Antiandrogens for COVID-19: real-time analysis of all 41 studies

Antiandrogens for COVID-19: real-time meta analysis of 34 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, recovery, cases, and viral clearance. 18 studies from 10 different countries show statistically significant improvements in isolation (11 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 23% [13‑32%] improvement. Results are better for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies.

• Results are robust — in exclusion sensitivity analysis 16 of 34 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• This analysis combines the results of several different antiandrogens. Results for individual treatments may vary. Proxalutamide is analyzed separately.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 15% of antiandrogen studies show zero events in the treatment arm.

Multiple treatments are typically used in combination, and other treatments are more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 5/24/2022, preprint, 1 author.

Higher premorbid serum testosterone predicts COVID-19-related mortality risk in men.

Yeap et al., European Journal of Endocrinology, doi:10.1530/EJE-22-0104

Prospective UK Biobank study showing higher premorbid testosterone levels associated with higher COVID-19 mortality.

Yeap et al., 5/10/2022, prospective, United Kingdom, Europe, peer-reviewed, 8 authors, study period 16 March, 2020 - 31 January, 2021.

In-Silico Molecular Docking, Validation, Drug-Likeness, and ADMET Studies of Antiandrogens to Use in the Fight against SARS-CoV-2

Saih et al., Physical Chemistry Research, doi:10.22036/pcr.2022.324549.2016

In Silico study of several antiandrogens identifying strong candidates for inhibition of SARS-CoV-2. Apalutamide and bicalutamide showed the best binding affinity against TMPRSS2.

Saih et al., 5/5/2022, Morocco, Africa, peer-reviewed, 11 authors.

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

Phase 2 study of oral sabizabulin for the treatment of SARS-CoV-2 in hospitalized patients at high risk for ARDS

Gordon, M., 32nd European Congress of Clinical Microbiology & Infectious Diseases

Phase 2 RCT of sabizabulin showing lower mortality with treatment. For more discussion see [twitter.com].

1. twitter.com, https://twitter.com/julienpotet/status/1518579945911562252.

risk of death, 82.0% lower, RR 0.18, p = 0.04, ITT.

ventilation time, 76.5% lower, relative time 0.24, p = 0.14.

ICU time, 72.9% lower, relative time 0.27, p = 0.03.

Gordon et al., 4/25/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, North America, peer-reviewed, 1 author.

Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19

Nickols et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.7852

Early terminated RCT with 62 very late stage (79% on oxygen) degarelix patients and 34 placebo patients, showing no significant differences with treatment.

For discussion of many issues with this study see [twitter.com].

1. twitter.com, https://twitter.com/FlavioCadegiani/status/1516908670705147905.

risk of death, 18.3% lower, RR 0.82, p = 0.66, treatment 11 of 62 (17.7%), control 7 of 34 (20.6%), NNT 35, adjusted, OR converted to RR, multivariable.

risk of mechanical ventilation, 18.8% higher, RR 1.19, p = 0.70, treatment 13 of 62 (21.0%), control 6 of 34 (17.6%).

risk of ongoing hospitalization, mortality, or mechanical ventilation, 16.7% higher, RR 1.17, p = 0.70, treatment 15 of 62 (24.2%), control 7 of 34 (20.6%), adjusted, OR converted to RR, multivariable, primary outcome.

hospitalization time, 20.0% higher, relative time 1.20, p = 0.94, treatment 62, control 34.

Nickols et al., 4/19/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, North America, peer-reviewed, 34 authors, study period 22 July, 2020 - 8 April, 2021, trial NCT04397718 (HITCH).

Veru’s Novel COVID-19 Drug Candidate Reduces Deaths by 55% in Hospitalized Patients in Interim Analysis of Phase 3 Study; Independent Data Monitoring Committee Halts Study Early for Overwhelming Efficacy

Veru News Release

RCT with 98 hospitalized moderate/severe patients treated with sabizabulin and 52 control patients, showing lower mortality with treatment. sabizabulin 9mg. For more discussion see [twitter.com].

1. twitter.com, https://twitter.com/julienpotet/status/1518579945911562252.

risk of death, 53.9% lower, RR 0.46, p = 0.004, treatment 20 of 98 (20.4%), control 23 of 52 (44.2%), NNT 4.2.

Veru et al., 4/11/2022, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, multiple regions, peer-reviewed, 1 author.

Protective trend of anti-androgen therapy during the COVID-19 pandemic: A meta-analysis

Meng et al., Journal of Infection, doi:10.1016/j.jinf.2022.03.020

Meta analysis of 15 antiandrogen studies showing a protective trend although there has been conflicting results to date.

Meng et al., 3/31/2022, peer-reviewed, 11 authors.

