COVID-19: Snake Oils and (Maybe) Cures

Clearly people have been desperate for cures and hope for the past year plus. There are a bunch of doctors and media outlets providing misinformation on treatments and cures. Whether their motivations are greed, self-aggrandizement, or jumping a news cycle for publicity, the results of misinformation can be both expensive and deadly. This article describes what helps, what hurts,  what used to work – but virus variants have escaped, and what may be coming. The details have been moved to the bottom of the article, with hyperlinks to them provided in the intro. Science isn’t done with COVID-19, but here’s where we stand at present.  Plus, there’s a cute hamster in the story!…

This update summarizes progress with therapies to treat people infected with the SARS-2 virus, focusing mainly on results from larger studies and clinical trials that have been published over the last six months or so. This is a huge topic, and new announcements are coming out daily. Here are the areas I’ll try to cover at this moment in medical science:

1. Summary (for those of you who are of the tl;dr persuasion)

2. FDA’s current list of EUAs for COVID treatments

3. Where we were a year ago: HCQ, dexamethasone, CCP, ivermectin

4. Good things that don’t appear to make much difference: zinc, vitamins C and D

5. Bad things that really don’t work, are illegal, and may be harmful

6. A look at the COVID drug pipeline – The NIH’s ACTIV initiative

7. The return of the Syrian golden hamsters: testing an oral anti-viral drug

8. What the future holds

1. Summary

A number of COVID therapies that were given attention in the early months of the pandemic (and continue to be hyped on social media) have not demonstrated statistical efficacy when put through rigorous trials. This list includes: chloroquine, hydroxychloroquine (HCQ) with and w/o azithromycin; ivermectin; zinc, vitamin C, or combo (high dose); and vitamin D (high dose). If you have a personal story about how a loved one or friend was saved by one of these treatments, I am very happy for that outcome. In this update, though, I’m going to present results from studies and clinical trials, where the statistical evidence is against the efficacy of these therapies.

Based on the history of convalescent plasma in treating other diseases, early expectations were high for COVID convalescent plasma (CCP), and it was granted emergency use authorization (EUA) by the FDA last September. But additional trials have shown that administration at low titers, and/or treatment of patients with severe COVID are not effective. So, the FDA revised the EUA in February, 2021, to grant more restricted use: high titer infusions administered early in the disease course, as they “may be effective, pending results of further RCTs [randomized clinical trials]”).

The evidence has been more positive for a few other treatments. The anti-viral remdesivir (Gilead’s Veklury) remains a standard of care for hospitalized COVID patients, along with dexamethasone – if started only when patients begin to require supplemental oxygen, or breathing aids. Also, patients who are treated early, before they develop severe COVID and require hospitalization have responded well to outpatient infusions of experimental monoclonal antibodies (mAb). The FDA has granted EUA for three of these: bamlanivimab; casirivimab + imdevimab (combo); and bamlanivimab + etesevimab (combo). But the news about mAb drugs is rapidly evolving. The EUA for bamlanivimab administered by itself was revoked on 16 Apr 2021, due to concerns about reduced efficacy against viral variants of concern.

There are many other therapies in the human clinical trial (CT) pipeline. For some of these, preliminary results are promising, if not yet fully reported. Yet others have shown very good results from animal studies, and are just now entering human CTs. Many of the accelerated CTs are being conducted under the auspices of an NIH-funded initiative known as ACVIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines.) ACTIV is a “public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies.” See: Dr. Francis Collins, “ACTIV Update: Making Major Strides in COVID-19 Therapeutic Development.” NIH Director’s Blog, 16 Feb 2021.

2. FDA’s current list of EUAs for COVID treatments

At this time, the FDA has granted full approval to just one therapy, remdesivir (Gilead’s Veklury). Emergency use authorization has been granted to an additional four treatments, counting convalescent plasma. The FDA maintains the current list of therapies with EUA here:

https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs

The list:

1. Remdesivir (Gilead’s Veklury) for use in hospitalized adult and pediatric patients age 12 and older. recommended for use in patients who require supplemental oxygen. However, it is not routinely recommended for patients who require mechanical ventilation due to the lack of data showing benefit at this advanced stage of the disease. (EUA on 05/01/2020; fully approved on 11/22/2020).

