COVID-19 early treatment: real-time analysis of 1,272 studies

The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry

Peacock et al., bioRxiv, doi:10.1101/2021.12.31.474653 (Preprint) (In Vitro)

In Vitro study showing that omicron can efficiently enter cells via the endosomal route, independent of TMPRSS2.

Peacock et al., 1/3/2022, preprint, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism

Willett et al., medRxiv, doi:10.1101/2022.01.03.21268111 (Preprint) (In Vitro)

In Vitro study showing that the entry process for omicron has moved towards TMPRSS2-independent fusion, indicating that TMPRSS2 inhibitors may be less effective for omicron.

Willett et al., 1/3/2022, preprint, 38 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

Cecon et al., bioRxiv, doi:10.1101/2021.12.30.474561 (Preprint)

K18-hACE2 mouse study showing treatment with melatonin and derived drugs agomelatine and ramelteon inhibited SARS-CoV-2 infection in the brain.

Cecon et al., 1/3/2022, preprint, 14 authors.

The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2

Efird et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19010447 (Peer Reviewed)

Retrospective 26,508 COVID+ veterans in USA, showing lower mortality with vitamin D use after testing positive (defined as being administered ≥7 days or half of the survival time within 2 weeks after testing), with statistical significance for hospitalized patients.

risk of death, 48.9% lower, RR 0.51, p = 0.10, treatment 11 of 544 (2.0%), control 413 of 15,794 (2.6%), NNT 169, adjusted, non-hospitalized patients, vitamin D + no corticosteroids vs. no vitamin D + no corticosteroids.

risk of death, 54.5% lower, RR 0.45, p = 0.02, treatment 11 of 192 (5.7%), control 553 of 4,340 (12.7%), NNT 14, adjusted, hospitalized patients, vitamin D + no corticosteroids vs. no vitamin D + no corticosteroids.

Efird et al., 12/31/2021, retrospective, USA, North America, peer-reviewed, 10 authors, 1 March, 2020 - 10 September, 2020, dosage varies.

Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis

Shimizu et al., Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.12.024 (Peer Reviewed)

Retrospective 88 ventilated COVID-19 patients in Japan, 39 treated with ivermectin within 3 days of admission, showing significantly reduced incidence of GI complications and mortality, and increased ventilator-free days with treatment.

risk of death, 99.9% lower, RR 0.001, p < 0.001, treatment 0 of 39 (0.0%), control 8 of 49 (16.3%), NNT 6.1, adjusted, Cox proportional hazard regression.

ventilator free days, 47.9% lower, RR 0.52, p = 0.03, treatment 39, control 49, adjusted, proportional odds logistic regression, RR approximated with OR.

ventilation time, 38.5% lower, relative time 0.62, p < 0.001, treatment 39, control 49.

ICU free days, 42.8% lower, RR 0.57, p = 0.06, treatment 39, control 49, adjusted, proportional odds logistic regression, RR approximated with OR.

ICU time, 37.5% lower, relative time 0.62, p < 0.001, treatment 39, control 49.

GI complications while ventilated, 77.9% lower, RR 0.22, p = 0.03, treatment 39, control 49, adjusted, Cox proportional hazard regression.

Shimizu et al., 12/31/2021, retrospective, Japan, Asia, peer-reviewed, 11 authors, December 2020 - May 2021, dosage 200μg/kg days 1, 14.

Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection

Vermillion et al., Science Translational Medicine, doi:10.1126/scitranslmed.abl8282 (Peer Reviewed)

African green monkey study of inhaled versus IV remdesivir, showing similar efficacy with inhalation. Comparable concentrations of the active triphosphate in the lower respiratory tract were found with ~20x lower dose using inhalation, and there was lower systemic exposure to remdesivir and metabolites.

Vermillion et al., 12/30/2021, peer-reviewed, 26 authors.

SIT1 transporter as a potential novel target in treatment of COVID-19

Semiz, S., Biomolecular Concepts, doi:10.1515/bmc-2021-0017 (Review) (Peer Reviewed)

Review of the potential connections between SLC6A20/SIT1, ACE2, Type 2 Diabetes, and COVID-19 severity. This provides another potential mechanism of action for ivermectin as a partial agonist of glycine-gated chloride channels, interfering with cytokine storm by inducing activation of glycine receptors. Author recommends investigating targeting of the SIT1 transporter and glycine levels in the treatment of COVID-19, particularly for severe cases associated with hyperglycemia, inflammation, and T2D.

Semiz et al., 12/30/2021, peer-reviewed, 1 author.

