At the COVID-19 pandemic’s start, there were no proven, effective medications to treat the disease. In the search for therapies, repurposing existing drugs offered a faster route to answers than developing drugs from scratch. Scientists scoured drug compound catalogs for contenders that worked in ways that might show promise against COVID-19.

Metformin was just such a contender.

NCATS’ role in finding and testing metformin as a treatment for COVID-19 has spanned the entire drug development process — from early observational studies all the way to large-scale clinical trials. Now, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership’s ACTIV-6 clinical trial, overseen by NCATS, is testing metformin as an outpatient treatment for people with mild-to-moderate COVID-19. Metformin’s addition to the nationwide ACTIV-6 testing lineup could bring clarity to the drug’s value in treating COVID-19 and potentially preventing long COVID.

“By leveraging our networks and data-driven tools, we are speeding the delivery of important answers on metformin’s ability to help people manage acute and long COVID symptoms,” said NCATS Director Joni L. Rutter, Ph.D. “These innovative approaches to study existing therapies could provide a foundation for integrating clinical trial and real-world data to get definitive answers from future clinical studies faster.”

The Case for Metformin in COVID-19

Metformin is a mainstay in type 2 diabetes treatment. Effective, safe and affordable, metformin does more than just moderate blood sugar levels. Metformin also suppresses key molecules that promote inflammation and blood clots. Those pro-inflammatory molecules contribute to type 2 diabetes and obesity — conditions that are primary risk factors for more severe COVID-19. Metformin may also have relevant antiviral activity. Research has shown that metformin blocks SARS-CoV-2 from replicating itself.

These properties spawned a hypothesis. If metformin reduces the inflammatory molecules that drive COVID-19 and the conditions known to increase COVID-19 risk, and if it also has antiviral activity, the diabetes drug might be repurposed as an effective COVID-19 treatment.

Observational Glimmers of Promise

Observational studies early in the COVID-19 pandemic pointed to just such potential.

In a 2020 review, NCATS Clinical and Translational Science Awards (CTSA) Program-supported researcher Carolyn Bramante, M.D., assistant professor of medicine at the University of Minnesota, and her colleagues examined electronic health records (EHRs) from adults with type 2 diabetes or obesity. They found that women taking metformin before they developed COVID-19 were significantly less likely to die after being hospitalized — although men didn’t see the same protective effect. Another 2021 observational study of EHRs found that people with diabetes who were on metformin when they developed COVID-19 were significantly less likely to die from COVID-19.

The NCATS National COVID Cohort Collaborative (N3C) enclave of EHR-derived data powered two large studies that reinforced a potential link between metformin and less-severe COVID-19 outcomes. One study of EHRs from more than 6,600 adults found that those with type 2 diabetes who were taking metformin before developing COVID-19 were less likely to be hospitalized, need mechanical ventilation or die. A second study of people with either prediabetes or polycystic ovary syndrome (a condition commonly treated with metformin) showed that metformin use was linked to less severe COVID-19.

Observational studies usually aren’t enough to change medical practice, however. Metformin would have to deliver results in large randomized, placebo-controlled trials specifically designed to answer the question of whether metformin is helpful for treating COVID-19.

Two such trials, TOGETHER and COVID-OUT, would give metformin the chance to prove itself as an effective COVID-19 treatment.

TOGETHER Trial: The First Clinical Test

Metformin’s first large randomized, placebo-controlled clinical trial was the TOGETHER trial —and it didn’t deliver clear evidence of effectiveness against COVID-19.

TOGETHER put a handful of repurposed drugs to the test as COVID-19 treatments in high-risk people in low- and middle-income countries. In TOGETHER’s metformin arm, researchers randomized high-risk adults in Brazil with COVID-19 to outpatient care with either metformin or placebo. Those on metformin took a 750-mg dose twice a day — 1,500 mg daily — for 10 days.

In their published results, the TOGETHER trial researchers found no benefit to back metformin as an outpatient treatment for early-stage COVID-19. Among the 418 people in the trial’s metformin arm, metformin didn’t significantly top placebo at reducing hospitalization or delivering better clinical improvement after 28 days.

Among those who stuck with the TOGETHER trial’s 1,500-mg dosing treatment regimen, data in the study’s appendix did show metformin presented an advantage over placebo.

COVID-OUT: Metformin Shows Promise

The 2022 COVID-OUT trial put metformin to a second test. Bramante and her fellow researchers conducted the trial at six sites in the United States. The COVID-OUT research team relied in part on grants from NCATS, as well as regulatory and logistical support from the University of Minnesota’s Clinical and Translational Science Institute, a CTSA Program-funded institution.