2. Baricitinib (Eli Lilly’s Olumiant), an anti-inflammatory, used in combination with remdesivir. (EUA on 11/19/2020).

3. Casirivimab and imdevimab (Regeneron’s REGEN-COV two mAb cocktail) for treatment of mild to moderate COVID-19 in adults and pediatric patients age 12 and older (EUA on 11/21/2020. Extended on 02/25/2021).

4. Bamlanivimab and etesevimab (Eli Lilly’s two mAb cocktail). (EUA on 02/09/2021).

Revised or revoked:

5. COVID convalescent plasma (CCP). (EUA on 08/23/2020. Revised on 03/09/2021 to exclude low titer CCP infusions because ineffective; but continue EUA for high titer infusions administered early in disease course, as they “may be effective, pending results of further RCTs”).

6. Bamlanivimab (Eli Lilly’s LY-CoV555 mAb). (EUA 11/09/2020. But EUA Revoked on 04/16/2021, as “risk-benefit assessment for using bamlanivimab alone is no longer favorable due to the increased frequency of resistant variants.”)

Relevant FDA News Releases:

“FDA Approves First Treatment for COVID-19.” FDA, 22 Oct 2020.

FDA letter extending EUA for Regeneron’s casirivimab and imdevimab, 25 Feb 2021.

Based on review of the analysis of phase 1 and 2 data from the ongoing trial R10933-10987-COV-2067 (NCT04425629), a phase 1/2/3, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of casirivimab and imdevimab 2400 mg IV or casirivimab and imdevimab 8000 mg IV or placebo in outpatients (non-hospitalized) with SARS-CoV-2 infection, it is reasonable to believe that REGEN-COV may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when used under the conditions described in this authorization, the known and potential benefits of REGEN-COV outweigh the known and potential risks of such product.

“FDA Revokes Emergency Use Authorization for Monoclonal Antibody Bamlanivimab.” FDA News Release, 16 Apr 2021.

“risk-benefit assessment for using bamlanivimab alone is no longer favorable due to the increased frequency of resistant variants.“

FDA letter granting EUA for Lilly’s bamlanivimab+ etesevimab, on 25 Feb 2020.

Revised EUA for COVID convalescent plasma (CCP), on 9 Mar 2021.

[When CCP was granted EUA on 23 Aug 2020] the totality of the scientific evidence supported a determination that the use of CCP in hospitalized patients with COVID-19 met the “may be effective” standard for issuance of an EUA. Following the EUA, emerging evidence from randomized controlled trials . . . indicates that 1) the use of low titer CCP in hospitalized patients no longer meets the evidentiary standard of “may be effective”, and 2) high titer CCP has not demonstrated benefit when administered late in the disease course in immunocompetent hospitalized patients. Additional data from RCTs and observational studies support a determination that high titer CCP may be effective when administered early in the course of illness, particularly prior to the expected time of host antibody response. In patients with impaired humoral immunity, the potential therapeutic window may be prolonged.

Recommendation: The conditions of Emergency Use Authorization for CCP for the treatment of hospitalized patients with COVID-19 should be revised to exclude the use of low titer CCP. High titer CCP continues to meet criteria for Emergency Use Authorization for the treatment of hospitalized patients with COVID-19 early in the course of hospitalization.

3. Where we were a year ago: HCQ, dexamethasone, CCP, ivermectin

Doctors who were desperate to save their sick COVID patients tried many different existing drugs to see if anything would help. Usually there was a plausible theory for why a drug might work. Observational results were published as preprints and even in peer reviewed journals, describing moderate successes with small numbers of patients, verging on the anecdotal.