Pattern of medication utilization in hospitalized patients with COVID-19 in three District Headquarters Hospitals in the Punjab province of Pakistan

Mustafa et al., Exploratory Research in Clinical and Social Pharmacy, doi:10.1016/j.rcsop.2021.100101 (Peer Reviewed)

Retrospective 444 hospitalized patients in Pakistan, showing lower mortality with aspirin treatment in unadjusted results, not reaching statistical significance.

risk of death, 44.1% lower, RR 0.56, p = 0.28, treatment 4 of 66 (6.1%), control 41 of 378 (10.8%), NNT 21.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Mustafa et al., 12/29/2021, retrospective, Pakistan, South Asia, peer-reviewed, 7 authors.

Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

Munafò et al., Research Square, doi:10.21203/rs.3.rs-1149846/v1 (Preprint) (In Vitro)

In Vitro and In Silico study showing quercetin and luteolin inhibiting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).

Munafò et al., 12/28/2021, preprint, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Kintor Pharma Provides Update on One of its Three Multi-Regional Phase 3 Trials of Proxalutamide for COVID-19

Kintor, News Releease (News)

News release reporting on interim analysis of NCT04870606, showing that statistical criteria were not met, there was a very low event rate, and that Kintor plans to amend the protocol and continue to enroll higher risk patients.

Kintor et al., 12/27/2021, preprint, 1 author.

Final Results of a Randomized, Placebo-Controlled, Two-Arm, Parallel Clinical Trial of Proxalutamide for Hospitalized COVID-19 Patients: A Multiregional, Joint Analysis of the Proxa-Rescue AndroCoV Trial

Cadegiani et al., Cureus, doi:10.7759/cureus.20691 (Peer Reviewed)

RCT 778 hospitalized patients in Brazil, 423 treated with proxalutamide, showing significantly lower mortality and improved recovery with treatment. NCT04728802 and NCT05126628. Authors note that cases in this trial were predominantly the P.1 Gamma variant, for which proxalutamide may be more effective compared to other variants.

risk of death, 78.0% lower, RR 0.22, p < 0.001, treatment 45 of 423 (10.6%), control 171 of 355 (48.2%), NNT 2.7, adjusted, 28 days, Cox proportional hazards.

risk of death, 79.0% lower, RR 0.21, p < 0.001, treatment 34 of 423 (8.0%), control 138 of 355 (38.9%), NNT 3.2, adjusted, 14 days, Cox proportional hazards.

recovery rate, RR 0.55, p < 0.001, treatment 423, control 355, adjusted, 28 days, Cox proportional hazards.

recovery rate, RR 0.45, p < 0.001, treatment 423, control 355, adjusted, 14 days, Cox proportional hazards.

hospitalization time, 33.3% lower, relative time 0.67, p < 0.001, treatment 423, control 355.

Cadegiani et al., 12/25/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 15 authors.

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

Self et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(21)00751-9 (Peer Reviewed)

RCT with 182 sotrovimab patients and 178 control patients, median 8 days from symptom onset, showing no significant differences and terminated early due to futility. TICO. NCT04501978.

risk of death, 2.0% higher, RR 1.02, p = 0.96, treatment 14 of 182 (7.7%), control 13 of 178 (7.3%), day 90.

risk of no recovery, 10.7% lower, RR 0.89, p = 0.29, treatment 22 of 160 (13.8%), control 27 of 178 (15.2%), NNT 70, day 90.

risk of no recovery, 7.4% lower, RR 0.93, p = 0.69, treatment 160, control 178, pulmonary-plus ordinal outcome @day 5.

Self et al., 12/23/2021, Double Blind Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 647 authors, 16 December, 2020 - 1 March, 2021.

Safety and Tolerability of Hydroxychloroquine in healthcare workers and first responders for the prevention of COVID-19: WHIP COVID-19 Study

McKinnon et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.343 (Peer Reviewed)

HCQ PrEP RCT with 201 weekly HCQ patients, 197 daily HCQ patients, and 200 control patients, concluding the prophylaxis is safe. There were no grade 3 or 4 AEs, SAEs, ER visits, or hospitalizations. There was only 4 confirmed cases, 2 in the placebo arm and one in each HCQ arm.

HCQ 400mg weekly or HCQ 200mg daily after a loading dose of 400mg on day 1. WHIP COVID-19. NCT04341441.

risk of symptomatic case, 2.5% lower, RR 0.98, p = 1.00, treatment 2 of 365 (0.5%), control 1 of 178 (0.6%), NNT 7219, daily and weekly HCQ combined.

risk of symptomatic case, no change, RR 1.00, p = 1.00, treatment 1 of 178 (0.6%), control 1 of 178 (0.6%), daily HCQ.

risk of symptomatic case, 4.8% lower, RR 0.95, p = 1.00, treatment 1 of 187 (0.5%), control 1 of 178 (0.6%), NNT 3698, weekly HCQ.

