Years ago, as a medical student, I volunteered for select medical experiments. These included vaccine trials for hepatitis B. and meningococcus. I even participated in a vaccine trial for “turista”, traveler’s diarrhea. For the capstone of that trial, I spent the weekend in a clinical research facility and swallowed a solution containing E. coli, the causative agent of turista. I fared well. As the walls were paper thin, I heard the test subject in the adjacent room. She was not as lucky. She spent all weekend in the bathroom. She was likely part of the control group.
Volunteers were paid but mostly they participated to be the lucky pioneers protected from these illnesses. As someone considering the practice of surgery, a needle stick by a patient with hepatitis B could end my career or even my life. While any clinical trial poses a risk, we participated for the perceived benefits.
Today, we have a new enemy, the coronavirus which causes the COVID-19 illness.
Our brothers and sisters providing healthcare around the world are working tirelessly to deliver care, preparing for the worst, and staying true to the Hippocratic oath. Those in non-clinical fields are researching paths to treatment and prevention. Everyone has a role to play.
The broader public has been asked to wash our hands and avoid close contact. There aren’t enough gloves, masks, and gowns to go around. Those delivering care need them — they are in the front lines.
Lockdown brought our economy to a screaming halt. When lives are at stake, we all want to help. If it’s for a reasonable period of time, it’s a small sacrifice.
Coronavirus is a tough opponent. It spreads easily and aggressively. Can we really enforce a functional quarantine for months? Can our parents and grandparents endure the isolation? How about those with less than optimal baseline health?
As a population, can we do more?
Yes. In reference to Drs. Colyer and Hinthorn’s thoughtful March 22 Wall Street Journal Commentary, These Drugs Are Helping Our Coronavirus Patients, we should embark on the largest clinical trial ever.
But first, some background.
For decades, public health officials distributed a medication named chloroquine to prevent and treat malaria. As the organism causing malaria became resistant, new compounds replaced chloroquine. A close cousin to chloroquine, hydroxychloroquine, is used today to treat conditions such as lupus and rheumatoid arthritis. Some astute scientist must have observed that lupus patients being treated for malaria received benefit against both
Over the past few weeks, several randomized controlled trials were conducted to test the effect of chloroquine in treating COVID-19. Therapeutic effects were observed in fever reduction, improvements on chest imaging studies and impeding disease progression. Chloroquine was declared useful medical agent for COVID-19 in the sixth edition of the New Coronavirus Pneumonia Diagnosis and Treatment Plan, released by the National Health and Care Commission of China on February 19th.
On March 17th, the AIFA Scientific Technical Commission of the Italian Medicines Agency expressed a favorable opinion to include the off-label use of chloroquine and hydroxychloroquine for treating COVID-19.
When options are few, life and death decisions must be made with the evidence at hand. That’s how it always works in the emergency department, the surgical suite, and the battlefield.
Researchers recently identified how chloroquine and hydroxychloroquine likely prevent the virus from entering the cell. They explained how the virus is more effectively eliminated when it does breach a cell. Hydroxychloroquine also has a known mechanism of action preventing “cytokine storm”, the body’s extreme overreaction to a virus which causes secondary damage as it tries to fight the infection. The science accumulated to date is more than an empiric anecdotal observation.
Many ER physicians, intensive care doctors, and pulmonologists have already stocked reasonable quantities of hydroxychloroquine for themselves. The existing data are enough for them– even if the FDA wouldn’t have agreed in more normal times. As this is a fast-moving target, FDA granted chloroquine and hydroxychloroquine emergency use authorization on March 29th.
Some doctors are not waiting. Dr. Vladimir Zelenko is a board-certified family practice physician who serves the Hasidic Jewish community in Orange County, New York. He estimates 60% of this community has been infected with coronavirus. He has been treating hundreds of patients with hydroxychloroquine and over-the-counter zinc supplements. Not one of his patients has needed to be hospitalized. His recommendation was to prescribe hydroxychloroquine to medium and high-risk patients in the earliest phase of suggested infection. Do not wait. And he continued, consider prophylactic treatment in high-risk patients.