Hydroxychloroquine (HCQ)

Some of the early papers on treatments with hydroxychloroquine (HCQ), with and without azithromycin are in this category. For example, this small French study of 20 hospital patients, which reported a significantly reduced viral load measured by nasopharyngeal swabs – after six days of a daily dose of 600mg of HCQ:

Philippe Gautret, et al, “Hydroxychloroquine /azithromycin for COVID-19: New Clinical Trial Results.” Physician’s Weekly, 30 Mar 2020.

This study was subsequently updated and published here: “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.” International Journal of Antimicrobial Agents, July 2020.

However, other trials ensued, and conclusions from those were that HCQ and chloroquine were unlikely to be effective in treating or preventing COVID-19. This led the FDA to revoke EUA for these drugs as a treatment for COVID, on 15 Jun 2020. See: “Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine.” FDA News Release, 15 Jun 2020.

The current NIH treatment guidelines for COVID recommend against the use of HCQ, in both hospitalized and non-hospitalized patients. See: “Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19.” Last Updated 11 Feb 2021.

Here are the recommendations from the NIH’s COVID-19 Treatment Guidelines Panel on that linked page:

– The Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients.

– In non-hospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial.

– The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19.

The results of some of the negative trials for HCQ did not find their way into peer reviewed publications until later. For example: Wesley H. Self, et al, “Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19A Randomized Clinical Trial.” JAMA, 1 Dec 2020.

This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.

In other words, the accumulated statistical evidence already overwhelmingly indicated no meaningful difference between outcomes when treated with HCQ vs placebo. Here are the statistics (Note the range of disease severity on admission to the study: almost 47% of patients on supplemental oxygen; and 20% in ICU on vent):

Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09])

On top of that, studies have reported significant numbers of adverse drug reactions from HCQ. For example: Perez et al, “Reported adverse drug reactions associated with the use of hydroxychloroquine and chloroquine during the COVID-19 pandemic.” Annals of Internal Medicine, 26 Jan 2021.

Dexamethasone

On the plus side, we have seen good results from dexamethasone, a well-established steroid that has been in clinical use since the 1960s for treatment of inflammatory and immune disorders such as rheumatoid arthritis and bronchospasm. Dexamethasone was demonstrated early on in the pandemic to have value in saving hospitalized COVID patients who had progressed to the need for supplemental oxygen and/or vent assisted breathing. See: Peter Horby, Martin J. Landray, et al, “Dexamethasone in Hospitalized Patients with COVID-19.” NEJM, 25 Feb 2021.

Here are two lay articles that discuss Horby’s RECOVERY trials with dexamethasone:

Kai Kupferschmidt, “One U.K. trial is transforming COVID-19 treatment. Why haven’t others delivered more results?” Science Mag, 2 Jul 2020.

Matthew Herper, “Major study finds common steroid reduces deaths among patients with severe Covid-19.” statnews, 16 Jun 2020.

From Herper’s article:

The study randomly assigned 2,104 patients to receive six milligrams of dexamethasone once a day, by mouth or intravenous injection. These were compared to 4,321 patients assigned to receive usual care alone. In patients who needed to be on a ventilator, dexamethasone reduced the death rate by 35%, meaning that doctors would prevent one death by treating eight ventilated patients. In those who needed oxygen but were not ventilated, the death rate was reduced 20%, meaning doctors would need to treat 25 patients to save one life. Both results were statistically significant.

There was no benefit in patients who didn’t require any oxygen. The researchers running the study, called RECOVERY, decided to stop enrolling patients on dexamethasone on June 8 [2020] because they believed they had enough data to get a clear result.

Convalescent plasma (CCP)

The case for efficacy of convalescent plasma is mixed. One study, published in the New England Journal of Medicine, found that elderly patients (age 65-74) who were treated with high IgG titers of CCP within 72 hours of onset of mild COVID symptoms were 48% less likely to progress to severe COVID, compared to patients who received placebo. See: Romina Libster, et al, “Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.” NEJM, 6 Jan 2021.