Screening Large Population Health Databases for Potential COVID-19 Therapeutics: A Pharmacopeia-Wide Association Study (PWAS) of Commonly Prescribed Medications

MacFadden et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac156

Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing lower cases with chronic use of spironolactone.

risk of case, 7.0% lower, OR 0.93, p = 0.008, RR approximated with OR.

MacFadden et al., 3/29/2022, retrospective, Canada, North America, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020.

Efficacy and Safety of Complementary Therapy With Jing Si Herbal Tea in Patients With Mild-To-Moderate COVID-19: A Prospective Cohort Study

Hsieh et al., Frontiers in Nutrition, doi:10.3389/fnut.2022.832321

Prospective study of 260 hospitalized patients in Taiwan, 117 treated with herbal formula Jing Si Herbal Tea which includes antiandrogen glycyrrhiza glabra, showing improved recovery with treatment, with statistical significance for SpO₂, Ct score, CRP, and Brixia score.

risk of death, 87.9% lower, RR 0.12, p = 0.13, treatment 0 of 117 (0.0%), control 4 of 143 (2.8%), NNT 36, relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 51.1% lower, RR 0.49, p = 0.46, treatment 2 of 117 (1.7%), control 5 of 143 (3.5%), NNT 56.

risk of ICU admission, 30.2% lower, RR 0.70, p = 0.76, treatment 4 of 117 (3.4%), control 7 of 143 (4.9%), NNT 68.

risk of no recovery, 87.9% lower, RR 0.12, p = 0.13, treatment 0 of 117 (0.0%), control 4 of 143 (2.8%), NNT 36, relative risk is not 0 because of continuity correction due to zero events.

relative increase in Ct score, 36.1% better, RR 0.64, p < 0.001, treatment mean 8.14 (±4.9) n=117, control mean 5.2 (±6.99) n=143.

Hsieh et al., 3/14/2022, prospective, Taiwan, Asia, peer-reviewed, 7 authors, study period 1 May, 2021 - 31 August, 2021, this trial uses multiple treatments in the treatment arm (combined with multi-herbal formula) - results of individual treatments may vary.

A population-level analysis of the protective effects of androgen deprivation therapy against COVID-19 disease incidence and severity

Lee et al., Frontiers in Medicine, doi:10.3389/fmed.2022.774773

Retrospective 3,057 androgen deprivation therapy patients in the USA, and 36,096 control patients with cancer, showing lower risk of cases and severity with ADT.

risk of severe case, 21.4% lower, RR 0.79, p = 0.03, treatment 76 of 295 (25.8%), control 727 of 2,427 (30.0%), NNT 24, adjusted, OR converted to RR, propensity score weighting, multivariable.

risk of case, 11.3% lower, RR 0.89, p < 0.001, treatment 295 of 3,057 (9.6%), control 2,427 of 36,096 (6.7%), adjusted, OR converted to RR, propensity score weighting, multivariable.

Lee et al., 3/7/2022, retrospective, USA, North America, peer-reviewed, 14 authors, study period 15 February, 2020 - 15 July, 2020.

Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial

Gomaa et al., Inflammopharmacology, doi:10.1007/s10787-022-00939-7

RCT with 50 hospitalized COVID+ patients in Egypt, 25 treated with glycyrrhizin and boswellic acid, showing improved recovery with treatment. Glycyrrhizin 60mg and boswellic acid 200mg bid for 2 weeks. NCT04487964.

risk of death, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 25 (0.0%), control 5 of 25 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events, day 14.

risk of mechanical ventilation, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 25 (0.0%), control 5 of 25 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events, day 14.

recovery time, 44.0% lower, relative time 0.56, p < 0.001, treatment 25, control 25.

risk of no recovery, 33.3% lower, RR 0.67, p < 0.001, treatment 25, control 25, relative clinical status, day 14.

Gomaa et al., 3/1/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Egypt, Africa, peer-reviewed, median age 60.0, 5 authors, study period June 2021 - November 2021, average treatment delay 6.0 days, this trial uses multiple treatments in the treatment arm (combined with boswellic acid) - results of individual treatments may vary, trial NCT04487964.

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

A Randomized Trial of Sitagliptin and Spironolactone With Combination Therapy in Hospitalized Adults With COVID-19

Abbasi et al., Journal of the Endocrine Society, doi:10.1210/jendso/bvac017

RCT including 51 spironolactone patients and 87 control patients in Iran, showing improved recovery with spironolactone, sitagliptin, and the combination of both.

risk of death, 55.1% lower, RR 0.45, p = 0.10, treatment 5 of 51 (9.8%), control 19 of 87 (21.8%), NNT 8.3, day 5.

risk of mechanical ventilation, 33.7% lower, RR 0.66, p = 0.36, treatment 7 of 51 (13.7%), control 18 of 87 (20.7%), NNT 14, day 5.

risk of ICU admission, 18.8% lower, RR 0.81, p = 0.67, treatment 10 of 51 (19.6%), control 21 of 87 (24.1%), NNT 22, day 5.

risk of no recovery, 47.3% lower, RR 0.53, p < 0.001, treatment mean 1.64 (±0.81) n=51, control mean 3.11 (±2.45) n=87, relative clinical score, day 5.