risk of symptomatic case, 53.3% lower, RR 0.47, p = 1.00, treatment 0 of 25 (0.0%), control 1 of 178 (0.6%), NNT 178, relative risk is not 0 because of continuity correction due to zero events, AD patients.

risk of case, 51.2% lower, RR 0.49, p = 0.60, treatment 2 of 365 (0.5%), control 2 of 178 (1.1%), NNT 174, daily and weekly HCQ combined.

risk of case, 50.0% lower, RR 0.50, p = 1.00, treatment 1 of 178 (0.6%), control 2 of 178 (1.1%), NNT 178, daily HCQ.

risk of case, 52.4% lower, RR 0.48, p = 0.61, treatment 1 of 187 (0.5%), control 2 of 178 (1.1%), NNT 170, weekly HCQ.

risk of case, 69.5% lower, RR 0.30, p = 1.00, treatment 0 of 25 (0.0%), control 2 of 178 (1.1%), NNT 89, relative risk is not 0 because of continuity correction due to zero events, AD patients.

McKinnon et al., 12/23/2021, Double Blind Randomized Controlled Trial, USA, North America, peer-reviewed, 10 authors.

Nigellidine (Nigella sativa, black-cumin seed) docking to SARS CoV-2 nsp3 and host inflammatory proteins may inhibit viral replication/transcription

Banerjee et al., Natural Product Research, doi:10.1080/14786419.2021.2018430 (Peer Reviewed)

In Silico study showing nigella sativa docking to SARS CoV-2 Nsp3 and host inflammatory proteins, which may inhibit viral replication.

Banerjee et al., 12/22/2021, peer-reviewed, 6 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients

Gottlieb et al., New England Journal of Medicine, doi:10.1056/NEJMoa2116846 (Peer Reviewed)

RCT high-risk outpatients, 279 treated with remdesivir and 283 control patients, median 5 days from symptoms, showing significantly lower hospitalization with treatment. NCT04501952.

risk of death/hospitalization, 87.0% lower, RR 0.13, p = 0.008, treatment 2 of 279 (0.7%), control 15 of 283 (5.3%), NNT 22, adjusted, COVID-19-related hospitalization or death from any cause @day 28.

risk of no recovery, 29.1% lower, RR 0.71, p = 0.31, treatment 43 of 66 (65.2%), control 45 of 60 (75.0%), NNT 10, adjusted, alleviation of symptoms @day 14.

risk of no recovery, 47.9% lower, RR 0.52, p = 0.003, treatment 108 of 169 (63.9%), control 132 of 165 (80.0%), NNT 6.2, adjusted, post-hoc alleviation of symptoms @day 14.

Gottlieb et al., 12/22/2021, Double Blind Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 30 authors, 18 September, 2020 - 8 April, 2021.

Clinical evaluation of antiseptic mouth rinses to reduce salivary load of SARS-CoV-2

Ferrer et al., Scientific Reports, doi:10.1038/s41598-021-03461-y (Peer Reviewed)

Small very late (>50% 7+ days from symptom onset, 9 PVP-I patients) RCT testing mouthwashing with cetylpyridinium chloride, chlorhexidine, povidone-iodine, hydrogen peroxide, and distilled water, showing no significant differences. Over 30% of patients show >90% decrease in viral load @2 hrs with all 5. Authors note that a trend was observed for viral load decrease with PVP-I @2h for patients <6 days from onset (p=0.06, Wilcox test).

relative decrease in log viral load, 34.0% better, RR 0.66, p = 0.82, treatment 9, control 12, calculated from Supplementary Table 1.

Ferrer et al., 12/22/2021, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 19 authors.

Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes

Chiodini et al., Frontiers in Public Health, doi:10.3389/fpubh.2021.736665 (Peer Reviewed)

Meta analysis concluding that "patients with low vitamin D levels present an increased risk of ARDS requiring admission to intensive care unit (ICU) or mortality due to SARS-CoV-2 infection and a higher susceptibility to SARS-CoV-2 infection and related hospitalization".

Chiodini et al., 12/22/2021, peer-reviewed, 13 authors.

Resistance conferring mutations in SARS-CoV-2 delta following sotrovimab infusion

Rockett et al., medRxiv, doi:10.1101/2021.12.18.21267628 (Preprint)

Retrospective 100 sotrovimab patients in Australia, 23 PCR+ more than 10 days post-infusion (68 with status unknown), showing rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro.