The study was a well-designed randomized, double-blind, placebo-controlled trial, but small, enrolling 160 patients across two arms. From the NEJM paper:

In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%.

Counterbalancing this study is a meta-analysis of four peer-reviewed clinical trials, which showed less promising results. See: Perrine Janiaud, et al, “Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19. A Systematic Review and Meta-analysis.” JAMA, 26 Feb 2021.

From the JAMA paper:

In a meta-analysis of 4 peer-reviewed and published randomized clinical trials including 1060 patients with COVID-19 treated with convalescent plasma vs control, the risk ratio for mortality was 0.93 and after the addition of 6 unpublished randomized clinical trials and 10 722 patients, the risk ratio for mortality was 1.02; neither finding was statistically significant.

In other words, treatment with CCP in these four trials did not significantly reduce risk of death, length of stay in the hospital, or need for mechanical ventilation, compared to outcomes for those given placebo and standard treatment. The authors do point out that the studies included in their analysis were small scale, and that future larger trials might demonstrate greater benefits:
The primary focus of this meta-analysis was on published RCTs. There are many ongoing trials (>100) assessing convalescent plasma that are at risk of being terminated early or never published, but a collaborative meta-analysis of all these data is underway.

There is a good summary of the situation with CCP written by Louis M. Katz, MD, in a companion editorial in NEJM: “(A Little) Clarity on Convalescent Plasma for Covid-19.” NEJM, 13 Jan 2021.

Dr. Katz writes,

The Food and Drug Administration (FDA) argued that a “totality of the evidence” suggested that the benefits of convalescent plasma would outweigh its risks, and given the lack of effective treatments, the FDA granted an Emergency Use Authorization (EUA) and provided guidance on the manufacture and use of convalescent plasma in hospitalized patients with signs of progressive infection. By contrast, a National Institutes of Health guidelines panel stated that “the data are insufficient to recommend for or against” the use of convalescent plasma. The Infectious Diseases Society of America and the AABB (formerly known as the American Association of Blood Banks) recommend that the use of convalescent plasma be limited to clinical trials, that critically ill patients and those in the intensive care unit (ICU) are unlikely to benefit from transfusions of convalescent plasma, and that convalescent plasma should be used as early as possible in the course of infection (preferably within 3 days after diagnosis) in order to achieve the best outcomes.

Ivermectin

Ivermectin was discovered in 1975, and has a good history of use in the treatment of various tropical diseases. It is FDA approved for treatment of a number of human parasites, including head lice, scabies, onchocerciasis (river blindness), and helminthiases. It is also used to prevent and treat heartworm and mite infections in animals. Merck, who currently manufactures ivermectin under the brand name Stromectol, has placed a disclaimer statement on their website: “Merck Statement on Ivermectin use During the COVID-19 Pandemic.”

It reads:

Company scientists continue to carefully examine the findings of all available and emerging studies of ivermectin for the treatment of COVID-19 for evidence of efficacy and safety. It is important to note that, to-date, our analysis has identified:

– No scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical studies;

– No meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease, and;

– A concerning lack of safety data in the majority of studies.

We do not believe that the data available support the safety and efficacy of ivermectin beyond the doses and populations indicated in the regulatory agency-approved prescribing information.

Despite this, there is a great amount of misinformation circulating on social media, claiming that ivermectin can successfully treat and even prevent COVID. A possible basis for these rumors may be some in vitro studies where ivermectin has demonstrated anti-viral properties against certain RNA viruses. But the problem is that the doses required to kill the virus in a test tube are well above deadly toxic levels in humans.

Currently, ivermectin is not approved for anti-viral use by the FDA. Moreover, the NIH has posted Treatment Guidelines for ivermectin here:

The NIH recommendation says,

Ivermectin is thought to be a host-directed agent, which may be the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever. Despite this in vitro activity, no clinical trials have reported a clinical benefit for ivermectin in patients with these viruses. Some studies of ivermectin have also reported potential anti-inflammatory properties, which have been postulated to be beneficial in people with COVID-19.

