A group of prominent New York-based physicians and scientists led by Cold Spring Harbor Laboratory, Northwell Health Cancer institute conducted a retrospective case series targeting ten (10) non-hospitalized patients with SARS-CoV-2, the virus behind the COVID-19 pandemic. It has been alleged that the over-the-counter histamine-2 receptor antagonist called Famotidine could possibly address the novel coronavirus. This insight originally derived from the analysis of Dr. Robert Malone and team associated with the U.S. government research contracts as well as observations of a prominent physician and research named Dr. Michael Callahan after his analysis of over 6,000 patient records at the Wuhan pandemic epicenter. After monitoring and quantitatively analyzing the longitudinal changes in patient reported outcome measures of patients who had been self-administering high-doses of Famotidine orally, the Cold Spring Harbor Laboratory and Northwell Health investigational team found that not only are high doses well tolerated but they are associated with improved patient-reported outcomes in non-hospitalized patients with COVID-19. Meanwhile, a large study at Northwell has commenced in April, including both hydroxychloroquine and Famotidine but there is uncertainty with the use of the anti-malarial drug moving forward.
Famotidine is a common over-the-counter drug that can be used to treat ulcers, gastroesophageal reflux disease (GERD), and conditions that cause excess stomach acid. It is also used to treat heartburn and acid indigestion. TrialSite News showcased the potential of this drug based on interactions with Dr. Robert Malone who was active in discovering the potential of this drug in regards to COVID-19.
The Robert Malone Story
President of RW Malone MD, LLC, Dr. Robert Malone, along with other consultants associated with U.S. Defense Threat Reduction Agency (DTRA) employed the use of supercomputer-based analyses to identify existing U.S. Food and Drug Administration (FDA) approved drugs that may be useful against the novel coronavirus called SARS-CoV-2. The team focused their attention on a SARS-CoV-2 virus protein that was overlooked by large pharmaceutical companies. Of the top ranked drugs identified by applying the drug discovery system for DTRA, the team determined that famotidine had the most attractive combination of safety, cost and pharmaceutical characteristics. Dr. Malone presented the findings and recommendations to Dr. Michael Callahan and the ASPR by March—see below.
Dr. Callahan Makes Interesting Observations in China
A prominent physician scientist, Dr. Michael Callahan, with expertise in mass casualty infections, is a staff physician for Massachusetts General Hospital in Boston. During the pandemic outbreak in Wuhan, China, Dr. Callahan traveled to China and got involved with an analysis of over 6,000 patient records, 1,100 of whom had severe COVID-19. The analysis revealed that about 600 of the patients were on antacid therapies and were found to have mild COVID-19 disease compared to others of similar age and health. The incidence of COVID-19 dropped quickly and Dr. Callahan and colleagues weren’t able to start a clinical trial to test famotidine as a promising oral treatment for COVID-19 disease but was certainly intrigued. Thereafter, Dr. Callahan took a leave of absence from current employer, where he serves as President of Cellular Therapies at United Therapeutics to support the government effort amidst the pandemic crisis as Special Advisor on COVID-19 to the Assistant Secretary of Public Health Preparedness and Response (ASPR), U.S. Department of Health and Human Services.
The Dr. Malone & Callahan Meeting
On March 18, 2020, Dr. Malone presented a summary of team findings and recommendations to the ASPR on the potential use of Famotidine. Both Callahan and Malone, collaborators from the past, were unaware of each other’s work connected to this anti-acid but connected and agreed to collaborate. They had worked together on another medical crisis in the past. With the convergence of these two independent discoveries, Northwell Health System (Feinstein) was contacted to explore the possibility of performing well-controlled trials with the Northwell hospital system. Northwell agreed that this repurposed drug candidate was worthy of rigorous evaluation of activity in randomized trials. As in New York, initially hydroxychloroquine was established as the standard of care for hospitalized COVID-19 patents, then Famotidine was added to the study.
Large Study Including Famotidine at Northwell Health
Just in April, Northwell Health launched a study led by Dr. Joseph Conigliaro to evaluate the clinical efficacy of COVID-19 treatments consisting of standard of care (SOC) combined with pharmaceutical antiviral management using hydroxychloroquine, or SOC with hydroxychloroquine combined with high-dose intravenous famotidine, in hospitalized patients meeting nucleic acid diagnostic and radiologic criteria for COVID-19 disease. It is not clear how the latest findings and controversy with hydroxychloroquine impacts this study, but TrialSite News will inquire.
