Proxalutamide Improves Inflammatory, Immunologic, and Thrombogenic Markers in Mild-to-Moderate COVID-19 Males and Females: an Exploratory Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial Early Antiandrogen Therapy (EAT) with Proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial)
Flávio Adsuara Cadegiani, MD Andy Goren, MD, PhD Carlos Gustavo Wambier, MD Ricardo Ariel Zimerman
doi:10.1101/2021.07.24.21261047
Background: The androgen theory on COVID-19 is based on the fact that males, in particular when affected by androgenetic alopecia, and females with hyperandrogenic states are more severely affected by COVID-19, while chronic users of antiandrogens experiment lower rates of COVID-19 complications. The theory finds plausibility on the androgen-mediated transmembrane protease serine 2 (TMPRSS-2), a key protein for SARS-CoV-2 cell entry. We demonstrated reduction of hospitalization rate using a potent non-steroidal antiandrogen (NSAA), proxalutamide, in both females and males COVID-19 outpatients. In this joint exploratory analysis, we aimed to demonstrate whether the efficacy of proxalutamide on mild-to-moderate COVID-19 could be justified by improvements in inflammatory, immunologic, and thrombogenic responses. Methods: This is a joint post-hoc analysis of two double-blind, placebo-controlled twoarm randomized clinical trials (RCTs) on proxalutamide 200mg/day for seven days for female and male COVID-19 outpatients, respectively, compared to standard of care (SOC), of hematocrit, neutrophils lymphocytes, eosinophils, platelets, neutrophil-tolymphocyte (N/L) ratio, ferritin, fibrinogen, D-dimer, ultrasensitive C-reactive protein (usCRP) lactate 1-hour erythrocyte sedimentation rate (1hESR), total testosterone, estradiol, sex hormone binding globulin (SHBG), oxygen saturation and heart rate measured on days 0, 1 and 7. Results: A total of 445 subjects were enrolled (268 males and 177 females) between October 21 th 2020 and February 28 th 2021, with similar baseline characteristics. Neutrophils were lower in proxalutamide group in Day 1 (p = 0.005) and Day 7 (p < 0.0001). Lymphocytes were higher in the proxalutamide group in Day 7 (p = 0.0001). Eosinophils were higher in the proxalutamide arm in Day 1 (p = 0.04) and Day 7 (p < 0.00010. In Day 7, platelets were higher in proxalutamide arm (p = 0.03). Ferritin levels were lower in proxalutamide arm in Day 7 (p = 0.03) Fibrinogen levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). D-dimer levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). UsCRP levels were reduced in proxalutamide group in Day 7 (p < 0.0001). 1hESR) was reduced in proxalutamide arm in Day 1 (p = 0.0009) and Day 7 (p < 0.0001). In males, testosterone levels were higher in proxalutamide group in Day 1 (p = 0.048) and Day 7 (p = 0.0001). In females, testosterone levels were higher in proxalutamide group in Day 7 (p = 0.018), .
24, 25 The use of antiandrogens as a promising therapy for COVID-19 is based on the androgen theory on COVID-19. We have previously shown that males, particularly those exhibiting AGA, BPH and or genetic polymorphisms in AR, were more severely affected by COVID-19 1,2-5 . Women with hyperandrogenism phenotypes have also been associated with worse prognosis. 7, 8 Finally, we have recently shown that athletes abusing DHT derived AAs may be predisposed to more severe SARS-CoV-2 infections and complications. 12 Males under androgenic deprivation therapy (ADT) for castrationresistant prostate cancer were linked to lower risk of severe COVID-19, which is unexpected, since ADT may lead to immunosuppression and increased frailty, compared to non-ADT. [9] [10] [11] In an early report of two of our randomized, placebo controlled, double blind clinical trials on Early Anti-androgenic Therapy (EAT) for COVID-19 with two antiandrogens, dutasteride and proxalutamide, we were able to prove the concept that anti-androgenic therapy has a definitive antiviral effect. 17, 26 In the case of proxalutamide, this effect was consistent for both male and females. Proxalutamide antiviral effects may be ascribed both to ACE-2 and TMPRSS-2 down regulation. 21 The importance of viral load as a surrogate marker has being increasingly recognized, as it directly relates to critical clinical outcomes, such as mechanical ventilation use and death. Unfortunately, because dependence on availability..
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The '
'androgen theory on COVID-19 is based on the fact that males, in particular when affected by '
'androgenetic alopecia, and females with hyperandrogenic states are more severely affected by '
'COVID-19, while chronic users of antiandrogens experiment lower rates of COVID-19 '
'complications. The theory finds plausibility on the androgen-mediated transmembrane protease '
'serine 2 (TMPRSS-2), a key protein for SARS-CoV-2 cell entry. We demonstrated reduction of '
'hospitalization rate using a potent non-steroidal antiandrogen (NSAA), proxalutamide, in both '
'females and males COVID-19 outpatients. In this joint exploratory analysis, we aimed to '
'demonstrate whether the efficacy of proxalutamide on mild-to-moderate COVID-19 could be '
'justified by improvements in inflammatory, immunologic, and thrombogenic '
'responses.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This is a '
'joint <jats:italic>post-hoc</jats:italic> analysis of two double-blind, placebo-controlled '
'two-arm randomized clinical trials (RCTs) on proxalutamide 200mg/day for seven days for '
'female and male COVID-19 outpatients, respectively, compared to standard of care (SOC), of '
'hematocrit, neutrophils lymphocytes, eosinophils, platelets, neutrophil-to-lymphocyte (N/L) '
'ratio, ferritin, fibrinogen, D-dimer, ultrasensitive C-reactive protein (usCRP) lactate '
'1-hour erythrocyte sedimentation rate (1hESR), total testosterone, estradiol, sex hormone '
'binding globulin (SHBG), oxygen saturation and heart rate measured on days 0, 1 and '
'7.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 445 '
'subjects were enrolled (268 males and 177 females) between October 21<jats:sup>th</jats:sup> '
'2020 and February 28<jats:sup>th</jats:sup> 2021, with similar baseline characteristics. '
'Neutrophils were lower in proxalutamide group in Day 1 (p = 0.005) and Day 7 (p < 0.0001). '
'Lymphocytes were higher in the proxalutamide group in Day 7 (p = 0.0001). Eosinophils were '
'higher in the proxalutamide arm in Day 1 (p = 0.04) and Day 7 (p < 0.00010. In Day 7, '
'platelets were higher in proxalutamide arm (p = 0.03). Ferritin levels were lower in '
'proxalutamide arm in Day 7 (p = 0.03) Fibrinogen levels were lower in proxalutamide group in '
'Days 1 and 7 (p < 0.0001 for both days). D-dimer levels were lower in proxalutamide group '
'in Days 1 and 7 (p < 0.0001 for both days). UsCRP levels were reduced in proxalutamide '
'group in Day 7 (p < 0.0001). 1hESR) was reduced in proxalutamide arm in Day 1 (p = 0.0009) '
'and Day 7 (p < 0.0001). In males, testosterone levels were higher in proxalutamide group '
'in Day 1 (p = 0.048) and Day 7 (p = 0.0001). In females, testosterone levels were higher in '
'proxalutamide group in Day 7 (p = 0.018), and estradiol levels were higher in proxalutamide '
'arm in Day 1 (p = 0.044). Oxygen saturation was higher in proxalutamide in Day 1 (p = 0.0006) '
'and Day 7 (p < '
'0.0001).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The '
'substantial improvements observed in immunologic, inflammatory, thrombotic and oxygen markers '
'with proxalutamide may support the reduction of hospitalization rate observed in both females '
'and males with COVID-19 using proxalutamide, compared to standard of '
'care.</jats:p></jats:sec>',
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