Recommendation: There are insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

As of 26 May 2021, the website clinicaltrials.gov shows at least 35 clinical trials of ivermectin in connection with COVID that are actively enrolling subjects. Some earlier studies have been completed, including this one: Eduardo López-Medina, et al, “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.” JAMA, 4 Mar 2021.

This was a double blind study done with 476 adults in Cali, Colombia, randomly selected from the state’s DPH database, but only patients with mild symptoms lasting under a week were enrolled, with a mix of outpatient and hospitalized cases. Those requiring oxygen were not eligible. Patients received a five-day course of either ivermectin (300 micrograms per kg of body weight), or placebo.

The primary outcome researchers were interested in was resolution of symptoms within 21 days. From the study findings:
The duration of symptoms was not significantly different for patients who received a 5-day course of ivermectin compared with placebo (median time to resolution of symptoms, 10 vs 12 days; hazard ratio for resolution of symptoms, 1.07).

Results: Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).

Conclusion and Relevance: Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

According to Wikipedia, the following:

Despite the absence of high-quality evidence to suggest any efficacy, use of ivermectin for prevention or treatment of early-stage COVID-19 has become increasingly widespread especially in Latin America, raising concerns about self-medication, safety, and the feasibility of future clinical trials. In response, the Brazilian Health Regulatory Agency, Brazilian Society of Infectious Diseases, and Brazilian Thoracic Society all issued position statements in January 2021 advising against the use of ivermectin for this purpose. Furthermore, the government of Peru rescinded a previous recommendation for the use of ivermectin (alongside azithromycin and hydroxychloroquine) in hospitalized patients, although as of January 2021 it is still prescribed for outpatient use.

In March 2021, both the FDA and the European Medicines Agency (EMA) issued guidance that ivermectin should not be used to treat or prevent COVID-19. After reviewing the evidence on ivermectin the EMA said that “the available data do not support its use for COVID-19 outside well-designed clinical trials”. Ivermectin is not authorized for use to treat COVID-19 within the European Union. In the United Kingdom the national COVID-19 Therapeutics Advisory Panel determined that the evidence base and plausibility of ivermectin as a COVID-19 treatment were insufficient to pursue further investigations. The WHO say that ivermectin should not be used to treat COVID-19 except in a clinical trial.

4. Good things that don’t appear to make much difference: zinc, vitamins C and D

I’m not a doctor, but here’s my takeaway from the studies I’ve read on these treatments. It may be a good idea to keep yourself topped up with daily doses of zinc, vitamin C and vitamin D at absorbable levels. But it is likely to be futile to try to play catch-up and defeat the virus with high doses of these supplements once you start to have COVID symptoms. And then there are the asymptomatic infections.

Vitamin D (high dose)

It is well known that people with low vitamin D levels can be more susceptible to upper respiratory tract infections. Indirect evidence suggests that vitamin D might help protect against a SARS-2 infection, or at least reduce the chance of developing serious COVID. A meta-analysis done in 2017 found that people who took vitamin D supplements, particularly those who had low vitamin D levels, were less likely to develop acute respiratory tract infections than those who didn’t. See: Adrian R Martineau, et al., “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.” BMJ, 15 Feb 2017.

From the study:
Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L [i.e. vitamin D deficient at outset] (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.

The above study offered indirect evidence and early encouragement that Vitamin D might protect against COVID-19 in two ways. First, it might boost the body’s natural defense against viruses and bacteria. Second, it could help prevent the exaggerated inflammatory response commonly seen in COVID. That said, efforts to treat sick COVID patients with a single high dose of vitamin D have not demonstrated efficacy. See: Igor Murai, et al., “Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19. A Randomized Clinical Trial.” JAMA, 17 Feb 2021.

From the paper:
This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020.

CONCLUSIONS AND RELEVANCE: Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19.

Zinc+vitamin C

High doses of zinc and vitamin C have long been recommended as a treatment for the common cold (caused by coronaviruses), so it’s natural to hope that such a regimen might be effective against SARS-2. A recent study published in JAMA sought to investigate this with a trial conducted with 214 patients in a single health care system with outpatient centers in Florida and Ohio. See: Suma Thomas, et al, “Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection. The COVID A to Z Randomized Clinical Trial.” JAMA, 21 Feb 2021.

Trial participants were 45 years old, on average, and all had confirmed positive PCR tests, but generally did not have severe symptoms of COVID, so were treated on an outpatient basis. Patients were randomly assigned to one of four arms, in which they were treated for 10 days with a daily dose of either: zinc (50mg); Vitamin C (8,000mg); both zinc and vitamin C; or placebo plus standard of care.

From the paper:
The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.

The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups.

On casual inspection, these differences in time to reduce symptoms by 50% might seem significant; but the P score of 0.45 is an indication that the confidence intervals for the observed recover times were overlapping, meaning that the time estimates are not statistically different between groups. Moreover, the researchers stopped recruiting additional patients and halted the study prematurely, when it became obvious from early results that it was statistically improbable that a benefit would emerge for any of the three treatments, from observing more patient outcomes.

5. Bad things that really don’t work, are illegal, and may be harmful

The FDA maintains a web page with a long list of fraudulent treatments and supplements that have been investigated and condemned as illegal, with warning letters issued to the businesses that sell them. See: “Fraudulent Coronavirus Disease 2019 (COVID-19) Products.”

You can find these products hyped on FB and other social media, where readers are directed to e-commerce websites. The FDA list goes on for pages. If you don’t see your favorite faux treatment, you can be a whistle blower, here: “Reporting Unlawful Sales of Medical Products on the Internet.”

For fun, I’ll just give the most recent example from the top of the list. It seems that a “Dr. Marc” at Trinity Natural Health & Pain Management, Inc., in Miami, has been illegally selling a product called “COVID-19 Formula.” The FDA’s warning letter to Dr. Marc, dated 13 Apr 2021, says:

The FDA has observed that your website offers “COVID-19 Formula” for sale in the United States and that this product is intended to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. Based on our review, this product is an unapproved new drug sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. § 355(a). Furthermore, this product is a misbranded drug under section 502 of the FD&C Act, 21 U.S.C. § 352. The introduction or delivery for introduction of this product into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. § 331(a) and (d).

This would be funny, except that so many people, particularly the elderly, are falling for this Snake Oil every day.

6. A look at the COVID drug pipeline – The NIH’s ACTIV initiative

NIH Director Francis Collins does a nice job of summarizing the purpose and scope of the NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative. ACTIV is a public-private partnership that was launched in April, 2020, with participation from 20 biopharmaceutical companies, numerous academic experts, and multiple federal agencies. See: “ACTIV Update: Making Major Strides in COVID-19 Therapeutic Development. NIH Director’s Blog“, 16 Feb 2021.

Dr, Collins explains:
ACTIV was founded to accelerate drug research that typically requires more than a decade of clinical ups and downs to develop a safe, effective therapy. Cutting through the usual red tape and working with an intense sense of purpose, the partnership took a mere matter of weeks to set up its first four clinical trials. Beyond the agents mentioned above that have already been granted an EUA, ACTIV is testing 15 additional potential agents, with several of these already demonstrating promising results.

Here is Dr. Collins’ summary of the program so far. Clinical trials for candidate drugs are grouped into the following categories:

ACTIV-1: A large-scale Phase 3 trial is enrolling hospitalized adults to test the safety and effectiveness of three medicines (cenicriviroc, abatacept, and infliximab). They are called immune modulators because they help to minimize the effects of an overactive immune response in some COVID-19 patients. This response, called a “cytokine storm,” can lead to acute respiratory distress syndrome, multiple organ failure, and other life-threatening complications.

ACTIV-2: A Phase 2/3 trial is enrolling adults with COVID-19 who are not hospitalized to evaluate the safety of multiple monoclonal antibodies (Lilly’s LY-CoV555, Brii Biosciences’s BRII-196 and BRII-198, and AstraZeneca’s AZD7442) used to block or neutralize the SARS-CoV-2 virus. The Lilly monoclonal antibody LY-CoV555 received an EUA for high risk non-hospitalized patients on November 9, 2020 and ACTIV-2 continued to test the agent in an open label study to further determine safety and efficacy in outpatients. Another arm of this trial has just started, testing inhaled, easy-to-administer interferon beta-1a treatment in adults with mild-to-moderate COVID-19 who are not hospitalized. An additional arm will test the drug camostat mesilate, a protease inhibitor that can block the TMPRSS2 host protein that is necessary for viral entry into human cells.

ACTIV-3: This Phase 3 trial is enrolling hospitalized adults with COVID-19. This study primarily aims to evaluate safety and to understand if monoclonal antibodies (AstraZeneca’s AZD7442, BRII-196 and BRII-198, and the VIR-7831 from GSK/Vir Biotechnology) and potentially other types of therapeutics can reduce time to recovery. It also aims to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Lilly’s monoclonal antibody LY-CoV555 [aka bamlanivimab] was one of the first agents to be tested in this clinical trial and it was determined to not show the same benefits seen in outpatients. [This resulted in bamlanivimab being taken off the FDA’s list of authorized therapies, administered by itself.]

ACTIV-4: This trial aims to determine if various types of blood thinners, including apixaban, aspirin, and both unfractionated (UF) and low molecular weight (LMW) heparin, can treat adults diagnosed with COVID-19 and prevent life-threatening blood clots from forming. There are actually three Phase 3 trials included in ACTIV-4. One is enrolling people diagnosed with COVID-19 but who are not hospitalized; a second is enrolling patients who are hospitalized; and a third is enrolling people who are recovering from COVID-19. ACTIV-4 has already shown that full doses of heparin blood thinners are safe and effective for moderately ill hospitalized patients.

ACTIV-5: This is a Phase 2 trial testing newly identified agents that might have a major benefit to hospitalized patients with COVID-19, but that need further “proof of concept” testing before they move into a registrational Phase 3 trial. (In fact, another name for this trial is the “Big Effect Trial”.) It is testing medicines previously developed for other conditions that might be beneficial in treatment of COVID-19. The first two agents being tested are risankizumab (the result of a collaboration between Boehringer-Ingelheim), which is already FDA-approved to treat plaque psoriasis, and lenzilumab, which is under development by Humanigen to treat patients experiencing cytokine storm as part of cancer therapy.

In addition to trials conducted under the ACTIV partnership, NIH has prioritized and tested other therapeutics in “ACTIV-associated trials.” These are NIH-funded, randomized, placebo-controlled clinical trials with one or more industry partners.

If you want to geek out on even more ACTIV details, go here: “COVID-19 Therapeutics Prioritized for Testing in Clinical Trials.”

Since Dr. Collins’ Feb Blog posting, I have seen two announcements about additional drugs being added to ACTIV trials, but things are happening so fast that I may have missed others.

One candidate I know has been added to the ACTIV-2 trials: a polyclonal antibody developed by SAB Biotherapeutics, called SAB-185. This therapy is explained here: “Large NIH clinical trial will test polyclonal antibody therapeutic for COVID-19.” NIH News Release, 21 Apr 2021.

From the release:

A Phase 2/3 trial to evaluate a new fully-human polyclonal antibody therapeutic targeted to SARS-CoV-2, called SAB-185, has begun enrolling non-hospitalized people with mild or moderate cases of COVID-19. SAB-185 is a fully-human polyclonal antibody therapeutic candidate for COVID-19 that has completed enrollment of Phase 1 and Phase 1b clinical studies. In previous pre-clinical studies, SAB-185 demonstrated neutralization of live SARS-CoV-2 at titers higher than convalescent plasma.

The second announcement I saw is an addition to the ACTIV-3 trials, described here: “Clinical trial of therapeutics for severely ill hospitalized COVID-19 patients begins.” NIH News Release, 22 Apr 2021.

ACTIV-3 will begin by testing Zyesami, a formulation of aviptadil acetate, produced by NeuroRx, Wilmington, Delaware, and the antiviral remdesivir (Veklury), developed by Gilead, Foster City, California. Aviptadil is a synthetic version of Vasoactive Intestinal Peptide or VIP, which is made naturally in the human body and appears to have lung-protective antiviral and anti-inflammatory effects. Administered intravenously, it may provide additional protection for lung cells commonly targeted by SARS-CoV-2, the virus that causes COVID-19. It is licensed in the United States for treating hospitalized patients with COVID-19. However, its benefit in patients with more severe COVID-19 is unclear. The trial will test Zyesami and remdesivir (alone and in combination), for their safety and efficacy in hospitalized COVID-19 patients who are experiencing Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition in which the lungs are severely inflamed and may be unable to maintain sufficient oxygen in the blood.

7. The return of the Syrian golden hamsters: testing an oral anti-viral drug

This brings me to the Syrian hamsters, who have been very busy helping humans to defeat SARS-2. Since I last wrote about them in the Hong Kong hamster masking experiments in Update 69 (15 Jul 2020), they have participated in a wide range of other studies. For a good survey article with lots of links that show their versatility, see: Regina Kelder, Steve Festin, “Syrian Hamster’s Starring Role in COVID-19 Research.” criver.com, 20 Oct 2020.

Last year, hamsters were testing anti-viral drugs for us, to see if they were safe and effective enough to warrant human trials. For example, hamsters helped to establish efficacy for Regeneron’s 2-mAb anti-viral drug cocktail, REGEN-COV (casirivimab + imdevimab). See: Alina Baum, et al, “REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters.” Pubmed.gov, 27 Nov 2020.

More recently, the hamsters were recruited to test an oral anti-viral drug originally developed to treat influenza and hepatitis C. This drug, initially known as MK-4482, was developed by Emory University’s Drug Innovation Ventures group with funding from NIAID. The rights were acquired by Ridgeback Biotherapeutics, and the drug was for a time called EIDD-2801. Most recently, Ridgeback has partnered with Merck to jointly develop and evaluate EIDD-2801 with additional human clinical trials. If successful, it will be brought to market with the brand name Molnupiravir. The very encouraging hamster tests are described in two NIH news releases:

“Experimental antiviral for COVID-19 effective in hamster study.” NIH News Release, 16 Apr 2021.

And:

“Oral antiviral drug effective against COVID-19 in hamsters.” NIH News, 27 Apr 2021.

8. What the future holds
In addition to the NIH-funded trials in the ACTIV program, there are any number of drugs and therapies being developed and tested by private companies with their own R&D funding. One example of this is the oral anti-viral drug known variously as MK-4482 or EIDD-2801.

For that, let’s return to Dr. Francis Collins’ blog from 16 Feb 2021. He wrote:
Looking a bit further down the road . . . One goal would be to develop an antiviral medication for SARS-CoV-2 that acts similarly to oseltamivir phosphate (Tamiflu®), a drug used to shorten the course of the flu in people who’ve had symptoms for less than two days and to prevent the flu in asymptomatic people who may have been exposed to the influenza virus. Yet another major long-term effort of NIH and its partners will be to develop safe and effective antiviral medications that work against all coronaviruses, even those with variant genomes. (And, yes, such drugs might even cure the common cold!)

So, while our ACTIV partners and many other researchers around the globe continue to harness the power of science to end the devastating COVID-19 pandemic as soon as possible, we must also consider the lessons learned this past year, in order to prepare ourselves to respond more swiftly to future outbreaks of coronaviruses and other infectious disease threats. Our work is clearly a marathon, not a sprint.

Sorry for the length. I hope you found at least some items of interest.

Stay safe,

BGL