Abbasi et al., 2/7/2022, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 11 authors, study period December 2020 - April 2021.

Mineralocorticoid Receptor Antagonist (Potassium Canrenoate) Does Not Influence Outcome in the Treatment of COVID-19-Associated Pneumonia and Fibrosis—A Randomized Placebo Controlled Clinical Trial

Kotfis et al., Pharmaceuticals, doi:10.3390/ph15020200

RCT with 24 patients treated with potassium canrenoate and 25 placebo patients in Poland, showing no significant differences.

risk of death, 16.7% lower, RR 0.83, p = 1.00, treatment 4 of 24 (16.7%), control 5 of 25 (20.0%), NNT 30.

risk of ICU admission, 10.7% lower, RR 0.89, p = 1.00, treatment 6 of 24 (25.0%), control 7 of 25 (28.0%), NNT 33.

relative TFS score, 30.4% better, RR 0.70, p = 0.51, treatment 24, control 25.

Kotfis et al., 2/5/2022, Randomized Controlled Trial, placebo-controlled, Poland, Europe, peer-reviewed, 10 authors, study period December 2020 - August 2021, trial NCT04912011.

Combination of Spironolactone and Sitagliptin Improves Clinical Outcomes of Outpatients with COVID-19: An Observational Study

Davarpanah et al., medRxiv, doi:10.1101/2022.01.21.22269322 (Preprint)

Prospective study of 206 outpatients in Iran, 103 treated with spironolactone and sitagliptin, showing lower hospitalization and faster recovery with treatment. spironolactone 100mg and sitagliptin 100mg daily.

risk of hospitalization, 78.3% lower, RR 0.22, p < 0.001, treatment 6 of 103 (5.8%), control 23 of 103 (22.3%), NNT 6.1, OR converted to RR.

recovery time, 64.4% lower, relative time 0.36, p < 0.001, treatment 103, control 103.

Davarpanah et al., 1/21/2022, prospective, Iran, Middle East, preprint, 9 authors, study period July 2021 - September 2021, average treatment delay 5.74 days, this trial uses multiple treatments in the treatment arm (combined with sitagliptin) - results of individual treatments may vary.

5α-Reductase Inhibitors Are Associated with Reduced Risk of SARS-CoV-2 Infection: A Matched-Pair, Registry-Based Analysis

Lyon et al., Journal of Urology, doi:10.1097/JU.0000000000002180

Retrospective 944 5ARI users in the USA and 944 matched controls, showing lower risk of COVID-19 cases with treatment.

risk of death, 16.9% lower, RR 0.83, p = 0.61, treatment 15 of 944 (1.6%), control 19 of 994 (1.9%), NNT 310.

risk of case, 7.2% lower, RR 0.93, p = 0.04, treatment 399 of 944 (42.3%), control 446 of 994 (44.9%), NNT 38, adjusted, OR converted to RR, multivariable.

Lyon et al., 1/31/2022, retrospective, USA, North America, peer-reviewed, 8 authors, study period 8 March, 2020 - 15 February, 2021.

An integrative approach to clinical recovery for COVID-19 patients using an Ayurvedic formulation: A multicentric double-blind randomized control trial.

Bhardwaja et al., Research Square, doi:10.21203/rs.3.rs-1165680/v1 (Preprint)

Small RCT with 39 patients treated with NOQ19 and 37 placebo patients, showing improved recovery, without statistical significance. NOQ19 has multiple ingredients including curcumin and antiandrogen glycyrrhiza glabra. CTRI/2021/05/033790.

risk of no hospital discharge, 36.8% lower, RR 0.63, p = 0.67, treatment 2 of 39 (5.1%), control 3 of 37 (8.1%), NNT 34, day 7.

risk of no recovery, 89.1% lower, RR 0.11, p = 0.05, treatment 0 of 39 (0.0%), control 4 of 37 (10.8%), NNT 9.2, relative risk is not 0 because of continuity correction due to zero events, oxygen supplementation, day 5.

risk of no recovery, 80.4% lower, RR 0.20, p = 0.23, treatment 0 of 39 (0.0%), control 2 of 37 (5.4%), NNT 18, relative risk is not 0 because of continuity correction due to zero events, day 7, dsypnea.

