On April 29, the NIH's National Institute of Allergy and Infectious Disease (NIAID), headed by Dr. Anthony Fauci, announced promising preliminary results of its clinical trial testing the effect of remdesivir in COVID-19 patients. The study has not been released even as a preprint.* Fauci told the press that he chose to speak about the data early because he was concerned that leaks of partial information could lead to confusion.
Please note that I am not a doctor and nothing herein is medical advice. I have a more detailed disclaimer at the bottom.
The NIAID Press Release and Rapid FDA Emergency Approval
Remdesivir was studied for intravenous use in ebola, but never approved because antibody therapies were more effective, and up until now had yet to be approved for anything. On May 1, shortly following the NIAID statement about the data, in response to the request of the drug's manufacturer, Gilead, the FDA approved emergency use of intravenous remdesivir for hospitalized COVID-19 patients.
The NIAID statement says very little about the data. An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27 to review the data and found the drug caused a 31% faster recovery time, with a median recovery time of 11 days in the remdesivir group and 15 days in the placebo group. The p value was 0.001, meaning there was a 0.1% chance that randomness could have caused that result. There was also a suggestive benefit for mortality, with a mortality rate of 8% in the remdesivir group and 11.6% in the placebo group. The p value was 0.059, meaning there was a 5.9% chance that randomness could have caused that result. By conventional standards, this is considered too weak to say it was not a result of chance, and is said to not be statistically significant.
The Lancet Study
The very same day of the NIAID statement, The Lancet published a fully peer-reviewed and final study suggesting remdesivir has little if any benefit. There was no difference in mortality, clinical improvement, or viral load of the upper or lower respiratory tracts at any time point.
The Lancet study was overseen by the World Health Organization, and an early version of the paper had been leaked or accidentally published on the WHO website over a week before it was published. In a Financial Times article following the leak, Gilead blamed the lack of results on low enrollment and poor statistical power.
Comparing and Contrasting the NIAID and Lancet Studies
Indeed, the Lancet study only had 237 subjects, whereas the NIAID study had 1063 subjects.
There are hints in the Lancet data suggesting that this underpowering was hiding a benefit to those who received the drug early on and a possible harm to those who received it late.
For example, while none of the mortality comparisons were statistically significant, 28-day mortality was 36% higher in the placebo group among those treated within the first ten days of symptom onset, but was 40% higher in the treatment group among those beginning treatment after ten days of symptom onset. The poor statistical power could be hiding opposite effects on mortality depending on when the drug is administered.
Patients experienced clinical improvement in a median of 23 days in the placebo group, regardless of when they started the placebo. In the remdesivir group, this number was 21 days for everyone but only 18 days in those who started the drug within the first ten days of symptoms. None of these differences were statistically significant.
Notably, the NIAID study is reporting significantly shorter times to clinical improvement (11 days for remdesivir, 15 days for placebo) than the Lancet study (18-21 days for remdesivir, 23 days for placebo).
The doses and protocols in the two studies were the same.
Perhaps the NIAID study effectively caught its subjects earlier in the course of the disease, and thereby achieved a greater effect.
Or, the difference could be a result of different definitions of clinical improvement:
- In the NIAID trial, this meant one of three things: still hospitalized, but no longer requiring supplemental oxygen or ongoing medical care; discharge from the hospital, but with limitations on activities or requiring home oxygen; no longer having limitations on activities or requiring home oxygen.
- In the Lancet study, this meant either discharge from the hospital or having at least a two-point reduction on the following scale: death, 6 points; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation, 5 points; hospital admission for non-invasive ventilation or high-flow oxygen therapy, 4 points; hospital admission for less invasive oxygen therapy, 3 points; hospital admission without oxygen therapy, 2 points; having been discharged or reached discharge criteria (relief from fever, normalized breathing rate and blood oxygen, and relief of cough, all maintained for 72 hours).
We shouldn't come to conclusions about the NIAID definitions until the paper is published, since it may include more detail. However, it seems that the Lancet patients must have had more severe cases. To count as improved, they had to move two points along a scale where 5 of the six points referred to inpatient treatment and none of the points ventured into home treatments. Two out of the three categories on the NIAID scale, by contrast, are for patients who are not hospitalized, and define their treatment at home. The NIAID patients moved along this less severe scale more quickly than the Lancet patients moved along their more severe scale.
