor of medicine, and Evelyn Ling, MD, MS, clinical assistant professor of medicine and SHC – ValleyCare physician research co-champion.

From left: Evelyn Ling, MD, MS; David Svec, MD, MBA; Minjoung Go, MD

The intense time frame put a great deal of pressure on everyone at Stanford Hospital and SHC – ValleyCare, from the physicians to the staff to the lab workers. When the first trial began, there was no real infrastructure for clinical trials.

As physician research champions, both Go and Ling were leaders on the ground at SHC – ValleyCare, although this was the first clinical trial that either of them had taken such a large part in.

“I was on the night shift, so trying to attend all the daily meetings was a little bit challenging,” Go admits. “It felt a little like trying to fly a plane while you’re building it. But it was a really, really rewarding experience. I got to learn a lot of the process of clinical trials and how to operationalize them.”

Results

That study’s trials showed that recovery time for patients infected with COVID-19 was reduced from 15 days to 11 days with the use of intravenous (IV) remdesivir.

“Data shows remdesivir has a clear-cut positive effect in diminishing the time to recovery,” said Anthony Fauci, MD, director of the NIAID, in a televised meeting at the White House on April 29, the day the results were announced. “What this has proven is that a drug can block this virus,” he said.

“This trial represents the fusion of the Stanford mission, bringing

the kind of research that’s typically only at academic centers to a

community center, but still being able to use our local nurses,

pharmacists, and lab”

“This trial represents the fusion of the Stanford mission, bringing

the kind of research that’s typically only at academic centers to a

community center, but still being able to use our local nurses,

pharmacists, and lab”

“I was very excited by the trial results,” says Ahuja. “Still, this is not a panacea. We don’t know if this is the best treatment. We still need to look for the most effective drug. Here we are in May 2021, a year later. We have the benefit of vaccines, but we still do not have the ideal combination of treatments to rapidly abate the virus.”

Ling says that “this trial represents the fusion of the Stanford mission, bringing the kind of research that’s typically only at academic centers to a community center, but still being able to use our local nurses, pharmacists, and lab. It was a really meaningful first trial. ”

Team Science Initiatives Aim to Investigate ‘Long-Haul COVID’

by | Feb 26, 2024 | 2021, all stories 2021

Team Science Initiatives Aim to Investigate ‘Long-Haul COVID’

Two multidisciplinary teams led by Department of Medicine faculty have applied for support to investigate why some people fully recover from COVID-19 while others have long-term effects months later, a condition commonly known as “long-haul COVID.” The groups are taking a team science approach—collaborating across different fields—to understand COVID-19’s myriad effects on the body.

“To solve complex problems, we need teams that bring different expertise to the table,” says Hannah Valantine, MD, professor of cardiovascular medicine and a member of one of the teams who has worked to encourage more team science initatives in the Department of Medicine. “To rapidly translate discoveries that impact the health of patients—that’s when we need the team science approach.”

Large, collaborative clinical research projects are a powerful way to build on the infrastructure established in the last year for COVID-19 clinical trials at Stanford. These include smaller independent trials and collaborations with pharmaceutical companies and the National Institutes of Health (NIH) Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program.

Demystifying Long-Haul COVID

At the new frontier of COVID-19 research is the question of why so many coronavirus patients suffer from a diverse collection of long-term symptoms, called post-acute sequelae of COVID-19 (PASC). Patients with PASC report shortness of breath and levels of fatigue that mirror chronic fatigue syndrome. Some experience a neurological symptom called “brain fog” and metabolic changes, including new-onset diabetes. Myocarditis is another frequent consequence of COVID-19, which can lead to arrhythmia or even sudden death. Some researchers suspect that a patient’s immune response may be to blame for the varied symptoms.

Upinder Singh, MD, professor and division chief of infectious diseases, is the lead for one team that applied for NIH funding to understand this complex condition. She has been involved with several multicenter COVID-19 clinical trials. Her co-investigators include PJ Utz, MD, professor of immunology and rheumatology; Catherine Blish, MD, PhD, professor of infectious diseases; and Yvonne Maldonado, MD, professor of pediatrics (infectious diseases) and of epidemiology and population health. Additionally, a steering committee composed of leaders from across the Department of Medicine and the Department of Epidemiology and Population Health will advise the project.

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains”

Hannah Valantine, MD

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains”

Hannah Valantine, MD

The team has already identified more than 2,500 patients who received care at Stanford to be included in study cohorts. Pregnant women and children will be included, as well as patients from Stanford’s transplant program. Since transplant patients receive immune-suppressing drugs, results from this cohort may offer insights into whether these drugs prevent or worsen the chances of a patient developing PASC, and if they interfere with a patient’s response to the vaccine. Researchers will also make use of the biorepository of COVID-19-related specimens, overseen by Blish.

Ultimately, the group hopes to answer basic questions about PASC, such as its incidence, its prevalence, and the full spectrum of symptoms. Moreover, by understanding the immune response, genetics, and life history of patients with PASC, they aim to tease out which factors cause one person to recover completely while another develops chronic effects.

“This is a project that requires a team science effort, not only because you need large cohorts, but because the virus results in many different syndromes, and that expertise lies in various domains,” says Valantine.