risk of no recovery, 2.8% higher, RR 1.03, p = 1.00, treatment 13 of 39 (33.3%), control 12 of 37 (32.4%), day 7, fever.

risk of no viral clearance, 24.1% lower, RR 0.76, p = 0.47, treatment 12 of 39 (30.8%), control 15 of 37 (40.5%), NNT 10, day 7.

risk of no viral clearance, 5.1% lower, RR 0.95, p = 1.00, treatment 19 of 39 (48.7%), control 19 of 37 (51.4%), NNT 38, day 5.

risk of no viral clearance, 12.4% lower, RR 0.88, p = 0.47, treatment 24 of 39 (61.5%), control 26 of 37 (70.3%), NNT 11, day 3.

Excluded in meta analysis: combined treatments may contribute more to the effect seen.

Bhardwaja et al., 12/27/2021, Double Blind Randomized Controlled Trial, India, South Asia, preprint, 26 authors, this trial uses multiple treatments in the treatment arm (combined with 18 other ingredients) - results of individual treatments may vary.

Androgen deprivation therapy, comorbidity, cancer stage and mortality from COVID-19 in men with prostate cancer

Gedeborg et al., Scandinavian Journal of Urology, doi:10.1080/21681805.2021.2019304

Case control study with 474 patients that died of COVID-19 in Sweden, showing higher risk with ADT, without statistical significance.

risk of death, 25.0% higher, OR 1.25, p = 0.11, treatment 271 of 474 (57.2%) cases, 5,181 of 23,700 (21.9%) controls, case control OR.

Gedeborg et al., 12/23/2021, retrospective, Sweden, Europe, peer-reviewed, 6 authors.

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

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. This paper also includes a retrospective study which is listed separately, and an In Vitro HBEC study showing no significant differences (p = 0.084). The supplementary data is not currently available. NCT04475601.

For discussion of issues with this study see [sciencedirect.com, sciencedirect.com (B), sciencedirect.com (C), sciencedirect.com (D)].

1. sciencedirect.com, https://www.sciencedirect.com/science/article/pii/S030228382201661X.

2. sciencedirect.com (B), https://www.sciencedirect.com/science/article/pii/S0302283822016591.

3. sciencedirect.com (C), https://www.sciencedirect.com/science/article/pii/S0302283822016062.

4. sciencedirect.com (D), https://www.sciencedirect.com/science/article/pii/S0302283822016050.

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.

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.

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

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

Welén et al., 12/14/2021, Randomized Controlled Trial, Sweden, Europe, peer-reviewed, 27 authors, average treatment delay 9.5 days, trial NCT04475601.

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

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.
This paper also includes a small RCT which is listed separately, and an In Vitro HBEC study showing no significant differences (p = 0.084). The supplementary data is not currently available. NCT04475601.

For discussion of issues with this study see [sciencedirect.com, sciencedirect.com (B), sciencedirect.com (C), sciencedirect.com (D)].

1. sciencedirect.com, https://www.sciencedirect.com/science/article/pii/S030228382201661X.

2. sciencedirect.com (B), https://www.sciencedirect.com/science/article/pii/S0302283822016591.

3. sciencedirect.com (C), https://www.sciencedirect.com/science/article/pii/S0302283822016062.

4. sciencedirect.com (D), https://www.sciencedirect.com/science/article/pii/S0302283822016050.

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

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

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

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

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

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

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

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

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

Welén et al., 12/14/2021, retrospective, Sweden, Europe, peer-reviewed, 27 authors, trial NCT04475601.

Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis

Duarte et al., Infectious Agents and Cancer, doi:10.1186/s13027-021-00406-y

Retrospective 199 prostate cancer patients hospitalized with COVID-19 in Brazil, showing no significant difference in mortality with active ADT.

risk of death, 11.2% lower, RR 0.89, p = 0.37, treatment 100 of 156 (64.1%), control 32 of 43 (74.4%), NNT 9.7, adjusted, OR converted to RR.

Duarte et al., 11/25/2021, retrospective, Brazil, South America, peer-reviewed, 4 authors.

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

Schmidt et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.34330

Retrospective 1,106 prostate cancer patients, showing no significant differences in COVID-19 outcomes with ADT.

risk of death, 20.4% lower, RR 0.80, p = 0.41, treatment 25 of 169 (14.8%), control 44 of 308 (14.3%), adjusted, OR converted to RR, propensity score matching, multivariable.

risk of severe case, 2.0% lower, OR 0.98, p = 0.94, treatment 169, control 308, adjusted, propensity score matching, multivariable, RR approximated with OR.