Participants were age 30–85 years, overweight or obese, and had a new COVID-19 diagnosis. COVID-OUT’s primary goal was to see how many people went on to develop severe disease after 14 days of outpatient treatment. Four factors defined “severe” COVID-19: low blood oxygen levels, tested by people at home; an emergency department visit; hospitalization; or death.

Like TOGETHER, COVID-OUT tested multiple repurposed drugs. Three groups of people were randomized to receive metformin in combination with fluvoxamine, ivermectin or placebo. A fourth group received placebo. Two more groups received either ivermectin or fluvoxamine with placebo.

Rather than starting at the TOGETHER Trial’s 1,500-mg daily metformin dose, COVID-OUT began lower and raised metformin doses over 6 days to reach the 1,500-mg level, where it remained through 14 days. The COVID-OUT trial also used immediate-release metformin, which has a higher systemic peak than the extended-release formulation used in the TOGETHER trial.

The COVID-OUT researchers analyzed data from 1,323 people who enrolled in the trial between December 2020 and January 2022. None of the three drugs — including metformin — significantly reduced people’s risk of severe COVID-19, compared with placebo.

Metformin’s outlook changed, however, when the researchers removed potentially problematic patient-measured oxygen levels from their definition of severe COVID-19. After the trial’s start, the U.S. Food and Drug Administration issued a safety communication on pulse oximeters’ accuracy.

When the researchers excluded low blood oxygen levels, people with COVID-19 who took metformin were 42% less likely to end up in the emergency department, hospitalized or dead. The effect was even greater when the researchers focused on the numbers for hospitalization or death — a 53% reduction with metformin.

COVID-OUT Zooms in on Long COVID

COVID-OUT’s results pointed to more than therapeutic potential in the early stages of COVID-19. In a separate research question, the investigators assessed the development of long COVID — the signs, symptoms, and conditions that linger or start after COVID-19 infection. Metformin use also showed links to lower rates of long COVID.

The COVID-OUT researchers followed study participants months after treatment. Among the 1,126 people followed long-term, 8.3% developed long COVID by 10 months. But those who took metformin for early-stage COVID-19 were 41% less likely to later develop long COVID (6.3% of people) than the people who received placebo (10.4% of people).

Metformin’s effect on reducing the risk of long COVID held regardless of people’s sex, body mass index, whether a person had been vaccinated, or the dominant SARS-CoV-2 variant during treatment. People who started metformin within three days of the start of COVID-19 symptoms were less likely to develop long COVID than those who started four or more days after their symptoms began.

ACTIV-6 Could Bring Greater Clarity

In the wake of TOGETHER and COVID-OUT, the ACTIV-6 trial could bring greater clinical-trial clarity on metformin.

ACTIV-6 is a large, randomized, placebo-controlled phase 3 clinical trial testing medications to treat mild-to-moderate COVID-19 in an outpatient setting. The trial is a public-private partnership that has already tested fluticasone, two dosages of fluvoxamine, and two dosages of ivermectin. None of those drugs delivered therapeutic benefit, compared with placebo, in ACTIV-6. A trial arm testing montelukast recently completed enrollment.

The trial’s new metformin arm(link is external) opened for enrollment Sept. 5, 2023. NCATS oversees ACTIV-6, and key players in the trial’s operations include CTSA Program-funded institutions. The Duke Clinical Research Institute is the ACTIV-6 clinical coordinating center, and the Vanderbilt Institute for Clinical and Translational Research is the trial’s data coordinating center. Other CTSA Program institutions are part of the trial’s enrollment treatment network, as is the Patient-Centered Outcomes Research Institute-funded National Patient-Centered Clinical Research Network (PCORnet)(link is external).

The metformin trial arm will have two primary outcomes. The first will be the time to sustained recovery from COVID-19 symptoms, assessed for up to 28 days after the start of treatment. The second will be hospitalization or death among study participants, also measured for up to 28 days. In addition, ACTIV-6 researchers will assess whether metformin prevents urgent care and emergency department visits, as well as any effects on quality-of-life measures. Those quality-of-life assessments will extend to six months after treatment begins. Researchers will use the trial’s extended follow-up to explore potential links between metformin treatment and symptoms suggestive of long COVID.

“Confronted by a global public health catastrophe, NCATS and the CTSA Program institutions have used a flexible, holistic approach to accelerate the search for effective COVID-19 treatments,” said Michael G. Kurilla, M.D., Ph.D., director of NCATS’ Division of Clinical Innovation. “By innovating in real time, we are working to deliver evidence-based COVID-19 therapies that demonstrably help people.”

Our latest TRIbune newsletter features a UAMS academic-community partnership recently funded by the Patient-Centered Outcomes Research Institute (PCORI) that was informed and inspired by TRI’s Community-Based Participatory Research Scholars Program. 