Transforming Clinical Research Through Team Science

Historically at Stanford, this type of large, multidisciplinary project has been rare. “There has been incredible clinical research over the decades here, but it has largely been done by relatively small groups or individual faculty members,” says Kenneth Mahaffey, MD, professor of cardiovascular medicine and director of the Stanford Center for Clinical Research (SCCR). Increasingly, however, the culture is shifting to recognize the value of collaborating with researchers across divisions and departments. These collaborations yield innovative, interdisciplinary discoveries that advance medicine and improve outcomes for patients, says Mahaffey. “Transformative clinical research that is going to alter how we deliver care and improve patient outcomes needs large, impactful science, and that requires large teams and large projects.”

To support faculty in performing large multicenter clinical trials, the Department of Medicine, through the efforts of Nancy Lonhart, associate director of finance and administration, has invested in a number of resources to help realize these projects.

Under the directorship of Mahaffey, SCCR has grown to almost 100 people dedicated to designing and running multicenter research programs. They can enroll Stanford patients in clinical trials, create opportunities for educational events, and assemble teams of faculty, project managers, and – through partnership with the Quantitative Sciences Unit (QSU) – data scientists, biostatisticians, and bioinformaticians for team science research.

The QSU includes practicing data scientists at the faculty, PhD, and master’s levels who can become fully integrated into a collaborating faculty member’s team to leverage all perspectives for effective study design and analysis. Through partnerships with other clinical departments within the Stanford University School of Medicine, the QSU is able to create teams that bridge multiple disciplines to solve particularly complex biomedical problems.

For researchers interested in the interface between health care and digital technologies, the Stanford Center for Digital Health, run by executive director Mintu Turakhia, MD, associate professor of cardiovascular medicine, can foster industry collaboration and help researchers develop innovative mobile and digital health projects.

While individual science will always be necessary for discovery, says Valantine, team science approaches can transform those discoveries into solutions that improve the health and well-being of patients. She credits Bob Harrington, MD, chair of the Department of Medicine, for creating the infrastructure necessary for faculty to participate seamlessly in this type of large, collaborative project. “This is his vision, to have team science as a core element of the research agenda for the Department of Medicine.”

Finding Answers From Data ‘in the Wild’

Another team, led by Melissa Bondy, PhD, professor of epidemiology and population health, and Manisha Desai, PhD, professor of biomedical informatics and director of the QSU, is applying for a second NIH PASC funding opportunity. Their project will ask similar questions and develop new inquiries using real-world data not collected for research purposes—electronic health records, claims information, and data collected “in the wild” from phones, smart watches, and other mobile devices.

As part of a larger research consortium, the team will use these unconventional data sources to understand the incidence and prevalence of PASC and who is at risk of developing the condition. They are also interested in the trajectory of the symptoms and whether those symptoms vary in relation to socioeconomic and demographic factors.

“It’s really an opportunity for us at Stanford to show off our team science skills and our willingness to play in the sandbox with other institutions,” says Desai.

Manisha Desai, PhD

The multiple principal investigators on the project include David Rehkopf, PhD, MPH, associate professor of primary care and population health; Steven Goodman, MD, MHS, PhD, professor of primary care and population health and co-director of the Meta-Research Innovation Center (Metrics); and Abby King, PhD, professor of epidemiology and population health and medicine at the Stanford Prevention Research Center.

The team will use data from a number of real-world data resources, including the American Family Cohort, which comprises 6 million people with diverse backgrounds and was gathered by the Stanford Center for Population Health Sciences, which Bondy and Rehkopf co-direct.

“From a statistical standpoint, these resources are appealing because we love having lots and lots of data,” says Desai. “But it often comes with a price.” Real-world data tend to be noisy and messy, because often they are collected for reasons other than research, but Desai’s QSU group has data scientists who are well-versed in study design, data management, and analysis for biomedical studies that leverage real-world data.

The Impacts of COVID-19 on the Community

Both projects will involve a strong community engagement piece, led by King, to gain perspectives and insights from affected individuals, especially those from the communities of color who have been so disproportionately impacted by the virus. Lisa Goldman Rosas, PhD, MPH, assistant professor of epidemiology and primary care and population health, will also be involved as the faculty director for the School of Medicine Office of Community Engagement.

“In taking a team science approach, we have learned that it is critical to bring in the knowledge and perspectives of community members themselves—those who are living day-to-day with COVID-19 and its longer-term effects,” says King. “They can contribute a wealth of knowledge concerning the real-world impacts of this disease and how we may be able to address those impacts.”

“In taking a team science approach, we have learned that it is

critical to bring in the knowledge and perspectives of community

members themselves—those who are living day-to-day with

COVID-19 and its longer-term effects”

“In taking a team science approach, we have learned that it is

critical to bring in the knowledge and perspectives of community

members themselves—those who are living day-to-day with

COVID-19 and its longer-term effects”

For both projects, King proposes to use a community-engaged citizen science method called Our Voice. This includes a mobile app available in multiple languages, called the Discovery Tool, to capture aspects of the users’ daily lives that impact their health and well-being.

If funded, these team science initiatives have the potential to vastly improve our understanding of the potential long-term effects of coronavirus infection. These answers may inform the development of more effective therapies or even strategies for preventing PASC.