Chloroquine and hydroxychloroquine have both been on the market for many years. We understand their safety profile. They are cheap and increasingly available. The companies that manufacture and distribute these compounds are ramping up quickly. It’s much easier than ramping up ventilator production (which should still be done). Furthermore, once a pill is made, it just needs to be distributed. Once a ventilator is made, it needs to be distributed and used by trained personnel. There are a finite number of people who can intubate patients, oversee, and manage ventilators. Once a COVID-19 patient requires a ventilator, the mortality rate goes up. We should be doing all we can to prevent patienst from ever deteriorating so much to need a ventilator.
The modest proposal.
Instead of just treating the sickest patients with chloroquine or hydroxychloroquine, let’s use these medications to prevent its spread and mitigate illness for those who are exposed. We used them to prevent and treat malaria. Let’s do the same for COVID-19. And then let’s study the results.
Sure, there should be reasonable restrictions, because there are risks. We can exclude people with medical problems made worse by the drugs – such as those with abnormal heart rhythms, certain eye diseases, liver, or kidney problems. Not everyone is a candidate for chloroquine or hydroxychloroquine. We can start with front line providers and those in the geographic hot zones – New York, San Francisco, New Orleans, Detroit and Seattle. Participation is this giant clinical trial would be entirely elective. Everyone has a different risk profile. Some are early adopters. Others are fast followers. Some will never participate. The more people who participate, the sooner we will know if the medications work to prevent and/or treat COVID-19.
We know that early use of antivirals can make a profound difference in limiting spread of influenza. In a JAMA article now almost 20 years old, post-exposure prophylaxis with oseltamivir (Tamiflu) protected close contacts of influenza-infected persons against influenza illness, prevented outbreaks within households, and was well tolerated. Also, viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy.
How long should seemingly healthy patients take this prophylactic medication? What about dose and frequency? Those designing the trial will make the call.
Importantly, we will need to ensure an adequate supply of hydroxychloroquine remains available for those who depend on it to treat lupus and arthritis. We cannot forget about these patients. Many have no alternative safe or effective treatment.
I can see the naysayers wringing their hands cautioning we first need to wait for more data. We should test versus placebo.[1] And the early reports are not large clinical trials.
We don’t have the luxury of time.
In addition, several medical licensing boards have warned physicians not to prescribe these medications to themselves or their families. The warning was based on near-term shortages affecting patients who depend upon hydroxychloroquine for treating lupus and rheumatoid arthritis. That’s a reasonable concern. And it’s a solvable problem. But some licensing boards went further. They argued it was unethical for physicians to pre-emptively prescribe such unproven medications for themselves or their families. That is unfair. Doctors are in the front-line treating patients with suspected coronavirus. You don’t send a SWAT team into a dangerous environment without Kevlar. If doctors believe such medications will protect, that’s enough for me. Perfectly ethical.
Let’s acknowledge the risk to broadly disseminating these medications. For many, these risks are counterbalanced by waiting and living in fear. Most Americans are clamoring to do more. It doesn’t feel right limiting ourselves to handwashing and isolation. Let’s embark on the largest clinical trial ever. As Todd Beamer reportedly commanded on United Flight 93, “Let’s roll.”
Share your thoughts in the comments below.
[1] My take, distributing the medication to as many people as possible may actually take advantage of the placebo effect. Sitting around waiting for badness to happen squeezes the adrenal glands. That can’t help. The better study would compare medication versus placebo versus nothing.
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I agree with the article’s premise that time for more traditional research is not a luxury we can afford. As an emergency physician working in the metro-Atlanta region where the number of COVID cases are climbing we need to approach this with an all-hands-on-deck approach. That includes hydroxychloroquine and azithromycin given the promising results from studies conducted in China and France. Risk-benefit analysis as always should be used in patient selection (screen for long QT syndrome) but for the vast majority of the population anti-malarial drugs on a short term basis are well tolerated and worth using given the current circumstances
Amen brother. Well said and let me know how I can help.
I have a vested interest in this. Not for myself, but for my brother David: I got THE call about 4:30am from Botsford Hospital in Farmington Hills, MI. David had been working for an S and L company as a programmer for about 2 years. He lost his job at the start of the Savings and Loan Crisis. He struggled for a year to find another but was subsequently fired.
