FAMOTIDINE SHOWN TO SIGNIFICANTLY DECREASE COVID SYMPTOMS IN 55-PATIENT RANDOMIZED TRIAL
Note that views expressed in this opinion article are the writer’s personal views.
Famotidine, the over-the-counter heartburn drug, pepcid, was shown to significantly decrease COVID symptoms in a 55-patient randomized trial authored by Dr. Tobias Janowitz and published in the BMJ journal Gut February 10, 2022. Famotidine has been studied since early in the pandemic after it appeared to decrease mortality in Wuhan. It has been the subject of numerous TrialSite News articles, including one I was involved with, The Promise of Famotidine 10/4/21.
Back in early 2020, it was thought that to treat hospitalized patients one needed to kill the virus. It took a while to realize that there was little to no viral replication ensuing after seven days and that illness in hospitalized patients is dominated by inflammation. The same flawed thinking was involved in studying Gilead’s antiviral, remdesivir, in inpatients. Not surprisingly, in non-drug company-sponsored inpatient trials, it has been shown to be ineffective in inpatients and the World Health Organization (WHO) recommends against using remdesivir. That did not stop the U.S. government from continuing to incentivize US hospitals to give it. In the first 9 months of 2021, hospitals spent $4.2 billion on the drug.
The three-dimensional structure of famotidine suggested it blocked the protease involved in viral replication, however a $21 million government-sponsored study of high dose IV famotidine at Northwell Health was never completed. Eventually, it was tried haphazardly both intravenously and orally and appeared to be beneficial in a number of nonrandomized studies. Dr. Tobias Janowitz, a cancer researcher, working at Cold Spring Harbor Labs in New York, affiliated with Northwell Health, treated 10 consecutive patients with an average of 80 mg orally 3 times a day with good results and reported it in Sept 2020 in the BMJ’s journal Gut.
By the summer of 2020, it was known that famotidine did not block the viral protease and it was working by blocking H2 receptors on mast cells which release histamine and other chemicals and are responsible for allergies. Mast cells lie just under the epithelium of the skin and endothelial lining of the gut and other places. They interact with adjacent nerves in a complex way. They respond to foreign substances like infectious agents via histamine and other substances to interact with other white blood cells. Only the allergy/immunology community has any understanding of them. It was then thought by many that mast cells initiate cytokine storms mainly via the release of histamine and/or other chemicals. In March 2021 Dr. Robert Malone and many other researchers published a series of experiments confirming that H2 blockade was the mechanism of action of famotidine. Dr. Robert Malone Famotidine and COVID
In 2020, the NIH ACTIV committee voted not to not do a large, randomized trial to look for evidence that famotidine could help COVID patients who at the time had no outpatient therapy available. No antivirals or monoclonal antibodies were available to Americans then. Donald Trump’s medical team treated him with famotidine. Vaccines had not yet been deployed. The ACTIV committee’s inaction made no sense to me. I had not yet figured out that NIH was doing its best to prevent all repurposed drugs from being used to treat COVID.
In January 2021, I sent an email with Dr. Lawrence Afrin’s review article to the American Academy of Allergy Asthma and Immunology(AAAAI). The letter was also sent to NIAID deputy director, Dr. Cliff Lane, and the head of their mast cell section, Dr. Dean Metcalfe. The review article by Dr. Afrin suggested that 17% of the population has underlying mast cell activation syndrome and that those were the people who were unexpectedly getting really sick because their mast cells were abnormal and in response to the virus released histamine and other chemicals which initiated cytokine storms caused by other white blood cells. Afrin COVID and mast cells
On January 25, 2021, I emailed Dr. Giselle Mosnaim, president-elect, and Dr. Mariana Castells at Brigham and Women’s, head of research for 7,000 members of the American Association of Asthma Allergy and Immunology (AAAAI). In that email, I suggested they study mast cell therapies and perform a study to determine if ivermectin’s anti-inflammatory activity was due to it being a mast cell stabilizer. Drs. Mosnaim and Castells sent back a pleasant response:
Thank you very much, Dr. Goodkin, for bringing to our attention the role of mast cells in the cytokine storm of Covid-19 infected patients and the potential use of ivermectin. It is of critical importance to have controlled clinical trials with placebo regarding ivermectin, and I believe my hospital, the Brigham and Women’s Hospital, is considering one.
