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At one point at the beginning of the pandemic, there was hope that a popular and inexpensive over-the-counter heartburn drug might hold promise for treating Covid-19, but a newly published study shows mixed results.

In the clinical trial, people with mild to moderate Covid-19 who took very high doses of famotidine, the active ingredient in Pepcid, had some improvement in their symptoms more quickly than those who took a placebo, a pill that does nothing.

But the trial, believed to be the first of its kind, was small, and the effect was far from dramatic. Among the 55 study participants, those who were assigned to take famotidine had an estimated 50% reduction in symptoms at 8.2 days, and those who were assigned a placebo saw that reduction in 11.4 days.

“I’m totally underwhelmed,” said Dr. Carlos del Rio, president-elect of the Infectious Disease Society of America.

“It certainly doesn’t rev my motor,” said Dr. William Schaffner, an infectious disease expert who serves as a vaccine adviser to the US Centers for Disease Control and Prevention. Neither he nor del Rio worked on the study.

In the clinical trial, participants took 80 milligrams of famotidine three times a day for 14 days. That dosage is six times higher than the highest recommended dose of maximum-strength Pepcid.

The editor-in-chief of Gut, the journal that published the paper Thursday, called the improvements for the famotidine patients “modest but significant.”

Dr. Emad El-Omar pointed out that after two weeks, twice as many people who received a placebo remained symptomatic as those who took famotidine.

“This is impressive!” El-Omar, a professor of medicine at the University of New South Wales Sydney in Australia, wrote in an email to CNN.

Famotidine interest started in China

The interest in famotidine to treat Covid-19 has roots in China, according to Dr. Kevin Tracey, a co-author of the Gut study.

In April 2020, Tracey told CNN that physicians there had observed that some people with lower incomes who caught the coronavirus were surviving longer than their wealthier counterparts who also had heartburn. When they looked more closely, they found that many of the lower-income patients were taking famotidine, whereas the wealthier patients tended to take a more expensive drug to treat their heartburn.

“The poor peasants really seemed to do well on famotidine,” Tracey, president of Feinstein Institutes for Medical Research at Northwell Health in New York, said at the time. “There are a lot of anecdotes passing around that give us some hope.”

Hope was particularly strong because Covid-19 was raging through New York at the time, and famotidine is inexpensive and has a long track record as a safe drug.

A few months later, Tracey and his team at Northwell and Cold Spring Harbor Laboratory in New York reported that 10 people recovering from Covid-19 at home in the US and Sweden noticed “rapid improvement” in their condition within a day or two of starting famotidine.

The team then tried to conduct a trial of the drug in hospitalized patients, but it ran into trouble as other treatment options became available for the dwindling number of Covid-19 patients in New York. That study was eventually scuttled.

Famotidine again made news when former President Donald Trump was treated with the drug when he was hospitalized with Covid-19 in December 2020.

But a few months later, a study conducted by researchers at two pharmaceutical companies found that famotidine didn’t help hospitalized people.

The Infectious Disease Society of America recommends against using famotidine to treat hospitalized Covid-19 patients and has no recommendations for or against using it in non-hospitalized people.

In April 2020, the National Institutes of Health announced a public-private partnership to accelerate the study of potential drugs to treat Covid-19, including about two dozen “repurposed” medications that are already being used to treat other conditions. Famotidine is not on the list.

Next steps are unclear

Now, the study of famotidine to treat Covid-19 is at a crossroads.

The team at Northwell and Cold Spring Harbor is considering how best to design a larger clinical trial that would put famotidine to the test.

“Can we take a safe drug off the shelf, one that could be manufactured [and essentially] given away to countries that have nothing to treat Covid?” Tracey asked. “It’s an important question for global health.”

Not everyone agrees.

Schaffner and del Rio, the infectious disease experts, say there’s no reason to spend money on a large clinical trial of famotidine, especially because in the US, there are antiviral drugs and a monoclonal antibody authorized to treat early-stage Covid.

They added that if someone with Covid-19 wants to try famotidine, there probably would not be any harm.

“The downside to this is virtually nil, so I would say sure, try it, but don’t expect too much,” said Schaffner, an infectious disease expert at Vanderbilt University Medical Center.

Another infectious disease expert sees more potential promise in famotidine.

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Dr. Paul Offit pointed to findings in the new study that examined inflammation markers in the blood of 35 of the participants. Those results showed that the people on famotidine had their inflammation resolve more quickly than those on placebo.

The NIH recommends using tocilizumab, an arthritis anti-inflammatory drug, to treat hospitalized Covid patients.

“Famotidine is kind of a poor man’s tocilizumab,” said Offit, a member of the US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee. He added that famotidine would have a far less dramatic effect than tocilizumab, but it would also have fewer side effects.

Offit encouraged more research on famotidine to treat Covid-19.

“I’m always up for studying more. That’s the last refuge of the academic scoundrel: more studies,” Offit said.

CNN’s Danielle Herman and Naomi Thomas contributed to this report.