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Nitazoxanide, Ivermectin, Hydroxychloroquine, or it Doesn’t Matter, For COVID-19?


July 05, 2021

Efficacy of different drugs for early-stage COVID-19 

THE EFFECTS OF THREE DIFFERENT POPULAT DRUGS ON COVID-19 OUTPATIENTS 

Before we started to conduct the trials on COVID-19, we began an observational study on the clinical course of patients with early COVID-19 using a variety of medications based on compassionate use and local government policies for allowance of these drugs.

We compared the three most used molecules: nitazoxanide, ivermectin, and hydroxychloroquine. In the overall analysis, all three drugs behaved similarly and disclosed similar outcomes. And, apparently, much better outcomes in terms of hospitalization and deaths than untreated patients.

From this study, we started a series of other observational studies, cohorts, and then clinical trials testing the drugs that were more plausible to demonstrate efficacy. 

Link:

https://www.researchsquare.com/article/rs-98106/v1 

Reference:

Flavio A. Cadegiani, Andy Goren, John McCoy et al. Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV Trial., 29 October 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-98106/v1] 

Study abstract 

Background: COVID-19 pandemic requires urgent responses in terms of identification of effective and safe therapies to reduce hospitalization, death, and post-COVID symptoms, while vaccines are not extensively available. Repurposing already existing medications for COVID-19 should be preferred over the development of new drugs due to their inherent advantages of well-established safety profile, familiarity, and cost. Although antiandrogens have strong plausibility to be effective against COVID-19, hydroxychloroquine, nitazoxanide and ivermectin gained unquestionable popularity due to their in vitro and in vivo direct or indirect antiviral activity, and preliminary observations of efficacy against COVID-19. The objective of the present open-label prospective observational study (the pre-AndroCoV trial) was to make a head-to-head comparative analysis between hydroxychloroquine, nitazoxanide and ivermectin, in terms of potential efficacy for COVID-19, combined with early COVID-19 detection, aiming to choose one of these three drugs to include in the AndroCoV randomized clinical trial (RCT).

Materials and methods: Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included. Patients were actively questioned for age, sex, body mass index (BMI), presence of approximately 40 existing diseases and regular use of 30 drug classes, and COVID-19 symptomatology. Hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice daily for six days, or ivermectin 0.2mg/kg/day for three consecutive days was given in a quasi-random manner, in association with azithromycin 500mg/day for five days, and optional addition of vitamin C, vitamin D and zinc, and glucocorticoids and anticoagulants in case of signs of lung injury or higher risk for thrombosis, respectively. Patients were followed up for 60 days, including active questions on disease course and symptoms on Days 0, 1, 2, 3, 7, 14 and 30, and virtual medical visits on Days 0 and 14, and whenever symptoms got worse on in the presence of severe adverse effects. 

Results: In total, 585 participants, including 270 females and 305 males, were included. Of these, 159, 357, and 110 patients received hydroxychloroquine, nitazoxanide, and ivermectin, respectively, with similar baseline characteristics and time-to-treat between them. The three groups had similar duration of positive rtPCR-SARS-CoV-2, clinical disease duration and recovery speed. Of the 585 patients, none was hospitalized, needed mechanical ventilation, or died, and 1.5% persisted with symptoms after recovery.

Conclusion: Hydroxychloroquine, nitazoxanide and ivermectin seem to be similarly effective for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. Between these drugs, nitazoxanide demonstrated the strongest broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile, at least at the time of the choice of the drug for the AndroCoV Trial.

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Proxalutamide Reduced Deaths In Hospitalized COVID-19 Patients


July 05, 2021

Proxalutamide for hospitalized COVID-19 patients 

THE EFFECTS OF PROXALUTAMIDE ON THE REDUCTION OF DEATHS IN COVID-19 HOSPITALIZED PATIENTS 

In the study with proxalutamide in outpatients, we observed that the drug was able to reduce inflammatory and thromboembolic markers without the need of glucocorticoids and anticoagulants, respectively. This fact called our attention to the possibility that proxalutamide could also work in later stages of COVID-19, particularly in hospitalized patients.

This trial was conducted with severe hospitalized patients that still did not require mechanical ventilation. The majority of the patients needed high-flow oxygen or non-mechanical ventilation at the time of the beginning of the trial.

In this trial, we observed a dramatic reduction of mortality rate of almost 80% considering all patients and more than 90% when only patients that completed treatment were considered, compared to usual care.

The strong findings leave very few doubts regarding the efficacy of proxalutamide. 

