What’s Behind the Ivermectin-for-COVID Buzz?

Here’s the reason you’ve been hearing more about ivermectin lately: the Front Line COVID-19 Critical Care Alliance (FLCCC).

The group — led by three physicians with a knack for making headlines — posted its own review and meta-analysis of the global ivermectin literature on its website.

In early December, these doctors held a press conference, and one testified at a Senate hearing on early treatments for COVID-19.

They maintain that ivermectin has a special combination of anti-viral and anti-inflammatory properties that make it useful preventively and for treating early and late-stage illness.

Too good to be true? Not in the mind of FLCCC co-leader Paul Marik, MD, chief of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, who co-authored the review and meta-analysis based mainly on studies from outside the U.S.

“People are dying,” Marik said during a phone interview. “We treat patients at the bedside. We don’t have the ivory tower syndrome where you tell people what to do though you have no idea what you’re doing.”

Group members, who are mostly critical care physicians, don’t see a need for more data and argue it would be unethical to give placebo to patients given the established safety of ivermectin. But that’s raising more than a few eyebrows among others in the field.

‘We See That This Works’

The FLCCC formed in March 2020, at the beginning of the COVID-19 pandemic in the U.S., as a way to keep each other updated on the latest COVID-19 science. Group members had known each other before that through their common interest in and work on vitamin C, Marik said.

Marik is known in the field for developing the HAT protocol for sepsis, which also hasn’t been without controversy. It’s a combination of hydrocortisone, ascorbic acid (vitamin C) and thiamine. His group’s 2017 observational study of the protocol, published in CHEST, garnered excitement about the combination. But that hasn’t been borne out in subsequent trials, including the ADRENAL study (which looked at steroids alone), the CITRIS-ALI study (which looked at vitamin C alone) and the VITAMINS trial, which randomized patients to the full protocol but was open-label. The VICTAS study has completed enrollment but hasn’t yet reported data.

Marik said the group adapted the protocol for COVID-19, using a more potent steroid and adding an anticoagulant, along with other elements. The new name was MATH+, for methylprednisolone, ascorbic acid, thiamine, and heparin, plus a statin, zinc, vitamin D, famotidine, melatonin, and magnesium.

Marik emphasized that the group used steroids at a time when major public health agencies, including the World Health Organization and the National Institutes of Health, were cautioning against them.

“We said, we see that this works,” Marik told MedPage Today. “Then lo and behold in June, the RECOVERY trial was published, and it showed that dexamethasone reduced the risk of dying in people with COVID in the hospital.” (Marik continues to advocate for methylprednisolone, which is more potent than dexamethasone.)

The group recently published their observational experience with MATH+ in COVID-19 from two centers — Marik’s and United Memorial Medical Center in Houston, where another FLCCC leader, Joseph Varon, MD, leads the critical care unit — in the Journal of Intensive Care Medicine. “The average hospital mortality at these 2 centers in over 300 patients treated is 5.1%, which represents more than a 75% absolute risk reduction in mortality compared to the average published hospital mortality of 22.9% among COVID-19 patients,” the paper states.

“Everyone in medicine will yell and scream that this paper is not a randomized controlled trial,” or RCT, said the third FLCCC leader, Pierre Kory, MD, a critical care physician who worked most recently at Aurora St. Luke’s Medical Center in Milwaukee (more on that below). “We didn’t believe in an RCT. We believe we’re supposed to doctor and use our expertise. If you’ve been doing this for decades, and you trust your assessment of the disease and your knowledge of medicine, it’s OK to doctor.”

Now Marik and colleagues have updated their protocols yet again, this time with a focus on early treatment. While the rationale for ivermectin existed early in the pandemic, thanks to an Australian basic science paper, there weren’t enough clinical data to advise on its use, Marik said. (The FDA warned against using veterinary ivermectin in humans following interest in that paper.)

But since then, some governments and hospitals began using the drug in an attempt to prevent or treat COVID-19.

So arose the group’s I-MASK+ protocol, which focuses on ivermectin, but also includes vitamins C and D, quercetin, zinc, and melatonin for prophylaxis, and adding aspirin; higher doses of some of the individual components may be used for early outpatient treatment. The group also emphasizes wearing masks and other public health measures to prevent transmission of the disease.

What the Science Says

FLCCC members see their data as strong, but many experts disagree with their interpretation.

Regarding ivermectin for prophylaxis, they cite four randomized controlled trials and three observational studies. Two of the RCTs were done in Egypt, one in Argentina, and one in Bangladesh, ranging in size from 100 to 300 patients. Marik and colleagues also cite “natural experiments” in Peru, Brazil, and Paraguay where ivermectin was distributed widely, with “large decreases in case counts … soon after distribution began.”

For ivermectin in mild illness, they cite five RCTs: two in Bangladesh, and one each in Iraq, Brazil, and Spain, varying in size from 24 patients (Spain) to 722 patients (Brazil). For ivermectin in hospitalized patients, they cite four RCTs in Egypt, Iran, India, and Bangladesh, ranging from 72 to 400 patients. They also cite a host of observational studies and case series in both mild and severe illness.

The lone study done in the U.S. was a retrospective study, published in CHEST, of 280 hospitalized patients in Florida by Juliana Rajter, MD, of Broward Health Medical Center, and colleagues, in which 173 patients who got ivermectin were compared with 107 who didn’t get the therapy. “Most patients in both groups also received hydroxychloroquine, azithromycin, or both,” the study states.

Kory is the corresponding author of the ivermectin review and meta-analysis. In an interview with MedPage Today, Kory said he was frustrated by criticism of the evidence.

“If someone wants to discount those studies … and says they want to do an RCT with placebo, that’s problematic for me,” Kory said. “I could not have a patient admitted to my care and give placebo knowing what I know about ivermectin.”

