With the increasing prevalence of the Delta variant and its higher viral loads, transmissibility, and hospital severity, additional and more potent options are sometimes required. Different drug combinations are now possible and use will depend on the availability and feasibility of prescribing the drug in various countries and regions. Ivermectin should be kept as the cornerstone of COVID-19 treatments and should be given at higher doses in Delta variant infected patients. Higher-doses of ivermectin can be combined with one or more options. Anti-androgens are good options to combine with high-dose ivermectin due to likely enhanced response, since they have distinct mechanisms of action. Nitazoxanide may also be combined with ivermectin. Fluvoxamine may cause significant side effects, thus we suggest using fluoxetine as an alternative to improve tolerance. Either way, such agents may improve responsiveness even further when combined with ivermectin. Lastly, higher risk patients often develop severe forms of COVID-19 therefore more numerous multi-drug therapy should be considered in such cases. In all cases, oral and nasal rinsing, vitamin D, vitamin C, zinc, melatonin, quercetin and aspirin are mandatory.

You do not need to use all these medications as explained in #1 above. Our objective is to provide additional options for different clinical circumstances and risk factors for severe COVID-19. However, we do encourage the use of higher doses of ivermectin, two-drug combinations, and the supplements for the Delta variant. All proposed medications in our protocols are already existing drugs repurposed for COVID-19 with a well-established long-term safety profile in both men and women. No significant pharmacological interactions have been described for any of the possible combinations.

Although androgens are hormones with testosterone-like actions, i.e., they interact with the testosterone receptor (more precisely called an “androgen receptor”), women not only have receptors for androgens but tend to present increased sensitivity to androgens.
Hence, anti-androgen therapy is not only for men, but also for women.

To better understand why anti-androgen therapy is an important new therapeutic target, a few points must first be emphasized:

1. There are clear gender disparities in terms of COVID-19 severity:

  • males with androgenic alopecia (hair loss, baldness) are at higher risk
  • users of anabolic androgenic steroids for recreational purposes are at higher risk
  • women with hyperandrogenic phenotypes (polycystic ovarian syndrome, hirsutism…) present with greater symptoms of COVID-19
  • children (pre-puberty) are notably protected against more severe COVID-19

2. There is evidence that TMPRSS-2 (an endothelial cell surface protein) is critical for SARS-CoV-2 cell entry since it primes (‘prepares’) the virus to couple to ACE-2 and enter cells. TMPRSS-2 is almost solely regulated by androgens.

3. In vitro (in the lab), we discovered that proxalutamide, an anti-androgen, blocks SARS-CoV-2 cell entry and reduces inflammatory markers, likely reflecting that this is the effect of the entire class of drugs.

4. There is evidence that chronic antiandrogen users of different modalities (5alpha-reductase inhibitors, non-steroidal anti-androgens, high-dose spironolactone) for a variety of diseases (prostate cancer, benign prostate hyperplasia, androgenéticos alopecia, hirsutism, polycystic ovarian syndrome, etc…) are protected against severe COVID-19.

5. Spironolactone, dutasteride and proxalutamide have been shown effective for early COVID-19 treatment, during this viral replicative phase.

6. Unexpected anti-inflammatory, immune-regulatory and antithrombotic effects were observed with dutasteride and proxalutamide use, allowing us to hypothesize its efficacy in later stages of COVID-19. Studies have confirmed that in the highly pathogenic variant of concern (VOC) gamma (P1) variant, the anti-androgen drug proxalutmide led to massive reductions in mortality in a large randomized controlled trial. Finasteride has also shown to be beneficial for hospitalized patients.

Androgens regulate SARS-CoV-2 receptor
Prostate drugs and SARS-CoV-2
Spironolactone and Covid-19

Nitazoxanide (nit-a-zox-a-nide) is, like ivermectin, a known anti-parasitic drug that was later found to be effective against a wide variety of viruses, from influenza to rotavirus. Nitazoxanide is officially approved (on-label) to treat rotavirus gastrointestinal infections in children in some countries. Although nitazoxanide and ivermectin have similar medical indications, their mechanisms of action against SARS-CoV-2 are completely independent from each other, suggesting that the combination could lead to synergistic effects, which has been found in preliminary observational studies.

RCT nitazoxanide
Nitazoxanide and healthcare workers

The FLCCC incorporates therapies into their treatment protocols based on numerous criteria, including biologic plausibility of the mechanism of action, safety, pharmacology, cost, scalability along with sufficient and consistent results from observational and randomized clinical trials data. With the increased evidence supporting monoclonal antibodies used in high-risk outpatients, we added it as an option in our protocol. The proposed monoclonal antibody combination has demonstrated efficacy but we must stress it should be administered within 7 days of first symptoms. We also must stress that monoclonal antibodies are an expensive treatment and likely not accessible by many patients not only in the U.S but around the world.

Monoclonal antibodies in treatment of Covid-19

Anti-androgens are contraindicated in case of pregnancy and breastfeeding and should not be administered to children. The safety of anti-androgen medications has been well-established in kidney, liver, and heart conditions and there are no contraindications for administration in these conditions. Anti-androgen medications have shown massive reductions in hospitalizations and mortality in two large randomized controlled trials. Spironolactone is preferred for heart disease and kidney failure, as it may have a protective function in these diseases. Based on current evidence we have found no contraindications in dialysis patients, immunocompromised patients, or patients who use blood thinners.