This larger trial has been designed to statistically compare the clinical benefit afforded by the two treatment strategies to internal historical “standard of care” data from Northwell patents treated without benefit of either hydroxychloroquine or high-dose Famotidine. The study team seeks to compare clinical outcomes associated with hydroxychloroquine and the addition of high-dose intravascular famotidine. The trial is designed to enroll at least 600 COVID-19 patients hospitalized with moderate to severe disease into each of the two active treatment arms, with a total enrollment target of at least 1200 patients. The proposed trial has been designed for rapid enrollment and completion and powered to support two interim analyses that will enable prompt assessment of benefits and risks of the two treatment groups while maintaining the rigorous gold standard of a randomized double blind clinical trial structure. Trial design has been guided by practical consideration of the current clinical context involving rapidly escalating demands on hospital staff and resources, and incorporates a minimalist approach employing existing laboratory information management systems and a clinically relevant binary primary outcome of 30-day endpoint of death or survival.
The Retrospective Case Series
This retrospective case series of patients self-medicated with Famotidine during COVID-19. Led by David A. Tuveson, MD, PhD, with Cold Spring Harbor Laboratory, the investigational team set out to collect de-identified patient reported outcome measures of patients with confirmed COVID-19 who self-medicated with Famotidine at any dose during the period of illness. Data was collected via questionnaire and telephone interview. Sponsored by Cold Spring Harbor Laboratory in collaboration with Northwell Health Cancer institute, the investigators received support from other researchers from Ruprecht-Karls-University Heidelberg (Germany), University of Cambridge, Columbia University, and Feinstein Institutes for Medical Research (part of Northwell).
The team sought to evaluate Famotidine, a histamine-2-receptor antagonist, widely available over-the-counter; a drug safely used for suppression of gastric acid production over a wide range of doses from 20mg once daily to 160mg four times daily.
In computer-based simulations, Famotidine has been identified as a potential inhibitor of the 3-chymotrypsin-like protease (3CLpro). In a propensity score matched retrospective cohort study, a significantly reduced risk for death or intubation (adjusted hazard ratio 0.43, 95% confidence interval 0.21-0.88) was identified for patients with COVID-19 who were taking Famotidine before or at the point of hospital admission. Some individuals have self-medicated with Famotidine while being outpatients with COVID-19. This study was aimed at collecting patient reported outcome measures from such individuals.
Upon executed informed consent documents, the team enrolled consecutive patients. Per the study protocol, they used patient-reported outcomes to investigate the impact of Famotidine, collecting data including demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores using questionnaires and telephone interviews. Ensuring National Institute of Health (NIH) endorsement of the protocol, they collected longitudinal severity scores of five symptoms including cough, shortness of breath, fatigue, headaches and insomnia as well as general unwellness on a four-point ordinal scale based on performance status scoring. Reporting data at the patient level, the team combined, calculated and statistically compared normalized symptom scores.
The study team identified ten COVID-19 patients who self-administered high-dose famotidine. The most common regimen as reported in the Gut article was 80 mg three times daily (n=6) for a median of 11 days (range: 5-21 days). The drug was well tolerated. All of these patients reported significant improvements of disease related symptoms once the famotidine regimen commenced. Interestingly, the combined symptom score improved greatly within 24 hours from commencing the famotidine regimen. Moreover, overall combined symptom scores improved within 24 hours. The investigators came to the conclusion that high-dose famotidine is not only well tolerated but also associated with improved patient-reported outcomes in non-hospitalized patients with COVID-19.
Dr. David Tuveson, Cold Spring Harbor Laboratory
Dr. Tobias Janowitz, Cold Spring Harbor Laboratory
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research
Joseph Conigliaro, MD, MPH (leading the larger Northwell study but also consulted on the retrospective case series)
Call to Action: This was not a randomized, controlled trial and, moreover, the patient sample size is considerably small so no conclusions can be made. But based on these observations based on those of Dr. Robert Malone and Dr. Michael Callahan in China, there very well could be something to the use of famotidine in at least targeting mild to moderate COVID-19 cases.