Schmidt et al., 11/12/2021, retrospective, USA, North America, peer-reviewed, 42 authors, study period 17 March, 2020 - 11 February, 2021.

The clinical impact of androgen deprivation therapy on SARS-CoV-2 infection rates and disease severity

Kazan et al., Türk Üroloji Dergisi/Turkish Journal of Urology, doi:10.5152/tud.2021.21278

Retrospective 365 prostate cancer patients in Turkey, 138 treated with ADT, showing no significant differences with treatment.

risk of hospitalization, 229.0% higher, RR 3.29, p = 0.20, treatment 4 of 138 (2.9%), control 2 of 227 (0.9%).

risk of case, 28.7% lower, RR 0.71, p = 0.32, treatment 13 of 138 (9.4%), control 30 of 227 (13.2%), NNT 26.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Kazan et al., 11/1/2021, retrospective, Turkey, Europe, peer-reviewed, 10 authors, study period August 2020 - June 2021.

Assessment Of The Efficacy Of Spironolactone For COVID-19 ARDS Patients

Ersoy et al., Aydin Sağlik Dergi̇si̇, doi:10.17932/IAU.ASD.2015.007/asd_v07i3002

Retrospective 30 COVID-19 ARDS ICU patients and 30 control patients, showing lower mortality with treatment.

risk of death, 46.2% lower, RR 0.54, p = 0.002, treatment 14 of 30 (46.7%), control 26 of 30 (86.7%), NNT 2.5.

Ersoy et al., 10/13/2021, retrospective, Turkey, Europe, peer-reviewed, 7 authors.

Influence of androgen deprivation therapy on the severity of COVID‐19 in prostate cancer patients

Jiménez-Alcaide et al., The Prostate, doi:10.1002/pros.24232

Retrospective 1,349 prostate cancer patients in Spain, 156 on ADT, showing no significant differences in COVID-19 outcomes with treatment.

risk of death, 33.0% lower, RR 0.67, p = 0.41, treatment 3 of 11 (27.3%), control 17 of 50 (34.0%), adjusted, multivariable.

risk of progression, 8.0% higher, RR 1.08, p = 0.77, treatment 11, control 50, adjusted, multivariable.

risk of case, 68.2% higher, RR 1.68, p = 0.15, treatment 11 of 156 (7.1%), control 50 of 1,193 (4.2%), excluded in exclusion analyses: excessive unadjusted differences between groups.

Jiménez-Alcaide et al., 9/13/2021, retrospective, Spain, Europe, peer-reviewed, 9 authors.

COVID-19 in Individuals Treated With Long-Term Hydroxychloroquine: A Propensity Score-Matched Analysis of Cicatricial Alopecia Patients

Shaw et al., Journal of Drugs in Dermatology, doi:10.36849/JDD.5843

PSM retrospective 144 alopecia patients in the USA, showing no significant difference in COVID-19 cases with anti-androgen use. The supplemental appendix is not available.

risk of case, 6.0% lower, OR 0.94, p = 0.006, treatment 47, control 97, adjusted, propensity score matching, multivariable, RR approximated with OR.

Shaw et al., 7/1/2021, retrospective, USA, North America, peer-reviewed, 10 authors, study period 1 March, 2020 - 15 May, 2020.

The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

Leach et al., Nature Communications, doi:10.1038/s41467-021-24342-y

In Vitro and animal study showing that the antiandrogen enzalutamide reduces TMPRSS2 levels in human lung cells and in mouse lungs.

Leach et al., 7/1/2021, peer-reviewed, 10 authors.

Do Anti-androgens Have Potential as Therapeutics for COVID-19?

Mauvais-Jarvis et al., Endocrinology, doi:10.1210/endocr/bqab114 (Review)

Review of research related to the potential benefits of anti-androgrens for COVID-19.

Mauvais-Jarvis et al., 6/5/2021, peer-reviewed, 1 author.

Finasteride in hospitalized adult males with COVID-19: A risk factor for severity of the disease or an adjunct treatment: A randomized controlled clinical trial

Zarehoseinzade et al., Medical Journal of The Islamic Republic of Iran, doi:10.47176/mjiri.35.30

RCT 80 hospitalized COVID-19 patients in Iran, 40 treated with finasteride, showing no significant differences other than improved oxygen saturation on the 5th day with treatment. There was significantly more patients with diabetes in the control group. 5mg finasteride for 7 days. IRCT20200505047318N1.

risk of death, 75.0% lower, RR 0.25, p = 0.36, treatment 1 of 40 (2.5%), control 4 of 40 (10.0%), NNT 13.

risk of ICU admission, no change, RR 1.00, p = 1.00, treatment 1 of 40 (2.5%), control 1 of 40 (2.5%).

