Top 10 Most Studied Treatments for COVID-19: A Consumer-oriented Meta-Analysis (updated January 2021)
As of January 2021, there are more than 4,300 studies that have been launched to investigate various treatments for COVID-19. You can review the details of these trials on ClinicalTrials.gov. This is a living article as new ones are being added every day. 
Over the last several weeks, the Critical Care physicians of the FLCCC Alliance conducted a comprehensive review of the rapidly emerging scientific evidence on Ivermectin from studies conducted around the world. (The link to their review is HERE.) This review led the team to develop the I-Mask+ Protocol and to call for its urgent adoption by health authorities — who could subsequently issue immediate guidance for the nation’s prescribing physicians.
“It is true that these rapidly emerging studies demonstrate the power of Ivermectin, are purposed, 40-year-old drug first approved by the World Health Organization (WHO) for treating parasitic infections,” said Dr. Paul Marik, the founder of the FLCCC Alliance, Professor of Medicine and the most highly published Critical Care physician in America.
Appearing as a witness on Dec. 8, 2020, before the Senate Committee on Homeland Security and Governmental Affairs—which held a hearing on “Early Outpatient Treatment: An Essential Part of a COVID-19 Solution”— Dr. Pierre Kory, President of the Frontline COVID-19 Critical Care Alliance (FLCCC), called for the government to swiftly review the already expansive and still rapidly emerging medical evidence on Ivermectin.
3. Antivirals
Convalescent plasma is a century-old treatment technique that has generated encouraging — yet early — results as a COVID-19 treatment.
The treatment requires recovered COVID-19 patients to donate blood that is rich in the antibodies that fight the virus. These are then infused into hospitalized patients with severe disease.
If further studies validate this approach, a critical challenge will be scaling up this treatment to address a pandemic. That requires having widespread and reliable antibody testing as well as the medical workers to collect blood and get plasma to patients in need.
The drug stopped the coronavirus from replicating in test tubes. US physicians are free to write prescriptions for hydroxychloroquine to treat COVID-19, since it is an approved drug. This is called off-label use, and data shows demand has skyrocketed for the pills.
Mesenchymal stem cells are used as immuno-modulators for severe COVID-19 patients and some of the trial projects are launched in combination with other medications such as interleukin (IL) 6 inhibitors e.g. tocilizumab. IL-6 inhibitors have been studied mainly for their potential to calm down the 'cytokine storm' associated with ARDS (acute respiratory distress syndrome), a severe COVID-19 lung complication.
There are more than 70 types of supplements that are being tested for COVID-19. You can review the details of these trials on clinicaltrials.gov. There are more than 120 trials testing the various nutrients and dietary supplements including vitamin D, vitamin C, zinc and melatonin. Vitamin D remains the most tested vitamin followed by vitamin C, for COVID-19.
The lung injury in COVID-19 patients is associated with ROS (reactive oxygen species) released by phagocytes, and thus the use of antioxidants is necessary for the management of COVID-19.
Below, we look at the top 10 most tested categories.
Editor's Note: The mRNA and vector-based therapies are not really very new technologies. MRNA and vector-based therapies have been in use since 2012 to treat patients with cancers, inherited immunodeficiencies, metabolic, eye, neuro-muscular diseases, even hypercholesterolemia.
1. Vaccine
This is the most watched and anticipated category. Technically, vaccine is not considered a treatment but rather a preventive strategy to boost your immune system and reduce the risk of getting COVID-19.
As of January 2021, researchers are currently testing 64 vaccines in clinical trials on humans, and 20 have reached the final stages of testing. The vaccine remains a promising agent for COVID-19 protection, and the published reports of the candidate vaccines showcase some encouraging results.
Major vaccine candidates:
- Pfizer/BioNTech COVID-19 mRNA vaccine - This is the first vaccine to receive WHO validation for emergency use.
- Oxford - AstraZeneca (inactivated vaccine)
- Moderna (mRNA vaccine)
- SinoVac Biotech inactivated vaccine (Beijing-based biopharmaceutical company Sinovac is behind the CoronaVac, an inactivated vaccine).