Kory emphasized that FLCCC members “are firm believers in evidence-based medicine. But we disagree with how most practice evidence-based medicine. We think they are way too biased toward randomized controlled trials and completely dismiss evidence from anything but RCTs. We think that’s harmful and loses a lot of valuable data.”

‘Lowering Standards’

Steven Joffe, MD, MPH, a medical ethicist at the University of Pennsylvania, said he doesn’t believe clinicians “should be lowering our standards of evidence because we’re in a pandemic.”

“This group should be advocating strongly for a large, generalizable randomized trial if they believe so strongly in the efficacy of ivermectin,” Joffe said. “If in fact it is effective, the only way to convince the clinical and scientific community and allow patients all over the world to benefit is to prove the case in such a trial.”

“With good data and safety monitoring, if the benefits are as overwhelming as they claim, the trial could be stopped early on the basis of interim data and the treatment rapidly instituted,” Joffe added.

Andrew Hill, PhD, a senior visiting research fellow in the pharmacology department at Liverpool University in England, recently presented a similar meta-analysis of the data on ivermectin, which was posted on YouTube just last week. It supported the FLCCC’s conclusions.

Marik and Kory said Hill has been contracted by the World Health Organization to conduct an updated review of the evidence on ivermectin, but MedPage Today was unable to confirm it.

Zain Chagla, MD, an infectious diseases physician at McMaster University in Hamilton, Ontario, reviewed each of the trials in Hill’s review in a Twitter thread. He called the overall evidence “very low grade” and was also unhappy that Hill disseminated it as a video.

“We always want to see these things published, rather than me walking through a video, pulling these studies myself,” Chagla told MedPage Today.

He said if there was indeed a signal for efficacy, he would have expected ivermectin to be rolled into the SOLIDARITY or RECOVERY study by now.

“I want it to work, but at the same time, this whole thing feels like déjà vu of the first two months of the pandemic when we weren’t decided about hydroxychloroquine,” Chagla said. “We don’t want to come around a year later saying it didn’t help and it may have hurt.”

No Financial Interests

Kory said he first learned of Hill’s work in mid-December during a 3-day conference on ivermectin in COVID-19 sponsored by MedinCell, a French biotech studying injectable ivermectin for COVID-19 prophylaxis.

Kory said he had been invited to deliver the opening lecture.

Kory, Marik, nor Varon said they had no financial relationships with companies involved with ivermectin, including MedinCell or Edenbridge Pharmaceuticals. MedinCell didn’t return a request for comment; Edenbridge said it has no financial relationships with any members of FLCCC.

“We have absolutely no conflicts of interest,” Marik said. “We’re not making money from this. We have no vested interest. We’re doing what we think is right as caring physicians.”

Championing ivermectin has cost Kory professionally. He resigned from the University of Wisconsin in May, saying he couldn’t stand by while patients were getting supportive care only. At the time, he felt they should be getting steroids, though their benefit wasn’t confirmed until June.

Kory’s resignation came not long after he testified at a May 6 Senate hearing led by Wisconsin Sen. Ron Johnson (R), in which he called for use of steroids in COVID-19 patients.

He subsequently joined Aurora St. Luke’s and testified in favor of ivermectin Dec. 8 at a second Senate hearing organized by Johnson. He then quit there, too, telling MedPage Today the hospital wanted to limit his freedom to speak.

Kory said he was able to prescribe ivermectin at St. Luke’s, but only after showing his data to the chief of pharmacy there. Marik, however, said Sentara Norfolk General Hospital, where he works, does not allow it.

Varon, who is also the facility’s board chairman, can prescribe ivermectin.

Varon has become something of a media star, not only for his ivermectin advocacy. He’s appeared in dozens of articles in the lay press for his hard work and his compassion for his COVID-19 patients. In July, he told CNN that doctors were fighting a “war against stupidity” with people not following public health advice to wear masks and physically distance.

It was at United Memorial in Houston where Varon, Kory, and Marik staged a press briefing on Dec. 4 to get people to pay attention to their findings on ivermectin. They wanted the WHO and the NIH to take a look at the data and change their recommendations — which at this time remain not giving ivermectin outside of a clinical trial.

Kory’s Senate testimony a few days later was picked up by Fox News, and the attention grew from there.

‘This is Real’

Marik and Kory say they’re frustrated that their work is now being championed by the political right, and that it’s become politicized at all. The group has had to distinguish itself from America’s Frontline Doctors, which gained notoriety for its pro-hydroxychloroquine, anti-lockdown rhetoric last summer.

“This is not a political issue and it should never be,” Marik said. “We are driven by the science and the data, not by politics or anything else.”

“It angers me, when I hear that it’s a conspiracy, that this virus doesn’t exist, that there aren’t that many deaths,” he added. “You have to come to the ICU and see that people are dying to realize this is no hoax, this is real.”

Marik finds it particularly disappointing that his work has been misinterpreted as potentially undermining vaccination.

“That’s complete nonsense,” he said. “I was vaccinated yesterday and I believe this is a bridge to vaccination,” noting that slow vaccine roll-outs, vaccine hesitancy, and vaccine quality will likely mean the world will be dealing with COVID-19 for a long time to come.

“We need to do something in the meantime,” he said.

Much of the rest of medicine believes that “something” should be a randomized trial.

“The time is now to do a good clinical trial,” Chagla said. “I don’t think the vaccine is going to eliminate COVID-19. It’s a disease we’re going to be dealing with. The vaccine rollout has been slow, we’re not going to see entire populations vaccinated. There are always going to be holes. To prove that this drug works is something that would be warranted.”

But, he continued, “the studies have to be done properly.”

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