The team led by Melissa Zielinski, Ph.D., is using a $250,000 PCORI award to address health disparities among women involved in the justice system. 

Our TRI Study of the Month features Laura Hays, Ph.D., and her UAMS Rural Research Network-supported study in collaboration with the UAMS North Central Family Medical Center in Batesville. 

We also highlight our two new Health Sciences Innovation and Entrepreneurship (HSIE) trainees, postdoctoral fellows who will receive two years of support as they learn how to commercialize their ideas. 

Read The TRIbune.

Akilah Jefferson, M.D., M.Sc., a TRI KL2 Mentored Research Career Development Award scholar, has been published in the journal Pediatrics, with an article titled, “Asthma Quality Measurement and Adverse Outcomes in Medicaid-Enrolled Children.”

Jefferson and her coauthors found that a key tool used to evaluate pediatric risk of asthma-related adverse events may be a poor method for guiding pediatric population health management programs across diverse settings. The findings related to the tool, called the asthma medication ratio (AMR), were based on analyses using the Arkansas All-Payer Claims Database to identify Medicaid-enrolled children.

“AMR performed poorly in identifying risk of adverse outcomes among Medicaid-enrolled children with asthma,” the article concluded. “New population health frameworks incorporating broader considerations that accurately identify at-risk children are needed to improve equity in asthma management and outcomes.”

Jefferson is an assistant professor in the College of Medicine Department of Pediatrics, Division of Allergy and Immunology.

The TRI KL2 Scholars Program provides promising young clinical and translational investigators the training, mentoring, and protected time to develop an independent research program. Learn more about the program here.

Congratulations to Dr. Akilah Jefferson, one of our early-career KL2 Scholars, who was recently published in the prestigious journal Pediatrics. Her research found that a key tool used to evaluate pediatric risk of asthma-related adverse events may be a poor method for guiding asthma care in diverse populations of children.

The UAMS Translational Research Institute Health Sciences Innovation and Entrepreneurship (HSIE) Postdoctoral Training Program has named two postdoctoral scholars for its class of 2023. The scholars, selected in a competitive application process, will receive two years of mentored entrepreneurship training.

The HSIE postdoctoral trainees, their research goals and mentors are:

Henry A. Palfrey, Ph.D., is a postdoctoral fellow in the College of Pharmacy Department of Pharmaceutical Sciences. His research goal is to conduct studies to screen a library of compounds and determine the ability of novel epoxylipid drugs to provide protection against radiation-induced kidney and cardiovascular injury

Mentor: John D. Imig, Ph.D., professor and chair, Department of Pharmaceutical Sciences; and vice president for therapeutics at BioVentures LLC. 

Ashley Pike, Ph.D., a postdoctoral fellow in the Brain Imaging Research Center of the Psychiatric Research Institute (PRI). Her primary research goal is to implement advanced neuroimaging techniques for clinical problem solving in multiple sclerosis (MS). Mentor: Tatiana Wolfe, Ph.D., assistant professor, medical imaging physicist, PRI, College of Medicine Department of Psychiatry

We are thrilled to announce that the AtKisson Training Group (ATG) will be conducting three grant-writing workshops for UAMS-affiliated researchers this fall, free of charge! If you are looking to advance your academic career and secure funding for your projects, this is an opportunity you don’t want to miss.

ATG, led by M.S. (Peg) AtKisson, Ph.D., an acclaimed public speaker and expert in the field, is known for empowering academic researchers with the skills to excel in grant writing and leadership. The workshops are sponsored by TRI and Pearl McElfish, Ph.D., MBA, director of the UAMS Division of Community Health & Research.

Here are the workshop details:

Developing and Funding Your Research (two sessions, four hours each):

Dates: Sept. 28, 29; Time: 9 a.m. – 1 p.m.

In this comprehensive workshop, you will learn valuable insights into planning, time management, and structuring your NIH grant proposals. Through engaging lectures and practical activities, you’ll gain the necessary tools to craft effective research proposals that stand out. The session will focus on specific aims, research strategy, significance, innovation, and approach, supported by hands-on exercises and helpful templates. In addition, this workshop also addresses team management, planning for productivity and publications, and working toward sustainable funding for your research. Take advantage of this opportunity to understand the “why” behind the “what” of successful grant writing.

Register here.

How to Craft Effective Grant Renewals and Resubmissions (four hours):

Date: Oct. 5; Time: 9 a.m. – 1 p.m.