Both Benefit and Harm Remain Unclear
If the smaller number of patients in the Lancet study is only hiding a weaker effect of remdesivir on time to clinical improvement in the patients given the drug too late, jumping to conclusions doesn't seem that dangerous. But what if the small number is also hiding the fact that remdesivir increases mortality when given late to the same degree it decreases mortality when given early?
In clinical practice, whether remdesivir gets the more hopeful results of the NIAID press release or the more lackluster and potentially harmful results of the Lancet paper might depend on whether it's given early or late in the course of disease, how severe the cases are, or the precise definition of improvement. If its benefit is so contextual and it remains unclear whether it increases mortality when given late in the course of a severe disease, it seems hard to weigh whether it will do more good than harm in practice.
Is Remdesivir a Reproductive Toxin?
Although COVID-19 mortality is highest in older men who are less likely to be reproductively active (though obviously not altogether inactive), the remdesivir trials were only limited to patients over the age of 18, and the FDA approval does not refer to the patient's age. Therefore, whether remdesivir is a reproductive toxin is of concern.
On April 23, Chinese researchers released a preprint of a paper investigating the drug's reproductive toxicity in male mice.
The remdesivir protocol used for COVID-19 is 200 milligrams infused intravenously on the first day and 100 miligrams per day thereafter, for a total of ten days. For the standard 70-kilogram reference man, this is 2.8 milligrams per kilogram bodyweight on the first day and 1.4 mg/kg thereafter.
The mouse study used 10, 50, and 150 micrograms per day for ten days. These doses are are 0.4, 2, and 6 mg/kg bodyweight. Without any further adjustments, the low dose is several-fold lower than the nine-day maintenance dose given to humans, and the middle dose is 71% of the first-day dose given to humans.
However, standard practice to convert human doses to mouse doses is to multiply the human dose by 12.3. This accounts for differences in body surface area, and works best when the drugs are not metabolized extensively and are eliminated in the urine. It also serves as a default when we lack sufficient data to compare and contrast how the drugs are metabolized between humans and mice.
If we make that adjustment, the appropriate test in mice would be 34.4 mg/kg on the first day and 17.2 mg/kg for the next nine days.
As such, even the high dose the mice were treated with, 6 mg/kg, is less than half the nine-day maintenance dose given to humans.
The low dose had no negative effects.
The middle dose slightly reduced the sperm count, but it wasn't statistically significant. It decreased the number of sperm that moved normally and increased the number of sperm with structural abnormalities, and these were statistically significant. The researchers then looked at the testicular tissues under a microscope and rated them on a ten-point scale where 10 represents normal and healthy sperm production. The middle dose caused slight abnormalities that led to a rating of 8 or 9.
The high dose reduced the total sperm count, reduced the number of motile sperm, increased the number of structurally abnormal sperm, and brought the health of the testicular tissues down to between 5 and 8. Scar tissue was laid down in the testicular tissue, which is called fibrosis. All the quantitative differences were statistically significant.
Overall it appears from the figures that the high dose reduced sperm counts by approximately 40%, decreased the motile sperm by about 35%, increased the abnormal sperm by close to 30%, and led to a 20-50% damage to the integrity of the sperm-producing cells of the testicular tissue.
Since the high dose is less than half the nine-day maintenance dose given to humans and less than one-fifth the first-day dose given to humans when adjusted for body surface area, this study makes it deeply concerning that remdesivir as it is currently being tested is toxic to male fertility.
The current human studies should absolutely be testing sperm count and quality.
The Bottom Line
Remdesivir may help COVID-19 patients get better 2-4 days faster, and may reduce the risk of mortality. However, preliminary data suggests this benefit may be limited to patients given it within the first ten days of symptoms, and possibly limited to patients with less severe cases. Patients given it late, and those with more severe cases, may be less likely to benefit. The Lancet study makes it concerning that it could increase mortality if given late in the course of a severe infection. The mouse study makes it deeply concerning that it could hurt fertility in men of reproductive age. I personally think it should be used with extreme caution. Please, however, as always, discuss any medical treatment with your physician and do not use anything written here as medical advice.
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* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.