Rockett et al., 12/21/2021, preprint, 26 authors.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic

Suzuki et al., medRxiv, doi:10.1101/2021.12.19.21268078 (Preprint)

Retrospective 949 patients in Japan, 314 treated with casirivimab/imdevimab showing significantly lower risk of deterioration with treatment.

risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 222 (0.5%), control 0 of 222 (0.0%), continuity correction due to zero event, propensity score matching.

risk of death, 59.6% lower, RR 0.40, p = 0.67, treatment 1 of 314 (0.3%), control 5 of 635 (0.8%), NNT 213, unadjusted.

risk of progression, 45.2% lower, RR 0.55, p = 0.02, treatment 17 of 222 (7.7%), control 31 of 222 (14.0%), NNT 16, propensity score matching.

risk of progression, 49.9% lower, RR 0.50, p = 0.002, treatment 34 of 314 (10.8%), control 70 of 365 (19.2%), NNT 12, OR converted to RR, multivariate.

Suzuki et al., 12/21/2021, retrospective, Japan, Asia, preprint, 49 authors, 24 July, 2021 - 30 September, 2021.

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

Sullivan et al., medRxiv, doi:10.1101/2021.12.10.21267485 (Preprint)

RCT 1,181 outpatients in the USA, mean 6 days from symptom onset, showing lower hospitalization with treatment. NCT04373460.

risk of death, 85.7% lower, RR 0.14, p = 0.12, treatment 0 of 592 (0.0%), control 3 of 589 (0.5%), NNT 196, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 25.4% lower, RR 0.75, p = 0.73, treatment 3 of 592 (0.5%), control 4 of 589 (0.7%), NNT 580.

risk of hospitalization, 54.3% lower, RR 0.46, p = 0.005, treatment 17 of 592 (2.9%), control 37 of 589 (6.3%), NNT 29.

Sullivan et al., 12/21/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 58 authors, 3 June, 2020 - 1 October, 2021.

Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19

Chew et al., medRxiv, doi:10.1101/2021.12.17.21268009 (Preprint)

RCT 317 outpatients in the USA showing faster viral load and inflammatory biomarker decline, but no significant differences in clinical outcomes. ACTIV-2/A5401. NCT04518410. Supplementary data is not currently available.

risk of hospitalization, 25.5% lower, RR 0.75, p = 0.60, treatment 6 of 159 (3.8%), control 8 of 158 (5.1%), NNT 78, combined.

risk of hospitalization, 52.1% lower, RR 0.48, p = 0.43, treatment 2 of 48 (4.2%), control 4 of 46 (8.7%), NNT 22, 7000mg, day 28.

risk of hospitalization, 0.9% higher, RR 1.01, p = 1.00, treatment 4 of 111 (3.6%), control 4 of 112 (3.6%), 700mg, day 28.

relative time to symptom improvement, 13.5% higher, relative time 1.14, p = 0.97, treatment 48, control 46, 7000mg.

relative time to symptom improvement, 17.1% higher, relative time 1.17, p = 0.08, treatment 111, control 112, 700mg.

viral load, 25.6% lower, relative load 0.74, p = 0.002, treatment 48, control 46, 7000mg, day 3.

viral load, 35.3% lower, relative load 0.65, p = 0.07, treatment 111, control 112, 700mg, day 3.

Chew et al., 12/21/2021, Randomized Controlled Trial, USA, North America, preprint, 23 authors, 19 August, 2020 - 17 November, 2020.

Fluvoxamine for Outpatient COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-Analysis

Lee et al., medRxiv, doi:10.1101/2021.12.17.21268008 (Preprint) (meta analysis)

Systematic review and meta analysis of outpatient RCTs, showing hospitalization RR 0.75 [0.57-0.97]. For discussion see [1].

[1] twitter.com/Covid19Crusher/status/1473623109525815296

Lee et al., 12/21/2021, preprint, 7 authors.

Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron)

Sheward et al., bioRxiv, doi:10.1101/2021.12.19.473354 (Preprint) (In Vitro)

In Vitro study showing that omicron is substantially resistant to neutralization by monoclonal antibodies REGN10933, REGN10987, Ly-CoV016 and Ly-CoV555. S309 (the parent of Sotrovimab) had only 2-fold loss in potency.

Sheward et al., 12/20/2021, preprint, 11 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The effect of casirivimab with imdevimab on disease progression in nonsevere COVID‐19 patients in a single hospital in Japan

Komagamine et al., Journal of General and Family Medicine, doi:10.1002/jgf2.516 (Peer Reviewed)

Combined retrospective/prospective study in Japan with 53 casirivimab/imdevimab patients and 75 control patients, showing significantly lower progression with treatment.

risk of mechanical ventilation, 77.3% lower, RR 0.23, p = 0.51, treatment 0 of 53 (0.0%), control 2 of 75 (2.7%), NNT 38, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 92.3% lower, RR 0.08, p = 0.04, treatment 0 of 53 (0.0%), control 7 of 75 (9.3%), NNT 11, relative risk is not 0 because of continuity correction due to zero events.

risk of progression, 67.8% lower, RR 0.32, p = 0.006, treatment 8 of 53 (15.1%), control 33 of 75 (44.0%), NNT 3.5, adjusted, OR converted to RR, multivariable.

hospitalization time, 28.9% lower, relative time 0.71, p < 0.001, treatment 53, control 75.