Link:

https://www.medrxiv.org/content/10.1101/2021.06.22.21259318v1 

Reference:

Flávio Adsuara Cadegiani, Daniel do Nascimento Fonseca, John McCoy, Ricardo ArielZimerman, Fatima Nadeem Mirza, Michael do Nascimento Correia, Renan NascimentoBarros, Dirce Costa Onety, Karla Cristina Petruccelli Israel, Brenda Gomes de Almeida, Emilyn Oliveira Guerreiro, José Erique Miranda Medeiros, Raquel Neves Nicolau, Luiza Fernanda Mendonça Nicolau, Rafael Xavier Cunha, Maria Fernanda Rodrigues Barroco, Patrícia Souza da Silva, Gabriel de Souza Ferreira, Flavio Renan Paula da Costa Alcântara, Ângelo Macedo Ribeiro, Felipe Oliveira de Almeida, Adailson Antonio de Souza Silva, Suzyane Serfaty do Rosario, Raysa Wanzeller de Souza Paulain, AlessandraReis, Marissa Li, Claudia Elizabeth Thompson, Gerard J. Nau, Carlos Gustavo Wambier, Andy Goren. Efficacy of Proxalutamide in Hospitalized COVID-19 Patients: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Clinical Trial.

medRxiv 2021.06.22.21259318; doi:https://doi.org/10.1101/2021.06.22.21259318 

Study abstract 

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is mediated by the androgen-promoted protease, transmembrane protease, serine 2 (TMPRSS2). Previously, we have shown that treatment with proxalutamide, a non-steroidal androgen receptor antagonist, accelerates viral clearance and clinical remission in outpatients with coronavirus disease 2019 (COVID-19) compared to placebo. The effects in hospitalized COVID-19 patients were unknown.

Methods: Men and women hospitalized but not requiring mechanical ventilation were randomized (1:1 ratio) to receive 300 mg of proxalutamide per day or placebo for 14 days. The study was conducted at eight sites in the state of Amazonas, Brazil. The primary outcome measure was the clinical status (8-point ordinal scale) at 14-days post-randomization. The primary efficacy endpoint was the 14-day recovery ratio (alive hospital discharge [scores 1, 2]).

Findings: A total of 645 patients were randomized (317 received proxalutamide, 328 placebo) and underwent intention-to-treat analysis. The 14-day median ordinal scale score in the proxalutamide group was 1 (interquartile range [IQR]=1–2) versus 7 (IQR=2–8) for placebo, P<0.001. The 14-day recovery rate was 81.4% for proxalutamide and 35.7% for placebo (recovery ratio, 2.28; 95% CI 1.95–2.66 [P<0.001]). The 28-day all-cause mortality rate was 11.0% for proxalutamide versus 49.4% for placebo (hazard ratio, 0.16; 95% CI 0.11–0.24). The median post-randomization time to recovery was 5 days (IQR=3– 8) for proxalutamide versus 10 days (IQR=6–15) for placebo.

Interpretation: Hospitalized COVID-19 patients not requiring mechanical ventilation receiving proxalutamide had a 128% higher recovery rate than those treated with placebo. All-cause mortality was reduced by 77.7% over 28 days. (ClinicalTrials.gov number, NCT04728802).

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Benefits of (A Decent) Early Treatment For COVID-19 on Females Through on Observational Study


July 05, 2021

Drugs for early COVID-19 in females 

AN OPEN-LABEL PROSPECTIVE OBSERVATIONAL STUDY OF THE EFFECTS OF ANTIANDROGENS AS ADD-ON THERAPIES FOR EARLY COVID-19 FEMALE: THE PRE-ANDROCOV FEMALE TRIAL 

In this study, we analyzed the effects of different treatment regimens including or not including antiandrogens for the treatment of early COVID-19 in females. All treatment regimens were successful in prevent hospitalizations or progression of the diseases. Women with hyperandrogenism had more symptoms than non-hyperandrogenic women, although this difference was mitigated by the use of spironolactone. 

Link: https://www.medrxiv.org/content/10.1101/2020.10.05.20206870v1 

Reference:

Flavio A. Cadegiani, Andy Goren, Carlos G. Wambier, John McCoy. 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.

medRxiv 2020.10.05.20206870; doi:https://doi.org/10.1101/2020.10.05.20206870 

Study abstract 

Background: While COVID-19 remains largely unclear and mortality continues to raise, early effective approaches prior to complications lack, as well as researches for characterization and therapeutical potential options in actual early COVID-19. Although females seem to be less affected than females, hyperandrogenic (HA) phenotype, like polycystic ovary syndrome (PCOS), idiopathic hirsutism, congenital adrenal hyperplasia (CAH) female androgenetic alopecia (AGA), or idiopathic HA may be at higher risk due to its inherent enhanced androgenic activity. The present study aimed to evaluate the effects of any early pharmacological approach to females diagnosed with COVID-19 before seven days of symptoms, as well as investigate whether HA is an additional risk factor in this population.

Materials and methods: Females with symptoms for less than seven days confirmed for COVID-19 through positive real-time polymerase chain reaction (rtPCR-SARS-CoV-2) were classified and divided as non-HA, HA, and HA using spironolactone (HA-spiro) groups. Patients were questioned for baseline characteristics, 23 different diseases, 44 drug classes and vaccines, 28 different symptoms, and eight different parameters to measure COVID-19 related clinical outcomes. Treatment was then provided, including azithromycin 500mg/day for five days in all cases, associated with hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice a day for six days, or ivermectin 0.2mg/kg/day por three days, and optionally spironolactone 100mg twice a day until cure. Patients were assessed for COVID-19 clinical course, clinical and viral duration, and disease progression.