Zarehoseinzade et al., 4/30/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 5 authors.

Effect of Spironolactone on COVID-19 in Patients With Underlying Liver Cirrhosis: A Nationwide Case-Control Study in South Korea

Jeon et al., Frontiers in Medicine, doi:10.3389/fmed.2021.629176

Retrospective 6,462 liver cirrhosis patients in South Korea, with 67 COVID+ cases, showing significantly lower COVID-19 cases with spironolactone treatment. Death and ICU results per group are not provided. Complications in this study included receipt of antivirals, e.g., treatment with oseltamivir.

risk of case, 77.0% lower, OR 0.23, p = 0.005, treatment 6 of 49 (12.2%) cases, 89 of 245 (36.3%) controls, NNT 6.5, case control OR, model 2, within 3 months.

Jeon et al., 2/23/2021, retrospective, South Korea, Asia, peer-reviewed, 3 authors.

Androgen Deprivation Therapy in Men with Prostate Cancer Does Not Affect Risk of Infection with SARS-CoV-2

Klein et al., Journal of Urology, doi:10.1097/JU.0000000000001338

Retrospective 1,779 prostate cancer patients, showing no significant differences in COVID-19 outcomes with ADT.

risk of death, 123.9% higher, RR 2.24, p = 0.12, treatment 6 of 304 (2.0%), control 13 of 1,475 (0.9%).

risk of case, 6.6% lower, RR 0.93, p = 0.80, treatment 17 of 304 (5.6%), control 85 of 1,475 (5.8%), NNT 586, adjusted, OR converted to RR, multivariable.

Klein et al., 2/1/2021, retrospective, USA, North America, peer-reviewed, 7 authors, study period 12 March, 2020 - 10 June, 2020.

Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial – Biochemical)

Cadegiani et al., Cureus, doi:10.7759/cureus.13047

RCT 130 outpatients in Brazil, 54 treated with dutasteride, showing faster recovery with treatment. All patients received nitazoxanide. There were no hospitalizations, mechanical ventilation, or deaths. Some percentages for viral clearance in Table 3 do not match the group sizes, and a third-party analysis suggests possible randomization failure. 34110420.2.0000.0008.

risk of no recovery, 62.0% lower, RR 0.38, p = 0.009, treatment 7 of 44 (15.9%), control 18 of 43 (41.9%), NNT 3.9.

recovery time, 43.6% lower, relative time 0.56, p < 0.001, treatment 44, control 43, all symptoms.

recovery time, 40.2% lower, relative time 0.60, p < 0.001, treatment 44, control 43, all symptoms except loss of smell or taste.

Excluded in after exclusion results of meta analysis: potential randomization failure.

Cadegiani et al., 2/1/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 4 authors.

Androgen-deprivation therapy and SARS-CoV-2 in men with prostate cancer: findings from the University of California Health System registry

Kwon et al., Annals of Oncology, doi:10.1016/j.annonc.2021.01.067

Retrospective 5,211 prostate cancer patients, 799 on ADT, showing no significant differences in COVID-19 outcomes with treatment.

risk of death, 21.1% lower, RR 0.79, p = 1.00, treatment 1 of 799 (0.1%), control 7 of 4,412 (0.2%), NNT 2985.

risk of case, 17.6% higher, RR 1.18, p = 0.54, treatment 18 of 799 (2.3%), control 79 of 4,412 (1.8%), adjusted, OR converted to RR, multivariable.

Kwon et al., 1/29/2021, retrospective, USA, North America, peer-reviewed, 7 authors.

Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)

Mareev et al., Кардиология, doi:10.18087/cardio.2020.11.n1440

Prospective 103 PCR+ patients in Russia, 33 treated with bromexhine+spironolactone, showing lower PCR+ at day 10 or hospitalization >10 days with treatment. Bromhexine 8mg 4 times daily, spironolactone 25-50 mg/day for 10 days.

relative SHOKS-COVID score, 11.3% better, RR 0.89, p = 0.47, treatment mean 2.12 (±1.39) n=33, control mean 2.39 (±1.59) n=33.

risk of PCR+ on day 10 or hospitalization >10 days, 38.8% lower, RR 0.61, p = 0.02, treatment 14 of 24 (58.3%), control 20 of 21 (95.2%), NNT 2.7, OR converted to RR.

hospitalization time, 8.2% lower, relative time 0.92, p = 0.35, treatment 33, control 33.

risk of no viral clearance, 87.4% lower, RR 0.13, p = 0.08, treatment 0 of 17 (0.0%), control 3 of 13 (23.1%), NNT 4.3, relative risk is not 0 because of continuity correction due to zero events, day 10.