Komagamine et al., 12/19/2021, retrospective, Japan, Asia, peer-reviewed, 4 authors.

开拓药业普克鲁胺治疗新冠预计本月发布临床数据

Kintor, News Comments (News)

News report noting that real-world results for proxalutamide in Paraguay show signfiicantly lower mortality and are consistent with the results of previous studies in Brazil.

Kintor et al., 12/17/2021, preprint, 1 author.

An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies

VanBlargan et al., bioRxiv, doi:10.1101/2021.12.15.472828 (Preprint) (In Vitro)

In vitro study (Vero-TMPRSS2 and Vero-hACE2-TMPRSS2) showing complete loss of inhibitory activity for B.1.1.529 omicron with LY-CoV555, LY-CoV016, REGN10933, REGN10987, and CT-P59, ~12-fold decrease for COV2-2196/COV2-2130, and minimal change for S309.

VanBlargan et al., 12/17/2021, preprint, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

Arribas et al., NEJM Evidence, doi:10.1056/EVIDoa2100044 (Peer Reviewed)

RCT 304 hospitalized patients, 218 treated with molnupiravir, showing no significant differences. MOVe-IN MK-4482-001. NCT04575584.

risk of death, 281.9% higher, RR 3.82, p = 0.31, treatment 11 of 216 (5.1%), control 1 of 75 (1.3%), combined, excluding imputed deaths.

risk of death, 216.9% higher, RR 3.17, p = 0.36, treatment 3 of 71 (4.2%), control 1 of 75 (1.3%), 800mg, excluding imputed death.

risk of death, 316.7% higher, RR 4.17, p = 0.20, treatment 4 of 72 (5.6%), control 1 of 75 (1.3%), 400mg, excluding imputed death.

risk of death, 311.0% higher, RR 4.11, p = 0.21, treatment 4 of 73 (5.5%), control 1 of 75 (1.3%), 200mg.

risk of no recovery, 1.0% lower, RR 0.99, p = 0.96, treatment 72, control 75, 800mg.

risk of no recovery, 11.5% lower, RR 0.88, p = 0.53, treatment 73, control 75, 400mg.

risk of no recovery, 1.0% higher, RR 1.01, p = 0.96, treatment 73, control 75, 200mg.

recovery time, no change, relative time 1.00, treatment 72, control 75, 800mg.

recovery time, no change, relative time 1.00, treatment 73, control 75, 400mg.

recovery time, no change, relative time 1.00, treatment 73, control 75, 200mg.

risk of no virological cure, 11.8% lower, RR 0.88, p = 0.57, treatment 26 of 52 (50.0%), control 34 of 60 (56.7%), NNT 15, 800mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 2.4% higher, RR 1.02, p = 1.00, treatment 29 of 50 (58.0%), control 34 of 60 (56.7%), 400mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 20.6% lower, RR 0.79, p = 0.27, treatment 27 of 60 (45.0%), control 34 of 60 (56.7%), NNT 8.6, 200mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 8.3% lower, RR 0.92, p = 1.00, treatment 9 of 53 (17.0%), control 10 of 54 (18.5%), NNT 65, 800mg, Table S16, day 29.

risk of no virological cure, 48.2% higher, RR 1.48, p = 0.35, treatment 14 of 51 (27.5%), control 10 of 54 (18.5%), 400mg, Table S16, day 29.

risk of no virological cure, 21.5% lower, RR 0.79, p = 0.61, treatment 8 of 55 (14.5%), control 10 of 54 (18.5%), NNT 25, 200mg, Table S16, day 29.

Arribas et al., 12/16/2021, Double Blind Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 21 authors.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Jayk Bernal et al., New England Journal of Medicine, doi:10.1056/NEJMoa2116044 (Peer Reviewed)

MOVe-OUT RCT, showing significantly lower risk of hospitalization or death. In subgroup analysis efficacy was much lower with the delta variant. NCT04575597.

Discussion of concerns with this trial can be found at [1, 2]. See also: [3, 4].

[1] trialsitenews.com/molnupiravir-mutagenic-carcinogenic-authorized-in-the-uk/

[2] defyccc.com/wp-content/uploads/Molnupiravir-Mutagenic-Carcinogenic-TSN.pdf

[3] twitter.com/Covid19Crusher/status/1464249681446420485

[4] twitter.com/Covid19Crusher/status/1464269071818661893

risk of death, 89.0% lower, RR 0.11, p = 0.01, treatment 1 of 709 (0.1%), control 9 of 699 (1.3%), NNT 87.

risk of death/hospitalization, 30.4% lower, RR 0.70, p = 0.05, treatment 48 of 709 (6.8%), control 68 of 699 (9.7%), NNT 34.

risk of death/hosp. (gamma variant), 94.1% lower, RR 0.06, p = 0.004, treatment 0 of 37 (0.0%), control 9 of 47 (19.1%), NNT 5.2, relative risk is not 0 because of continuity correction due to zero events.

risk of death/hosp. (mu variant), 49.5% lower, RR 0.50, p = 0.15, treatment 6 of 75 (8.0%), control 13 of 82 (15.9%), NNT 13.

risk of death/hosp. (delta variant), 23.7% lower, RR 0.76, p = 0.41, treatment 18 of 237 (7.6%), control 22 of 221 (10.0%), NNT 42.

risk of death/hosp. (other variants), 42.2% lower, RR 0.58, p = 0.36, treatment 5 of 47 (10.6%), control 7 of 38 (18.4%), NNT 13.

Jayk Bernal et al., 12/16/2021, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 22 authors.

Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2

Liu et al., bioRxiv, doi:10.1101/2021.12.14.472719 (Preprint) (In Vitro)

In vitro study (Vero-E6-TMPRSS2) showing 18 of 19 monoclonal antibodies were no longer effective or significantly impaired with B.1.1.529 omicron.

Liu et al., 12/15/2021, preprint, 23 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The spike protein of SARS-CoV-2 virus induces heme oxygenase-1: Pathophysiologic implications

Singh et al., Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, doi:10.1016/j.bbadis.2021.166322 (Peer Reviewed) (In Vitro)

In Vitro study transfecting SARS-CoV-2 viral spike protein in kidney cell lines, showing syncytia formation and upregulation of the cytoprotective gene HO-1, and that quercetin, which induces HO-1, can reduce syncytia formation. Authors conclude that quercetin may be protective for AKI in COVID-19.

Singh et al., 12/14/2021, peer-reviewed, 9 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Vitamin C inhibits Angiotensin-Converting Enzyme-2 in Isolated Rat Aortic Ring

Amssayef et al., Cardiovascular & Hematological Disorders-Drug Targets, doi:10.2174/1871529X21666211214153308 (Peer Reviewed) (Ex Vivo)

Ex Vivo study showing vitamin C inhibiting vascular ACE2.

Amssayef et al., 12/14/2021, peer-reviewed, 3 authors.

Ex Vivo studies are an important part of preclinical research, however results may be very different in vivo.

A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data

Welén et al., European Urology, doi:10.1016/j.eururo.2021.12.013 (Peer Reviewed)

Very small late stage RCT with 10 control patients and 29 enzalutamide patients, showing mixed results. Discharge and hospitalization time favored the control group, while viral load reduction was better with treatment on days 4&6 (day 4 ΔCt −5.6 p = 0.084), and the only death occurred in the control group. 27% of enzalutamide patients had diabetes compared to 0% of the control group.

Retrospective 7,894 COVID+ prostate cancer patients, analyzing patients on antiandrogen treatment, ADT, and ADT + abiraterone acetate or enzalutamide, showing mixed results and higher mortality for ADT + abiraterone acetate or enzalutamide.

In Vitro HBEC study showing no significant differences (p = 0.084).

The supplementary data is not currently available. NCT04475601.

risk of death, 79.6% lower, RR 0.20, p = 0.26, treatment 0 of 29 (0.0%), control 1 of 10 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events, RCT result.

risk of mechanical ventilation, 31.0% lower, RR 0.69, p = 1.00, treatment 2 of 29 (6.9%), control 1 of 10 (10.0%), NNT 32, RCT result.

risk of no hospital discharge, 132.6% higher, RR 2.33, p = 0.03, treatment 29, control 10, RCT result.

hospitalization time, 50.0% higher, relative time 1.50, p = 0.01, treatment 29, control 10.

risk of death, 2.0% lower, RR 0.98, p = 0.94, treatment 21 of 358 (5.9%), control 167 of 4,980 (3.4%), adjusted, retrospective study, antiandrogen treatment.

risk of death, 11.0% lower, RR 0.89, p = 0.66, treatment 20 of 334 (6.0%), control 167 of 4,980 (3.4%), adjusted, retrospective study, ADT.

risk of death, 151.0% higher, RR 2.51, p < 0.001, treatment 24 of 152 (15.8%), control 167 of 4,980 (3.4%), adjusted, retrospective study, ADT and abiraterone acetate or enzalutamide.

risk of ICU admission, 28.0% higher, RR 1.28, p = 0.28, treatment 24 of 358 (6.7%), control 216 of 4,980 (4.3%), adjusted, retrospective study, antiandrogen treatment.