Are you looking to renew your R01 or R15 grant? This workshop will guide you through the details involved in the renewal process. Delve into topics such as productivity, projected budget, and research trajectory, as well as writing a compelling progress report and navigating NIH Type 2 submissions. Gain the confidence to strengthen your grant renewal submissions effectively. Registrants with a planned resubmission to work on in this workshop should submit their “pink sheet” of reviewer comments at registration. You will engage in some hands-on work and leave this workshop with a specific roadmap to success on your resubmission. 

Register here.

How to Prepare Your NIH K Award Application (four hours):

Date: Oct. 12; Time: 9 a.m. – 1 p.m.

If you are aspiring to secure an NIH K award, this intensive workshop is tailored to meet your needs. Receive in-depth guidance on every aspect of a K award proposal, understanding the purpose of each section and how they must align. With the knowledge gained from this workshop, you’ll be better equipped to create a standout K award application.

Register here.

Special Note:

Another free ATG-led grant-writing workshop, “Structuring Proposals” will be held March 21 and 22, 2024, 9 a.m. – noon, each day. Be sure to save the dates, and you can register early here. 

(Note: It is recommended that if you attend the Developing and Funding Your Research workshop, you should not also attend Structuring Proposals, as there is significant overlap on the grant development training in both sessions.)

Contact: Adam Kleinerman, AKleinerman@uams.edu

Submit Your Manuscript(s) in the 2023 Summer Writing Challenge!

Calling all UAMS-affiliated researchers! If you received any TRI support since 2017, we invite you to join your colleagues for this friendly manuscript competition and the opportunity to win great prizes and recognition. 

Prizes will be awarded based on academic rank. Last year, David Ussery, Ph.D., won the Sage Scribe Award for Most Submitted Manuscripts for the Rank of Professor. Who will be this year’s Sage Scribe?

Other award categories for most manuscripts include: 

• Astounding Apprentice (assistant professors/instructors)
• Wise Wordsmith (associate professors)

Please submit your manuscripts here through Aug. 31.

Associate professors and assistant professors are currently tied with the most submitted manuscripts so far. We are still awaiting the first manuscript submission from a postdoctoral fellow! View the Leaderboard here. 

TRI will host a mixer Thursday, Sept. 7, 3-4 p.m., to celebrate the winners and recognize all participants at both the Little Rock and Northwest Arkansas campuses.

View the flyer.

Questions? Contact Nikolas Berardi, NDBerardi@uams.edu.

We are thrilled to announce the release of the 2023 UAMS Translational Research Institute (TRI) Annual Report! This 52-page magazine-style publication is a testament to the dedication and talent of UAMS-affiliated faculty and staff, showcasing noteworthy advances in translational science.

The TRI Annual Report serves as a window into our world, capturing the essence of our work and highlighting the translational research successes that have unfolded over the past year. This report brings to life the research advances achieved by many of you and your talented UAMS-affiliated colleagues. 

While it was challenging to condense all of the success stories into a single publication, we are proud of the diverse range of projects and advancements featured within its pages. We applaud everyone who played a role in making these achievements possible.

We hope that you find this report as inspiring and enlightening as we do. Read the 2023 TRI Annual Report. 

In this issue of The TRIbune, we feature the successful opioid prescribing reduction efforts of Kyle Kalkwarf, M.D., a TRI Implementation Science Scholars Program participant.

The story highlights the potential for implementation science to improve medical practices. Kalkwarf’s work produced a 20% reduction in opioid use for surgery patients on a ventilator.

Our Study of the Month features Larry Johnson, M.D., and TRI’s Faryal Jalbani, M.D., MSPH, and Monica Smith, B.A.

We also highlight our six new KL2 Mentored Research Career Development Scholar Award recipients and the 2023 Summer Writing Challenge! 

Read The TRIbune.

The UAMS Translational Research Institute has named three UAMS researchers who will receive pilot study grants of up to $25,000 each.

The one-year awards went to projects led by researchers in the College of Medicine and College of Nursing. The awardees and their project titles are: 

Jonathan Bona, Ph.D., assistant professor, College of Medicine Department of Biomedical Informatics

“Accelerating Insights with an Open Drug Information Toolkit (ADROIT),” which will create and evaluate a novel software tool designed to provide non-informaticists with easy access to drug information.

Laura Hays, Ph.D., APRN, assistant professor, College of Nursing Department of Nursing Practice

“Arkansas – Making History,” which will address the lack of genetic risk assessment services among rural Arkansas providers.  

Mario Schootman, Ph.D., vice chair and professor, College of Medicine Department of Medicine; co-director, TRI Workforce Development Program “Assessing the Quality of the Linked Arkansas Cancer Registry and Arkansas All-Payer Claims Database Data,” which aims to generate preliminary data for an NIH R01 application focused on identifying reasons for elevated mortality in colorectal cancer patients in persistent poverty areas.