David put a bullet through his head while parked in his car, in our mother’s driveway. The ER doctor assured me he would not survive. He was pronounced on August 19, 1994. There are details I will leave out. Somewhere there is a man who as a young kid, a paper delivery boy, still has dreams about “that car, all that blood and that body.” He discovered David. I had to call my sister and tell her. There is always a constellation of trauma around suicide.
Other people, yet unknown will share my family’s burden. It may already be too late for some. I pray it is not.
Our Country has a once- in-a generation opportunity from a man, who in 1934 invented Chloroquine. His name is Johann (Hans) Andersag, Ph.D. We need to remember his name. It needs to be drummed into the heads of college students who are taught that “white-Christian men are oppressors” and that we must exclude and revile them.
It is already being used as a prophylactic against Covid-19 in India, mainly for first-line responders: https://www.expresshealthcare.in/news/advisory-on-use-of-hydroxy-chloroquine-as-prophylaxis-for-sars-cov-2-infection/417793/
Like Dr. Segal, I don’t expect this to be perfect. But unlike other drugs, including vaccines for H1N1, we know that Hydroxychloroquine does not produce Guillian-Barre syndrome. Quinones may have a “peculiar” feature as a group. They may block Cytokine storms. Perhaps others, like Malarone, do the same. But we know that Hydroxychloroquine both interrupts Cytokine storms and has a lysis action against the Sars group of viruses, including Novel Sars Covid-2. It was approved for medical use in 1955.
Nobody expects a panacea. I would be very satisfied with people going back to work with alacrity and no fear. Even if it is not 100% effective, it could BREAK THE BACK OF THIS PANDEMIC. Saving of 40,000+ lives would be a miracle. A medical miracle.
There are already doctors taking it. You know some of them. They are just not telling you. They have doses home for their family in the bedroom.
We need to find “celebrity” physicians to start this ball rolling: Dr. Mehmet Oz? Others?
Dr. Segal’s monograph was not English. It was poetry. David would have been grateful that so many care, even though it is too late for him.
Michael M. Rosenblatt, DPM
We should be very careful about getting our treatments ahead of the science. Hydroxychloroquine has many potential serious side effects including cardiovascular. And ther report are mixed. An actual trial of the drug which was small but randomized did not show effectiveness and actually showed longer persistence of the virus.Pilot study suggests hydroxychloroquine offers no additional benefit to patients with COVID-19 receiving standard care
(3/25, McCall) reports researchers found in a pilot study with 30 patients diagnosed with COVID-19 that “hydroxychloroquine offers no additional benefit to coronavirus patients already being treated with current methods, including bed rest and antiviral drugs.” The findings were published in the Journal of Zhejiang University and the study’s authors said more research is needed to further examine the efficacy of the treatment.
The purpose of the article was to promote a trial, a large trial. I would argue that IS science. The drug has already been approved by the FDA more than once as being safe for intended indication, namely malaria prophylaxis and treatment, lupus, and rheumatoid arthritis. So, we have already moved on to efficacy trial. This would be an extremely large phase 3 trial. How is that not science? You test, you get data, you publish data. While I have not met a doctor who has seen any of the cardiac arrhythmias in any of their patients either receiving such medications now for COVID-19 or in the rheumatological community, point taken. The blog advanced exclusions for patients with arrhythmias, renal, or hepatic disease.
Regarding your conclusion, “An actual trial of the drug which was small but randomized did not show effectiveness and actually showed longer persistence of the virus. Pilot study suggests hydroxychloroquine offers no additional benefit to patients with COVID-19 receiving standard care.”
I respectfully disagree.
Most patients in the study’s control group were actually treated with other antiviral therapies at the same time, including AbbVie’s HIV combo med Kaletra and flu drug Arbidol. Most, but not all, patients in the hydroxychloroquine group were also treated with Arbidol. All patients got interferon-alpha. In my proposal of giving the medication to patients EARLY in the process, it is hard to imagine that such patients would receive such a cocktail of these other therapies. Also, Arbidol is only available in China, so it would have to go through a full FDA process to better understand its safety in large numbers.
Bravo!
1) Since these drugs are already approved by the FDA for other purposes, they have already passed safety trials.
2) There is a concept of trial by combat. In this realm of a pandemic, knowing that significant anecdotal and some styde evidence exists about efficacy, there is little to be lost by proceeding to large scale testing on actual patients. One of my friends was infected with Covid 19, and was treated with hydroxychloroquine and zithromycin. He had to go on to a vent because after 5 days he was completely warn out breathing against increased resistance. He received the drugs one day before he wound up on the vent. However his numbers and xrays once on the vent were very good. Five days of mechanical ventilation and he was successfully weaned off the vent, extubated and discharged from ICU. He is still recovering in the hospital but he is getting better every day. We will not know for certain, but it is reasonable to assume that his ventilator course would not have been so good if he had not received those medications.
3) There is no harm in trial for those so sick that they are in the hospital already.
4) Since 95% of patients only have mild symptoms from Covid 19 infection, it seems unreasonable to use the drugs for those folks, where the risk might outweight the benefit.
Agree wholeheartedly. What better option do we have? If none, then let’s do it. How do we get the ball rolling?
Also agree that it is not inethical for physicians to prescribe a medication that may save the lives of their family and friends. After all, we all “stockpile “ Tylenol or Advil in our cabinets just in case of discomfort or fever… is that inethical? If there is a shortage, it is sign to produce more. And quickly!!
There is very little downside to taking zinc. One could get some nausea if you take too much and maybe some loss of sense of smell, however, it has been shown in some studies to shorten the duration of the upper respiratory symptoms of benign coronavirus infections. There’ve been no formal studies on this and certainly none with Covid but there is little downside.
With respect to the chloroquine or hydroxychloroquine, otherwise known as Plaquanil, there is data from China showing decrease in vitro activity of the coronavirus A clinical trial was done in France .This had several methodologic issues including very small sample size, single institution, lack of randomization, significant dropout in the treatment group and did not have clinical endpoints just degree of viral load as an endpoint.
Nonetheless many doctors are using this in Covid patients after giving them informed consent and checking them with electrocardiograms and retinal examination. This is because there is no good treatment for this at this time and chloroquine or hydroxychloroquine may work.
I would point out that in the French trial which only involved hospitalized patients they were excluded if they had history of retinopathy, G6PD deficiency or QT prolongation on their electrocardiogram. There is concern that people who would probably get better anyway with minimal symptoms would take chloroquine or hydroxychloroquine without getting checked out with an electrocardiogram and could have sudden death or severe ophthalmological symptoms where they would almost certainly have recovered spontaneously.
In addition the American Society of rheumatology issued guidelines showing how important this drug as to their lupus patients and that a shortage would become a real hardship for them people if started hoarding this drug for use.
There’s been some misinformation from the government that this drug is FDA approved. This is not the whole truth as it is approved for malaria and lupus and rheumatoid arthritis but it is not approved for Covid.
In any event I think zinc would be harmless but if one would wish to take him chloroquine or hydroxychloroquine I think I would take hydroxychloroquine over chloroquine would get checked out with an electrocardiogram and a retinal exam first.
This week an interesting post was made.
It stated that hydroxychloroquine’s effect on the red blood cell was the basis for its effectiveness against malaria.
The post went on to say that hydroxychloroquine’s effect on the red blood cell, by a different mechanism, was the reason that the the drug was effective against the Corona virus.
I have not seen any other information regarding this.
In fact I cannot find anything that directly describes the mechanism of action in malaria, other than disrupting heme and affecting the parasite directly.
I would be curious to know if there is anything to this or if it was just pure speculation.
I hate that I am late to this party, but I have an idea, which may already be happening. We should enlist the companies that are ramping up production to offer a daily dose of the medication to their employees working on the production lines and if they pass EKG, medical history, and retina exams, give it to them (and their adult family members who might also pass those hurdles?) and see if they have a lower infection rate than the population at large. The numbers would likely be pretty large and the costs VERY low.