risk of ICU admission, 13.0% lower, RR 0.87, p = 0.62, treatment 16 of 334 (4.8%), control 216 of 4,980 (4.3%), adjusted, retrospective study, ADT.

risk of ICU admission, 21.0% lower, RR 0.79, p = 0.60, treatment 6 of 152 (3.9%), control 216 of 4,980 (4.3%), NNT 256, adjusted, retrospective study, ADT and abiraterone acetate or enzalutamide.

risk of hospitalization, 23.0% higher, RR 1.23, p = 0.09, treatment 126 of 358 (35.2%), control 1,108 of 4,980 (22.2%), adjusted, retrospective study, antiandrogen treatment.

risk of hospitalization, 24.0% higher, RR 1.24, p = 0.09, treatment 126 of 334 (37.7%), control 1,108 of 4,980 (22.2%), adjusted, retrospective study, ADT.

risk of hospitalization, 40.0% higher, RR 1.40, p = 0.06, treatment 66 of 152 (43.4%), control 1,108 of 4,980 (22.2%), adjusted, retrospective study, ADT and abiraterone acetate or enzalutamide.

Welén et al., 12/14/2021, Randomized Controlled Trial, Sweden, Europe, peer-reviewed, 27 authors.

A Case-Control Study for the Effectiveness of Oral Zinc in the Prevention and Mitigation of COVID-19

Gordon et al., Frontiers in Medicine, doi:10.3389/fmed.2021.756707 (Peer Reviewed)

Prospective study of zinc supplementation with 104 patients randomized to receive 10mg, 25mg, or 50mg of zinc picolinate daily, and a matched sample of 96 control patients from the adjacent clinic that did not routinely recommend/use zinc, showing significantly lower symptomatic COVID-19 with treatment.

risk of death, 67.6% lower, RR 0.32, p = 0.48, treatment 0 of 104 (0.0%), control 1 of 96 (1.0%), NNT 96, relative risk is not 0 because of continuity correction due to zero events.

risk of symptomatic case, 85.3% lower, RR 0.15, p = 0.02, treatment 2 of 104 (1.9%), control 9 of 96 (9.4%), NNT 13, adjusted, OR converted to RR.

Gordon et al., 12/13/2021, prospective, USA, North America, peer-reviewed, 2 authors.

Determinants of Outcome Among Critically Ill Police Personnel With COVID-19: A Retrospective Observational Study From Andhra Pradesh, India

Jamir et al., Cureus, doi:10.7759/cureus.20394 (Peer Reviewed)

Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir.

risk of death, 53.0% higher, RR 1.53, p = 0.13, treatment 32 of 76 (42.1%), control 69 of 190 (36.3%), adjusted, multivariable Cox regression.

Jamir et al., 12/13/2021, retrospective, India, South Asia, peer-reviewed, 6 authors, June 2020 - October 2010, dosage not specified.

Pfizer announces additional phase 2/3 study results confirming robust efficacy of novel COVID-19 oral antiviral treatment candidate in reducing risk or hospitalization or death

Pfizer Press Release (News)

EPIC-SR trial interim results, 428 patients treated with paxlovid (PF-07321332 + ritonavir) and 426 control patients, showing lower hospitalization with treatment. NCT05011513.

risk of hospitalization, 70.1% lower, RR 0.30, p = 0.05, treatment 3 of 428 (0.7%), control 10 of 426 (2.3%), NNT 61.

Pfizer et al., 12/14/2021, Double Blind Randomized Controlled Trial, multiple countries, multiple regions, preprint, 1 author.

Ivermectin Prophylaxis Used for COVID-19 Reduces COVID-19 Infection and Mortality Rates: A City-Wide, Prospective Observational Study of 220,517 Subjects Using Propensity Score Matching

Kerr et al., Research Gate (Preprint)

PSM retrospective 220,517 patients in Brazil,133,051 taking ivermectin as part of a citywide prophylaxis program, showing significantly lower hospitalization and mortality with treatment. CAAE:47124221.2.0000.5485.

risk of death, 70.0% lower, RR 0.30, p < 0.001, treatment 25 of 3,034 (0.8%), control 79 of 3,034 (2.6%), NNT 56, adjusted, multivariate linear regression, propensity score matching.

risk of hospitalization, 67.0% lower, RR 0.33, p < 0.001, treatment 44 of 3,034 (1.5%), control 99 of 3,034 (3.3%), NNT 55, adjusted, multivariate linear regression, propensity score matching.

risk of case, 7.0% lower, RR 0.93, p = 0.003, treatment 4,311 of 133,051 (3.2%), control 3,034 of 87,466 (3.5%), NNT 437, adjusted, propensity score matching.