Mareev et al., 12/3/2020, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 20 authors, this trial uses multiple treatments in the treatment arm (combined with bromhexine) - results of individual treatments may vary.

5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia

McCoy et al., Journal of the European Academy of Dermatology and Venereology, doi:10.1111/jdv.17021

Retrospective 48 androgenetic alopecia patients in Brazil treated with dutasteride, compared with 48 propensity score matched androgenetic alopecia patients not taking any 5ARis, showing a statistically significant reduction in the frequency of 20 of 29 COVID-19 symptoms with treatment.

McCoy et al., 11/2/2020, retrospective, Brazil, South America, peer-reviewed, 11 authors.

An open-label prospective observational study of antiandrogen and non-antiandrogen early pharmacological approaches in females with mild-to-moderate COVID-19. The Pre-AndroCoV Female Trial

Cadegiani et al., medRxiv, doi:10.1101/2020.10.05.20206870 (Preprint)

Prospective study of 270 female COVID-19 patients in Brazil, 75 with hyperandrogenism, of which 8 were on spironolactone. Results suggest that HA patients may be at increased risk, and that spironolactone use may reduce the risk compared to both other HA patients and non-HA patients. SOC included other treatments and there was no mortality or hospitalization.

recovery time, 76.7% lower, relative time 0.23, p = 0.006, treatment 8, control 262, excluding anosmia.

recovery time, 82.8% lower, relative time 0.17, p = 0.002, treatment 8, control 262, including anosmia.

time to viral-, 37.9% lower, relative time 0.62, p = 0.02, treatment 8, control 262.

Excluded in after exclusion results of meta analysis: significant unadjusted differences between groups.

Cadegiani et al., 10/6/2020, prospective, Brazil, South America, preprint, 4 authors, average treatment delay 3.0 days.

Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men

Goren et al., Journal of the European Academy of Dermatology and Venereology, doi:10.1111/jdv.16953

Prospective study of 77 men hospitalized with COVID-19, 12 taking antiandrogens (9 dutasteride, 2 ﬁnasteride, 1 spironolactone), showing lower ICU admission with treatment (statistically significant with age-matched controls only when excluding the spironolactone patient). NCT04368897.

risk of ICU admission, 81.0% lower, RR 0.19, p = 0.08, treatment 1 of 12 (8.3%), control 17 of 36 (47.2%), NNT 2.6, adjusted, age-matched controls.

risk of ICU admission, 86.0% lower, RR 0.14, p = 0.04, treatment 1 of 12 (8.3%), control 38 of 65 (58.5%), NNT 2.0, adjusted, all controls.

risk of death, 50.0% higher, RR 1.50, p = 1.00, treatment 1 of 12 (8.3%), control 2 of 36 (5.6%), age-matched controls.

risk of death, 35.4% higher, RR 1.35, p = 0.58, treatment 1 of 12 (8.3%), control 4 of 65 (6.2%), all controls.

Goren et al., 9/25/2020, prospective, Brazil, South America, peer-reviewed, 15 authors, trial NCT04368897.

Impact of anti-androgen therapies on COVID-19 susceptibility: a case-control study in male population from two COVID-19 regional centers of Lombardy (Italy)

Lazzeri et al., medRxiv, doi:10.1101/2020.04.20.20068056 (Preprint)

Retrospective case-control study in Italy with 943 male COVID-19 patients, 45 on chronic 5ARI treatment (finasteride/dutasteride). There was significantly fewer COVID-19 patients >55 on 5ARI treatment compared to age-matched controls (5.57 vs. 8.14%, p=0.0083). The difference was greater for men aged >65 (7.14 vs. 12.31%, p=0.0001). There was no significant difference for ICU admission or death.

risk of death/ICU, 23.0% higher, OR 1.23, p = 0.33, multivariable, RR approximated with OR.

Lazzeri et al., 9/21/2020, retrospective, Italy, Europe, preprint, 11 authors.

The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients

Vicenzi et al., Journal of Clinical Medicine, doi:10.3390/jcm9092943

Retrospective 69 consecutive hospitalized COVID-19 patients in Italy, 30 patients receiving canrenone, and 39 treated with vasodilator agents or renin–angiotensin–aldosterone system (RAAS) inhibitors, showing lower mortality with canrenone.

risk of death, 93.0% lower, HR 0.07, p < 0.001, treatment 30, control 39, adjusted, model 2, multivariable.

risk of death/intubation, 81.0% lower, HR 0.19, p = 0.002, treatment 30, control 39, adjusted, model 2, multivariable.

Vicenzi et al., 9/11/2020, retrospective, Italy, Europe, peer-reviewed, 10 authors, this trial compares with another treatment - results may be better when compared to placebo.