- CanSino Biologics
- Fasiliti Covax
- Gamaleya Research Institute (inactivated vaccine from Russia)
Related Publications and News:
- The recently authorised Moderna's COVID-19 vaccine was 94% effective in preventing symptomatic COVID-19, according to phase 3 trial results published December 30th, 2020 in the New England Journal of Medicine.
- Two vaccines, from Pfizer/BioNTech and Moderna, have received emergency use authorization from the US Food and Drug Administration (CNN). Both began Phase 3 trials in the US in July and enrolled over 30,000 participants. Both are two dose vaccines and have been shown to have 95% and 94.1% efficacy respectively.
- AstraZeneca began the Phase 3 US trial of its coronavirus vaccine in September. Johnson & Johnson, which is testing a single-dose vaccines, expects efficacy results from its Phase 3 trial by January or February.
- Novavax Announces Initiation of PREVENT-19 Pivotal Phase 3 Efficacy Trial of COVID-19 Vaccine in the United States and Mexico (Novavax). It is the fifth company to launch a large-scale trial of a coronavirus vaccine in the United States.
- Sinopharm, a Chinese state-owned company, is developing two Covid-19 vaccines, which, like Sinovac are also inactivated vaccines that work in a similar way (BBC). Sinopharm announced on 30 December 2020 that phase three trials of the vaccine showed that it was 79% effective - lower than that of Pfizer and Moderna. However, the United Arab Emirates, which approved a Sinopharm vaccine earlier this month, said the vaccine was 86% effective, according to interim results of its phase three trial.
- CoronaVac (SinoVac) had been undergoing phase three trials in Brazil, Indonesia and Turkey. Earlier last week, interim data from a late-stage trial in Turkey showed that the vaccine was 91.25% effective (BBC).
- CanSino Biologics (China), which is reportedly in phase three clinical trials in countries including Saudi Arabia (BBC).
Leading vaccines (New York Times - Updated January 7, 2021) >
2. Ivermectin
As of January 2021, there are 39 on-going trials on Ivermectin registered on ClinicalTrials.gov.
Over the last several weeks, the Critical Care physicians of the FLCCC Alliance conducted a comprehensive review of the rapidly emerging scientific evidence on Ivermectin from studies conducted around the world. (The link to their review is HERE.) This review led the team to develop the I-Mask+ Protocol and to call for its urgent adoption by health authorities — who could subsequently issue immediate guidance for the nation’s prescribing physicians.
“It is true that these rapidly emerging studies demonstrate the power of Ivermectin, are purposed, 40-year-old drug first approved by the World Health Organization (WHO) for treating parasitic infections,” said Dr. Paul Marik, the founder of the FLCCC Alliance, Professor of Medicine and the most highly published Critical Care physician in America.
Related Publications:
- The pre-AndroCoV trial from Brazil reported that early detection of COVID-19 followed by a pharmaceutical approach with different drug combinations (Azithromycin, Hydroxychloroquine, Nitazonide, Ivermectin) yielded irrefutable differences compared to non-treated controls in terms of clinical outcomes, ethically disallowing placebo-control randomized clinical trials in the early stage of COVID-19 due to the marked improvements.
- The ICON study in US, published in Chest, Oct 2020 reported that Ivermectin treatment was associated with lower death rate vs Control (13.3% vs 24.5%) during treatment of COVID-19, especially in patients with severe pulmonary involvement.
- A multi-centre randomised controlled study in Egypt (Elgazzar, Research Square) reported that the death rate was significantly lower in Ivermectin treated patients group (severe patients) vs non-Ivermectin group (2% vs 20%).
- A double-blinded randomised controlled study in Bangladesh (Mahmud et al) reported that the death rate was 0% (0/183) in the Ivermectin arm vs 1.67% (3/180) in the control arm in mild to moderate COVID-19 patients.
- The IDEA (Ivermectin, Dexamethasone, Enoxaparin and Aspirin) study from Argentina reported 1 death out of 167 patients studied. The patient that died was a severe COVID-19 patient that required ventilator support.
Editor's Note: Future evidence will only do two things. Either to prove that the current evidence is wrong or right. If the current science is wrong, doctors would have given an unnecessary treatment to their patients. But what if the science is right?
There are currently more than 200 trials involving various antivirals including lopinavir/ritonavir, remdesivir, favipiravir and umifenovir. This category is the 2nd largest treatment category that are being tested for COVID-19 in the world.
Related publications:
- WHO trial (Solidarity): The interim trial results (NEJM, Dec 2020) reported that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
- Preliminary results from one randomized controlled study from China comparing the drug against standard care found Lopinavir–Ritonavir (Kaletra) did not improve COVID-19 outcomes (NEJM. 2020).
4. Convalescent Plasma
Convalescent plasma is a century-old treatment technique that has generated encouraging — yet early — results as a COVID-19 treatment.
This remains the 3rd most tested treatment in the world for COVID-19 with more than 200 trials as of November 2020.
If further studies validate this approach, a critical challenge will be scaling up this treatment to address a pandemic. That requires having widespread and reliable antibody testing as well as the medical workers to collect blood and get plasma to patients in need.
Related publications:
- Li, JAMA, Jun 2020 - Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days
- The PLACID trial in India (BMJ, Nov 2020) - Convalescent Plasma ineffective against COVID-19
- Simonivich, NEJM, Nov 2020 - No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo (control).
5. Hydroxychloroquine / Chloroquine
We have combined hydroxychloroquine and chloroquine under 1 category. Hydroxychloroquine, a less toxic derivative of Chloroquine is a widely used medication by people with lupus or arthritis. It was first approved in the 1950s. Chloroquine is used to treat and prevent malaria and amebiasis.
Although results have been mixed, some of the major ones have been published as covered below.
- WHO trial (Solidarity): The interim trial results (NEJM, Dec 2020) reported that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
- UK's Recovery Trial (University of Oxford): It concluded that "there is no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19" and the drug has now been pulled from the trial.
- Check out c19study.com for real-time tracking of hydroxychloroquine publications and studies.
- Most of the current trials are using this drug in combination with other treatments for patients with COVID-19 and there are also trials testing it as 'prevention' for high risk individuals.
- The University of Oxford is recruiting 40,000 participants to test the malaria drug as preventive treatment for frontline healthcare workers. Volunteers will receive either hydroxychlorouqine in Europe or chloroquine in Asia and be compared against a placebo arm (link).
- The “Will Hydroxychloroquine Impede or Prevent COVID-19,” or WHIP COVID-19, study is a 3,000-subject look at whether hydroxychloroquine prevents front-line workers from contracting the COVID-19 virus (link).
6. Stem Cell Therapy
Just for 2020 alone, there are already more than 600 publications published on "stem cell and covid19" on the National Library of Medicine (PubMed).
As of November 2020, there are more than 90 studies that have been launched to investigate the benefits of stem cell therapy and COVID-19. You can review the status and details of these trials on Global COVID-19 Trial Tracker.
As of November 2020, there are more than 90 studies that have been launched to investigate the benefits of stem cell therapy and COVID-19. You can review the status and details of these trials on Global COVID-19 Trial Tracker.
Mesoblast is an Austalian regenerative medicine company that is now applying an experimental stem cell treatment called remestemcel-L (a stem cell product based on allogeneic mesenchymal stem cells) to the pandemic.
The company is working with NIH researchers to run a large randomized trial for patients with respiratory distress due to COVID-19. Like other medicines being tested, the treatment is aiming to quiet an overactive immune response in certain patients.
For a more information, check out Can Stem Cell Therapy Help Against the Latest Coronavirus?
7. Azithromycin
Azithromycin is a widely prescribed generic antibiotic. While it's mainly used to fight bacteria, not viruses, there is some research suggesting the drug has antiviral properties.
As of January 2021, there are more than 120 studies that have been launched to investigate the benefits of Azithromycin against COVID-19. You can review the status of these trials on clinicaltrials.gov.
Several trials are testing azithromycin in combination with hydroxychloroquine.
One potential concern is serious heart side effects. Both drugs can cause abnormal changes in the rhythm of the heart. These can be fatal, particularly for susceptible patients who already have heart problems. Many studies are using EKG tests to closely monitors patients receiving this treatment combination.
While QT-prolonging medication use has been associated with increased risk of death, this risk may be smaller than the potential benefit from treatment of COVID-19 for some patients (American College of Cardiology).
Azithromycin is a widely prescribed generic antibiotic. While it's mainly used to fight bacteria, not viruses, there is some research suggesting the drug has antiviral properties.
As of January 2021, there are more than 120 studies that have been launched to investigate the benefits of Azithromycin against COVID-19. You can review the status of these trials on clinicaltrials.gov.
Several trials are testing azithromycin in combination with hydroxychloroquine.
One potential concern is serious heart side effects. Both drugs can cause abnormal changes in the rhythm of the heart. These can be fatal, particularly for susceptible patients who already have heart problems. Many studies are using EKG tests to closely monitors patients receiving this treatment combination.
While QT-prolonging medication use has been associated with increased risk of death, this risk may be smaller than the potential benefit from treatment of COVID-19 for some patients (American College of Cardiology).
Major studies to watch:
- Intermountain Health Care and the University of Utah will treat 300 COVID-19 patients with either azithromycin or hydroxychloroquine. (link) They are also testing 1,550 COVID-19 patients in an outpatient setting with either hydroxychloroquine or azithromycin (link)
- Rutgers University is planning to test 160 COVID-19 patients with either hydroxychloroquine or hydroxychloroquine and azithromycin (link)
- Duke University will test 500 hospitalized COVID-19 patients randomly with either standard of care or hydroxychloroquine. Those selected for hydroxychloroquine will also be randomized to either receive azithromycin in addition or just hydroxychloroquine (link)
8. Dietary Supplements (Vitamin D, C, Zinc and Melatonin)
There are more than 70 types of supplements that are being tested for COVID-19. You can review the details of these trials on clinicaltrials.gov. There are more than 120 trials testing the various nutrients and dietary supplements including vitamin D, vitamin C, zinc and melatonin. Vitamin D remains the most tested vitamin followed by vitamin C, for COVID-19.
Do take note that for optimal effectiveness, each supplement should not be considered as a single intervention as most of the supplements are given as part of a combination protocol. Further, each nutrient will also have influence on another nutrient. For example, vitamin C and zinc need to be given together with copper. Also, vitamin D3 needs to be given with vitamin K2 and magnesium.
For more information, check out Best 10 Most Studied Supplements for COVID-19: A December 2020 Review
9. Steroids (Methylprednisolone, Dexamethasone, Hydrocortisone)
As of January 2021, there are more than 30 on-going trials in this treatment category:
Do take note that most patients that suffered the COVID-19 disease will normally go through 2 overlapping but distinct phases i.e. viral phase and followed by inflammatory phase. Steroids remain a promising treatment category for COVID-19 especially for those with inflammatory organ injury.
Related publication:
- The RECOVERY trial (NEJM, Jul 2020) provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with COVID-19 who are receiving respiratory support. The authors found no benefit (and the possibility of harm) among patients who did not require oxygen.
Editor's Note: According to RECOVERY, treatment with Dexamethasone was only effective for those who required oxygen support (on ventilators or required oxygen) but not for those who did not require oxygen support (mild cases). Although it was effective, the death rates for those on dexamethasone were still relatively high as compared to other major studies i.e. 29.3% (on ventilators) and 23.3% (oxygen support without ventilators).
10. Interleukin Receptor Blockers (Tocilizumab, Sarilumab)
Kevzara (trade name for sarilumab) was approved in the US in 2017 to treat rheumatoid arthritis. The biologic injection is an anti-inflammatory medication. Regeneron and Sanofi co-promote the drug.
It may help the most severe COVID-19 patients who are suffering from an overactive immune response. This condition, known as a cytokine storm, may be the reason some patients crash. Kevzara inhibits a key cytokine called IL-6.
Major Publications:
- Salvarani, JAMA, Oct 2020 - Tocilizumab did not reduce the risk in COVID-19 hospitalised patients in Italy.
- Stone, NEJM, Dec 2020 - Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19.
- Hermine, JAMA, Oct 2020 - Tocilizumab did not reduce death by day 28 in moderate to severe COVID-19 patients in France.
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