Kerr et al., 12/11/2021, retrospective, propensity score matching, Brazil, South America, preprint, 9 authors, July 2020 - December 2020, dosage 200μg/kg days 1, 2, 16, 17, 0.2mg/kg/day for 2 days every 15 days.

Vitamin D Levels among Hospitalized and Non-Hospitalized COVID-19 Patients in Dr. M. Djamil General Hospital Padang

Putra et al., European Journal of Medical and Health Sciences, doi:10.24018/ejmed.2021.3.6.1131 (Peer Reviewed)

Case control study in Indonesia with 31 moderate to critical hospitalized COVID-19 patients, and 31 asymptomatic or mild non-hospitalized COVID-19 patients, showing lower vitamin D levels in the hospitalized patients, without reaching statistical significance.

risk of hospitalization, 25.6% lower, RR 0.74, p = 0.59, high D levels 9 of 31 (29.0%) cases, 11 of 31 (35.5%) controls, NNT 14, case control OR.

Putra et al., 12/10/2021, retrospective, Indonesia, South Asia, peer-reviewed, 3 authors, February 2020 - September 2020.

Iota-Carrageenan Inhibits Replication of SARS-CoV-2 and the Respective Variants of Concern Alpha, Beta, Gamma and Delta

Fröba et al., International Journal of Molecular Sciences, doi:10.3390/ijms222413202 (Peer Reviewed) (In Vitro)

In Vitro study of iota-, lambda-, and kappa-carrageenan sulfated polysaccharides extracted from red seaweed on SARS-CoV-2 Wuhan type and variants Alpha, Beta, Gamma and Delta, showing that all three carrageenan types had antiviral activity. Iota-carrageenan had comparable IC₅₀ values against all variants. Authors conclude that iota-carrageenan might be effective for prophylaxis and treatment of SARS-CoV-2 for existing and potentially future variants.

Fröba et al., 12/8/2021, peer-reviewed, 14 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19

Finberg et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab56310 (Peer Reviewed)

Small very late treatment RCT in the USA, with 25 favipiravir and 25 control patients, showing faster viral clearance with treatment. The benefit was only seen in patients <8 days from symptom onset. There were no significant differences in clinical outcomes. The death in the favipiravir group occurred after discharge and was believed to be unrelated to COVID-19 or favipiravir.

risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event.

risk of mechanical ventilation, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 25 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event.

hospitalization time, 19.8% higher, relative time 1.20, treatment 25, control 25.

risk of no recovery, 58.1% lower, RR 0.42, p = 0.08, treatment 25, control 25, day 8 mid-recovery, 6-point ordinal scale, RR approximated with OR.

risk of no recovery, 46.2% higher, RR 1.46, p = 0.54, treatment 25, control 25, day 15, 6-point ordinal scale, RR approximated with OR.

recovery time, 42.9% lower, relative time 0.57, treatment 25, control 25, median time to aggregate NEWS2 score ≤2 or discharge.

recovery time, 15.4% higher, relative time 1.15, treatment 25, control 25.

time to viral-, 46.7% lower, relative time 0.53, p = 0.04, treatment 25, control 25.

Finberg et al., 12/7/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 10 authors.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption


Random effects meta-analysis of all studies combined (pooled effects, all stages). Treatments with ≤3 studies with distinct authors or with <50 control events are shown in grey. Pooled results across all stages and outcomes depend on the distribution of stages and outcomes tested - for example late stage treatment may be less effective and if the majority of studies are late stage this may obscure the efficacy of early treatment. Please see the specific stage and outcome analyses. Protocols typically combine multiple treatments which may be complementary and synergistic, and the SOC in studies often includes other treatments.


Random effects meta-analysis of early treatment studies (pooled effects). Treatments with ≤3 studies with distinct authors or with <50 control events are shown in grey. Pooled results across all outcomes are affected by the distribution of outcomes tested, please see detail pages for specific outcome analysis. Protocols typically combine multiple treatments which may be complementary and synergistic, and the SOC in studies often includes other treatments.


Random effects meta-analysis of all mortality results (all stages). Treatments with ≤3 studies with distinct authors or with <25 control events are shown in grey. Pooled results across all stages depend on the distribution of stages tested - for example late stage treatment may be less effective and if the majority of studies are late stage this may obscure the efficacy of early treatment. Please see the specific stage analyses. Protocols typically combine multiple treatments which may be complementary and synergistic, and the SOC in studies often includes other treatments.


Random effects meta-analysis of early treatment mortality results. Treatments with ≤3 studies with distinct authors or with <25 control events are shown in grey. Protocols typically combine multiple treatments which may be complementary and synergistic, and the SOC in studies often includes other treatments.