Androgen deprivation therapy may constitute a more effective COVID-19 prophylactic than therapeutic strategy

Bennani et al., Annals of Oncology, doi:10.1016/j.annonc.2020.08.2095

Retrospective 118 prostate cancer patients, 4 on androgren deprivation therapy, not showing significant differences (as expected with only 4 patients in the treatment group).

risk of death, 94.9% lower, RR 0.05, p = 1.00, treatment 0 of 4 (0.0%), control 18 of 114 (15.8%), NNT 6.3, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 119.2% higher, RR 2.19, p = 0.40, treatment 1 of 4 (25.0%), control 13 of 114 (11.4%).

risk of hospitalization, 25.0% lower, RR 0.75, p = 0.60, treatment 2 of 4 (50.0%), control 76 of 114 (66.7%), NNT 6.0.

risk of severe case, 8.1% lower, RR 0.92, p = 1.00, treatment 1 of 4 (25.0%), control 31 of 114 (27.2%), NNT 46.

Bennani et al., 8/17/2020, retrospective, Italy, Europe, peer-reviewed, 2 authors.

Does androgen deprivation therapy protect against severe complications from COVID-19?

Patel et al., Annals of Oncology, doi:10.1016/j.annonc.2020.06.023

Retrospective 58 prostate cancer patients in the USA, showing lower risk of hospitalization with ADT.

risk of death, 55.2% lower, RR 0.45, p = 0.22, treatment 4 of 22 (18.2%), control 10 of 36 (27.8%), adjusted, OR converted to RR, multivariable.

risk of mechanical ventilation, 69.0% lower, OR 0.31, p = 0.19, treatment 22, control 36, adjusted, multivariable, RR approximated with OR.

risk of hospitalization, 77.0% lower, OR 0.23, p = 0.02, treatment 22, control 36, adjusted, multivariable, RR approximated with OR.

Patel et al., 7/9/2020, retrospective, USA, North America, peer-reviewed, 7 authors, study period 1 March, 2020 - 4 June, 2020.

Androgen deprivation and SARS-CoV-2 in men with prostate cancer

Koskinen et al., Annals of Oncology, doi:10.1016/j.annonc.2020.06.015

Retrospective 352 prostate cancer patients in Finland, showing no significant differences in COVID-19 with ADT.

risk of death, 45.8% lower, RR 0.54, p = 1.00, treatment 1 of 134 (0.7%), control 3 of 218 (1.4%), NNT 159.

risk of death/ICU, 45.8% lower, RR 0.54, p = 1.00, treatment 1 of 134 (0.7%), control 3 of 218 (1.4%), NNT 159.

risk of case, 11.3% lower, RR 0.89, p = 1.00, treatment 6 of 134 (4.5%), control 11 of 218 (5.0%), NNT 176.

Koskinen et al., 6/29/2020, retrospective, Finland, Europe, peer-reviewed, 7 authors.

Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The “Gabrin sign”

Wambier et al., Journal of the American Academy of Dermatology, doi:10.1016/j.jaad.2020.05.079

Analysis of 175 patients hospitalized with severe COVID-19, showing androgenetic alopecia (AGA) in 42% of women and 79% of men. Authors hypothesize that COVID-19 severity is androgen-mediated, and recommend study of antiandrogen treatments.

Wambier et al., 5/21/2020, peer-reviewed, 14 authors.

Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532)

Montopoli et al., Annals of Oncology, doi:10.1016/j.annonc.2020.04.479

Retrospective 5,273 prostate cancer patients on androgen-deprivation therapy (ADT), and 37,161 not on ADT, showing lower risk of cases with treatment.

risk of death, 95.4% lower, RR 0.05, p = 0.15, treatment 0 of 5,273 (0.0%), control 18 of 37,161 (0.0%), NNT 2064, relative risk is not 0 because of continuity correction due to zero events.

risk of severe case, 74.5% lower, RR 0.25, p = 0.01, treatment 1 of 5,273 (0.0%), control 31 of 37,161 (0.1%), NNT 1551, OR converted to RR.

risk of case, 75.3% lower, RR 0.25, p = 0.004, treatment 4 of 5,273 (0.1%), control 114 of 37,161 (0.3%), NNT 433, OR converted to RR.

Montopoli et al., 5/6/2020, retrospective, Italy, Europe, peer-reviewed, 12 authors.

Antiandrogens	(meta)	Lactoferrin	(meta)
Aspirin	(meta)	Melatonin	(meta)
Bamlaniv../e..	(meta)	Metformin	(meta)
Bebtelovimab	(meta)	Molnupiravir	(meta)
Bromhexine	(meta)	N-acetylcys..	(meta)
Budesonide	(meta)	Nigella Sativa	(meta)
Cannabidiol	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption