We have all been waiting for the results of a randomized controlled trial (RCT) of hydroxychloroquine (HCQ) to treat COVID-19. The first such study has just been published in the New England Journal of Medicine (June 3, 2020). The disappointing hydroxychloroquine data will leave a lot of people frustrated.
An RCT vs. an Observational Study
It’s really important to understand the difference between a double-blind, randomized clinical trial and an observational study. RCTs are the gold standard when it comes to research. That’s because investigators do their best to eliminate expectations, bias, suggestibility or other factors. If neither the subjects of the study nor the researchers know who got the real medicine or the placebo pills, it is much harder to influence the results.
In an observational or epidemiological trial, there can be many factors that influence the outcome other than the drug in question. If doctors believe that the medications they are administering are helpful, that may influence the way they talk them up to their patients. The anticipation that something is going to work can have a profound impact on the patient’s experience and the way the investigators record the results.
One of the very first randomized controlled trials of diabetes drugs was called the University Group Diabetes Program (UGDP). It involved the medicine tolbutamide (Orinase) and was stopped prematurely in 1969. That’s because the people getting the “real” drug were dying faster than those taking a placebo. This might not have been discovered if the study were observational. Details at this link.
The New England Journal of Medicine & Hydroxychloroquine:
The latest HCQ study compared hydroxychloroquine with placebo to prevent infection in health care workers or family members exposed to people with the disease. More than 800 people in the United States and Canada participated in this research.
Here is the protocol in the words of the researchers:
“We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure).”
Participants were randomly assigned to get hydroxychloroquine (414 people) or placebo (407 people). To be perfectly clear, these people were not sick. They were not hospitalized. The goal of the study was to determine whether treatment with HCQ within four days of contact could prevent people with moderate to high-risk exposures from developing COVID-19. This is prophylaxis. The question: Would HCQ prevent illness?
The volunteers were followed for two weeks. They were tested for COVID-19 when possible (this was early in the testing program). Symptoms were carefully recorded. These were the primary outcomes. Secondary outcomes included hospitalization or death.
Disappointing Hydroxychloroquine Results:
Of the 821 exposed people in the trial, 13% developed COVID-19. Here’s how it broke down. Of those getting HCQ, 11.8% came down with the coronavirus. Of those getting placebo, 14.3% came down with the coronavirus.
That was not a statistically significant difference.
“Two hospitalizations were reported (one in each group). No arrhythmias or deaths occurred. There was no meaningful difference in effectiveness according to the time of starting postexposure prophylaxis or in any of the prespecified subgroups.”
The authors described the disappointing hydroxychloroquine results this way:
“In this randomized, double-blind, placebo-controlled trial, we investigated the efficacy of hydroxychloroquine as Covid-19 postexposure prophylaxis. In this trial, high doses of hydroxychloroquine did not prevent illness compatible with Covid-19 when initiated within 4 days after a high-risk or moderate-risk exposure.”
Readers React to Disappointing Hydroxychloroquine Results:
There will be other randomized controlled trials that may be more definitive. But this study does answer many of the questions raised by visitors to this website. Here are several examples:
A.M. was quite adamant that prior negative HCQ research was flawed. Her point:
“HCQ is effective as a prophylaxis or if it is taken early in the disease and with zinc.”
Lin agrees that prior studies were conducted on hospitalized patients who were sick:
“I have read in several articles that people with the virus have good results when the 3 drug combination is given early in the illness. If it is given when the patients are extremely ill, the results are poor. That could skew numbers for the efficacy of hydroxychloroquine.”
Robin adds:
“Note that the trials were on those patients that were sick enough to all be in the hospital for treatment and the exact stage of the disease in most was not noted in your summary. The success of the drug in the USA and in many countries has been largely on those at early stages of the disease and most of them (but not always) not at their final breath on ventilators which was not as effective etc.”
Laurie says prior studies gave HCQ too late:
“Several comments suggested the need to start HCQ early for it to be effective, to which twice there was the reply that it was given within 24-48 hours of patients being hospitalized, implying that it had indeed been given early enough. Everything that I have read from credible sources on the subject shows that once someone has become ill enough to warrant being hospitalized, it is already too late. I’d call that a flawed study.”
People’s Pharmacy Response to Timing:
If timing is the critical factor with hydroxychloroquine, then this week’s study in the New England Journal of Medicine should put those concerns to rest. If you give the drug before people get sick, it should eliminate the timing issue. As you have read, giving the drug as a preventive measure was not effective in this study.
Prior Studies were not RCTs!
William points out that the study published in The Lancet (May 22, 2020) was not a randomized controlled trial. He was absolutely right about that.
The study has been retracted.
“This was an observational study. There is no statement that the doctors chose randomly who got the viral drug treatment. My guess is that hospital doctors gave the antiviral drugs to those that appeared the sickest. This the study is seriously flawed.”
That is why this week’s randomized controlled trial of HCQ published in the New England Journal of Medicine is so important.
What About Zinc and Vitamin C?
Many of the readers who criticized prior studies published in the New England Journal of Medicine (May 7, 2020) and JAMA (May 11, 2020) pointed out that zinc was missing from the protocols. They were also dismayed that azithromycin was not included. Dozens of people believe that the magic formula is hydroxychloroquine plus zinc plus vitamin C plus azithromycin. Here are some of the comments:
Michael says zinc allows HCQ to work:
“HCQ needs zinc to work. Without zinc it is like a boat without oars.”
Kim says much the same plus adding the antibiotic azithromycin:
“This is just one more instance of big Pharma saying hydroxychloroquine doesn’t work while they conveniently choose to leave out the ZINC. The original success reports were hydroxychloroquine, azithromycin and ZINC. ZINC was the key to success with this cocktail.”
Bonnie agrees:
“Too bad they didn’t give the study participants zinc along with the hydroxychloroquine. From my reading, hydroxy works to get zinc into the cells, which aids recovery.”
What Did The NEJM State About Zinc?
The authors observe that the in vitro (test tube) study that originally suggested zinc would be important when combined with chloroquine did not reflect in vivo (in the body) reality.
They note:
“Importantly, this lab experiment was not designed to emulate zinc levels in the average human body, but in a cell culture media which started with minimal zinc. North Americans have a very low prevalence of inadequate dietary zinc intake (<15% prevalence). Based on this sub-group analysis, we found no evidence of supplementary zinc intake had any effect on incidence of new Covid-19 compatible illness after high-risk exposure.”
Although the numbers were relatively small, people who self-reported taking zinc or vitamin C were no less likely to get COVID-19 while on hydroxychloroquine. Azithromycin was excluded because of concerns that combining hydroxychloroquine and azithromycin could increase the risk for serious heart rhythm abnormalities.
The People’s Pharmacy Perspective:
Like many of our readers, we are disappointed that the latest results were not promising. We really were hoping that HCQ would be highly effective at preventing infection with SARS-CoV-2. That would have been very good news for health workers and family members of COVID-19 patients.
Although this was the first randomized controlled trial of HCQ, it will not be the last. The study had limitations. There were not enough diagnostic tests available during the trial to really measure everyone who participated. It was an Internet-based study. The researchers had to rely upon participant reports. Nevertheless, it was the first RCT and it did provide some important additional data to previously published observational studies.
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One final note. Our syndicated public radio program this Saturday deals with cytokine storm. Our guest is Dr. David Fajgenbaum. He almost died five times because of cytokine storms brought on by a rare condition called Castleman disease. His book is Chasing My Cure. He discusses what he has learned and why it might be very important for treating COVID-19. We think you will find the program quite compelling. You can download the free mp3 file or stream the audio starting on Monday.
