A cutting-edge federated technology-powered network known as TriNetX powered an impressive real-world evidence study involving approximately 400 million patients across 30 countries. Based on a federated, distributed model the system pulls electronic medical records—that is from diagnoses and procedures to medications and more—in an aggregated format supporting deep analytics of the de-identified patient data. American and German researchers represent the University of Virginia at Charlottesville and Charité–Universitätsmedizin Berlin analyzed a cohort of 22,560 COVID-19 patients receiving H1/H2 receptor antagonists, with a special focus on 1,379 severe cases requiring respiratory support. Establishing mortality as a primary endpoint the researchers explained they hoped to mitigate cofounder by employing propensity-score matching with a goal of “stratified and balanced sub-cohorts across age and gender.” What they found was stunning. Among other benefits famotidine provided what the authors declared was “an immense benefit” to COVID-19 patients.

Famotidine Background

Known for its trade name Pepcid, this drug is a histamine H receptor antagonist medication reducing stomach acid production. Used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome, the drug can be administered orally or intravenously.

The TrialSite advisory committee member Dr. Michael Goodkin recently educatedTrialSite readers about the significant progress associated with this economical, widely available treatment. Can famotidine help treat COVID-19?

Early in the pandemic another TrialSite advisory committee member, Dr. Robert Malone identified famotidine as a potential inhibitor of SARS-CoV-2, the virus behind COVID-19. In fact, Dr. Goodkin notes at least some scientists have wondered why some people became very ill with COVID-19 while others didn’t. Could this observation be associated with the responses of individuals’ mast cells to infection?

Drs. Malone, Goodkin, and many other prominent investigators suspect that “Therapies to blunt their response appear to be effective, most commonly the over-the-counter H2 blocker famotidine (Pepcid).” Goodkin argues, “numerous observational studies suggest its [famotidine] benefit, yet the medical establishment has paid little attention.”

This RWE TriNetX study led by researchers from the University of Virginia and Charité–Universitätsmedizin Berlin sought to investigate this question further.

The Study

In this study, the author shared results in the form of a letter published in Nature. Led by corresponding authors Cameron Mura and Saskia Preissne, the investigators sought to tap into and capitalize on the massive TriNetX data set in a bid to identify if there are any “beneficial effects of famotidine detectable on population-wide international scales.”

The authors ask other important questions:

Is it synergistic to treat with famotidine in conjunction with aspirin or general-purpose anti-inflammatory?

Does famotidine use correlate with any measurable parameters that may serve as biomarkers, perhaps offering mechanistic clues (e.g., serum C-reactive protein [CRP] levels a proxy for inflammation and the cytokine storm

The American and German team worked first with the following data set:

TotalDescription257,864Total COVID-19 cases7,479Deaths18,624Famotidine8,335Cetirizine3,928loratadine23,148Aspirin5,955Aspirin and Famotidine

The research team ran a series of statistical analyses such as quantifying association, risk ratios (RRs) as well as odds ratios (ORs) as reported in Nature. The study team established respective 95% confidence intervals (CIs) in addition to Kaplan-Meier survival curves.

Conducting a series of statistical analyses involving “(i) the H1RAs loratadine (e.g., Claritin®) and cetirizine (e.g., Zyrtec®), (ii) the H2RA famotidine, (iii) aspirin, and (iv) a combination of famotidine and aspirin, the authors found that famotidine treatment reduced fatality risk in cases needing respiratory support (OR 0.73, CI 0.57-0.94).

The authors didn’t find an observable benefit using dual-histamine receptor blocker targeting H1 and H2 receptors versus famotidine alone (OR 0.75, CI 0.39-1.46). To the authors’ surprise, “the combination of famotidine and aspirin (344 severe cases before matching) did exhibit a significant synergistic survival benefit (OR 0.55, CI 0.39-0.78).”

Benefits associated with fatalities became even more pronounced. With a decreased Risk Ration of 32.5% the authors declare, “An immense benefit, given the more than 3.8 million COVID-19-related deaths thus far.

Limitations

The study team shared some limitations they shared: they didn’t use sub-cohorts categorized by disease severity as they declared “a limitation of our work stems from the distribution of such severities almost certainly being related to the efficacy of any therapeutic intervention.” For other limitations follow the link at source to the journal.

What is TriNetX?

TrialSite’s InvestorWatch has profiled TriNetX. Founded by an ex-Microsoft technology executive in 2013, the Boston-based global health research network has raised tens of millions in at least four venture capital rounds.

In 2020 the company was acquired by the prestigious private equity group called Carlyle Group.

TriNetX positions itself as connecting the world of drug discovery and development from pharmaceutical company to study site, and investigator to patient by sharing real-world data to make clinical and observational research easier and more efficient. The company’s federated technology combines real-time access to longitudinal clinical data with state-of-the-art analytics to optimize protocol design and feasibility, site selection, patient recruitment, and enable discoveries through the generation of real-world evidence. The TriNetX platform is HIPAA and GDPR compliant.

Lead Research/Investigator

Cameron Mura, Ph.D. Assistant Professor, Chemistry