We have a manuscript under revision indicating that patients with mast cell activation disorders, including cutaneous and systemic mastocytosis have mild Covid19 infections, and there have been no deaths, Intubations or ICU needs, indicating that mast cell activation disorders are not a risk factor for Covid19 infections or severity. More importantly, we have international collaboration with several European laboratories and have been looking at the expression of the ACE-2 receptor on mast cells and mast cells do not have the protein or the RNA for the ACE-2 receptor and cannot be infected by Covid19. It is unlikely that IL-6 is coming from mast cells currently, and we are further investigating its origin. We have a manuscript under revision with this important information.
Mariana Castells, M.D., Ph.D.
Director Drug Hypersensitivity and Desensitization Center
Director Mastocytosis Center
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Dr. Castells subsequently showed that the mast cells in the nose of her mast cell patients did not have ACE2 receptors. Her contention was that the lack of ACE2 receptors in the noses and probably all the mast cells of her patients with cutaneous and systemic mastocytosis was why they failed to become very sick if they contracted COVID. Dr. Theoharis Theoharides had said that normal mast cells do have ACE2 receptors. He suggested the use of mast cell stabilizers Quercetin and luteolin. Theoharides Mast Cells and COVID Further confusing things is that most mast cell disease patients are on H1 and H2 blockers. The data suggest that mast cells clearly are involved in the morbidity of COVID and that the morbidity can be helped by famotidine and quercetin. A lot of work needs to be done.
AAAAI made their interest known to the coronavirus task force, including forwarding my email but then they mysteriously lost interest and did nothing with famotidine or any of the other mast cell therapies. I was informed that Dr. Afrin’s article was just theories. Either they decided COVID had nothing to do with mast cells or were scared off by the government. I assumed, with no actual evidence, that the latter was true. In either event, they did the world a terrible disservice by not encouraging further research into mast cell therapies for COVID by the allergy/immunology community.
At the AAAAI annual meeting in Phoenix 2/25-2/28, none of the 227 abstracts mention mast cell therapies for COVID. Looking at their program one would not know there was any relationship between COVID and mast cells. I have been very upset with AAAAI and have let some board members know about it. I, possibly incorrectly, assumed they had been shut down by our government who has fought hard to prevent early COVID patients from receiving any repurposed drugs. Had been shut down by our government, I now realize that had they gone public about government interference, they would not have been believed, the press would have ignored them, they would have gotten no funding to do any research, and they would have been attacked mercilessly. On the other hand, had they told their 7000 allergists about mast cells and COVID, those allergists would have done a lot of good.
Back to Dr. Janowitz’ article. From January to April 2021 they randomized 55 patients to famotidine 80 mg orally 3 times a day(N=28) or placebo(N=27) fr 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory).
Results Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms.
Significance of this study
What is already known on this subject?
• COVID-19 is caused by the SARS-CoV-2.
• Cytokine release drives inflammation and poor outcome in patients with COVID-19.
• Famotidine is a histamine 2 receptor antagonist that is globally used to reduce gastric reflux symptoms and treat gastric ulcers.
• In laboratory studies, famotidine reduced type-I interferon release from virally infected epithelial cells.
• Famotidine improved the outcome of patients with COVID-19 in some retrospective studies and a case series, but evidence from a clinical trial is lacking.
What are the new findings?
• In this randomised, double-blind and placebo-controlled clinical trial, oral famotidine was safe and well tolerated.
• Patients with mild to moderate symptoms from COVID-19 on famotidine experienced more rapid symptom resolution.
• Famotidine induced earlier resolution of type-I interferon levels in patients with COVID-19.
The study results were not overwhelming in a group of patients 35 years old although I would think that almost anyone who gets COVID would want to take a cheap, safe, over-the-counter drug, which would make them get better faster and be twice as likely to make them be asymptomatic at two weeks. At this point, we have no idea whether famotidine alone or in combination with other mast cell therapies would lower rates of hospitalization and mortality in high-risk patients. These are very important questions for the world. We have no idea what the combination of famotidine and fluvoxamine, another drug with substantial data, would do for omicron patients. The failure of everyone of any importance in the United States to encourage doctors to recommend famotidine and fluvoxamine to early COVID patients is incomprehensible.
In a CNN article, Drs. William Schaffner and Carlos Del Rio of the Infectious Disease Society of America were unimpressed with the results and said there was no reason to do a large randomized trial because antivirals and monoclonal antibodies are available in the US. They obviously are much more effective when taken early. The problem with that statement is that they are hideously expensive, not readily available, have no long-term safety record, must be used within the first 5 days and will never be widely available outside the US where few countries can afford them. The IDSA website shows that they have not reviewed famotidine since June 2020. There is no evidence that IDSA has any expertise with or interest in mast cell activation syndrome and the use of the multiple agents that could treat or prevent it. One would have thought that since it has been postulated since the summer of 2020 that mast cells initiate cytokine storms, that IDSA might have shown some interest. The National Institute of ALLERGY and Infectious Diseases(NIAID) has also shown no interest.
Had NIH started a large trial in 2020, it is likely that patients would have been able to go to a drug store and get a cheap, safe drug to help themselves. 3 other over-the-counter drugs were likely to help, H1 blocker zyrtec(cetirizine), mast cell stabilizers luteolin and quercetin. Generic cromolyn sodium and montelukast were likely to help. My daughter has mast cell activation syndrome related to Ehlers-Danlos Syndrome and POTS and has greatly benefitted from IgE antibody omalizumab(Xolair). Anti-IgE monoclonal antibodies as potential treament for COVID-19. A 200 patient trial in inpatients with COVID has started at McGill.
At this point, it appears very likely that besides its increased infectivity, the biggest difference between SarsCov2 and prior coronaviruses is its ability to cause mast cells to initiate cytokine storms. In the future, resistance could develop to any antiviral drugs and mutations could render monoclonal antibodies ineffective as happened with omicron. The ability to protect our mast cells and the complications of cytokine storm would appear crucial to protect us in future pandemics involving coronaviruses. Unfortunately, this concept has been lost on our governmental healthcare agencies and IDSA.
It has also been found that mast cell activation is involved in long COVID but few are aware of it.
Therapies are badly needed. Treatment for mast cell disorders is likely to be effective and should be studied in randomized trials.
Thankfully, there are some researchers who have figured out the importance of mast cells and are doing the appropriate research. In 2020, Dr. Kevin Tomera and Dr. Robert Malone, the same Robert Malone who put mRNA into nanoparticles and who has been vilified for his anti-government healthcare policies views, did a trial of 25 consecutive inpatients treated with high dose famotidine and celecoxib with very good results. No one died. Getting it published was impossible, and the FDA did its best to nitpick new study protocols to delay things per Dr. Malone. A randomized trial of famotidine and celecoxib was unsuccessful which was attributed to the coadministration of corticosteroids that had come into use in the interim. In the meantime, Dr. Malone has been involved with Leidos of the Department of Defense who is sponsoring trials of high dose oral famotidine plus celecoxib(Celebrex) in outpatients and inpatients with COVID not on corticosteroids which have begun enrolling patients.
In my opinion, the failure of NIH and AAAAI to do anything with mast cell therapies during the pandemic has been a major blunder. In the case of NIH, it was intentional. I’m not sure what happened with AAAAI. People could have walked into a drug store and treated themselves with famotidine, certirizine(zyrtec), luteolin, and quercetin.
We would be better prepared for future coronavirus pandemics. About 6 months ago I got an email from NIH that they were submitting famotidine to the ACTIV committee. It’s no surprise that nothing happened. I will send this to Dr. Anne Maitland from Mt. Sinai, now head of mast cells for AAAAI. She’s terrific and I expect her to fix the problem.
Michael B. Goodkin MD, FACC