Results: In total, 270 females were enrolled, including 195, 67, and eight in non-HA, HA, and HA-spiro groups, respectively. Prevailing symptoms were anosmia (71.1%), ageusia (67.0%), headache (48.1%), myalgia (37.4%), dry cough (36.3%), nasal congestion or rhinorrhea (34.1%), fatigue (33.3%), weakness (29.5%), hyporexia (27.8%), thoracic pain (24.8%), diarrhea (24.1%) and dizziness (21.5%). Earliest symptoms (days) were dizziness (1.0 ± 0.2 day), abdominal pain (1.1 ± 0.3);conjunctival hyperemia (1.1 ± 0.5), nasal congestion or rhinorrhea (1.2 ± 0.5), headache (1.2 ± 0.5), dry cough (1.2 ± 0.5), myalgia (1.2 ± 0.4), nauseas (1.3 ± 0.5) and weakness (1.3 ± 0.5). Time-to-treat, positive rtPCR, and duration of symptoms with and without anosmia and ageusia were significantly lower in HA-spiro than non-HA, HA, and overall non-users. Time-to-treat was similar while all duration of symptoms and positive rtPCR-SARS-CoV-2 were significantly shorter in non-HA than HA. Spironolactone users were more likely to be asymptomatic than non-users during COVID-19. Fewer non-HA than HA females were affected by anosmia, ageusia, dry cough, fatigue, weakness and hyporexia. Ageusia, weakness and myalgia lasted shorter in non-HA than HA. None of the patients needed hospitalization or any other COVID-19 complication.

Conclusions: A sensitive, early detection of COVID-19 followed by a pharmaceutical approach with different drug combinations yielded irrefutable differences compared to sex-, age-, body mass index (BMI)-, and disease-matched non-treated controls in terms of clinical outcomes, ethically disallowing placebo-control randomized clinical trials in the early stage of COVID-19 due to the marked improvements. HA females presented more severe and prolonged clinical manifestations, although none progressed to worse outcomes. Spironolactone mitigated the additional risks due to HA.

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Different Treatment Regimens for Early COVID-19 Males


July 05, 2021

Early treatment for COVID-19 males 

DIFFERENT COMBINATIONS OF DRUGS FOR TREATMENT OF EARLY COVID-19 

Sex differences were observed in COVID-19 in terms of disease course and outcomes. Men are more severely affected than women, likely due to higher expression of a protein called TMPRSS2, that facilitates the SARS-CoV-2 (the virus that causes COVID-19) into the cells.

Specifically for men we evaluated through an observational study the use of different drug combinations with ow without dutasteride. All combinations showed good results in terms of prevention of hospitalization and disease progression. This precluded us to conduct full placebo clinical trials. Instead, we conducted studies either using a standardized baseline therapy or usual care. Dutasteride showed promising results, which led us to conduct the studies with dutasteride.

This preprint was not only screened, but its methods were thoroughly reviewed and badged as reviewed. 

Link:

https://www.researchsquare.com/article/rs-88952/v2 

Reference:

Flavio A Cadegiani, Andy Goren, Carlos G Wambier et al. Azithromycin with nitazoxanide, hydroxychloroquine or ivermectin, with or without dutasteride, for early stage COVID-19: an open-label prospective observational study in males with mild-to-moderate COVID-19 (The Pre-AndroCoV Male Trial)., 20 October 2020, PREPRINT (Version 2) available at Research Square [https://doi.org/10.21203/rs.3.rs-88952/v2] 

Study abstract 

Background: COVID-19 is a multisystemic disorder caused by SARS-CoV-2 that has led to more than 1,000,000 deaths until the end of September 2020. Besides aging, obesity, and metabolic diseases, males, in particular those affected by androgenetic alopecia (AGA), are at higher risk to develop complications. While policies for diagnosis of COVID-19 still focus on the presence of fever or shortness of breath, these symptoms tend to appear only in later and more severe stages of the disease, when viral infectivity is already, hampering potential antiviral approaches. In addition, clinical characterization of early COVID-19 stages still lacks. The objective of the present observational study was to characterize prospectively clinical features and predictors in males during early COVID-19, and to evaluate whether the combination of more sensitive case-detection, early diagnosis and early pharmacological approaches would lead to improved clinical outcomes.

Material and methods: Males confirmed for COVID-19 through positive real-time polymerase chain reaction (rtPCR) for SARS-CoV-2 with less than seven days of symptoms and three days of COVID-19 confirmation were divided into non-AGA, AGA not using dutasteride (AGA no-5ARi), and AGA using dutasteride (AGA-5ARi) groups. Patients were actively characterized for baseline and lifestyle characteristics, 22 different diseases, 42 drug classes and vaccines, 26 different symptoms, and 10 different parameters to measure COVID-19 related clinical outcomes. Azithromycin plus hydroxychloroquine, nitazoxanide 500mg or ivermectin, with or without dutasteride or spironolactone were used. Patients were then evaluated for COVID-19 clinical course, duration, and progression.

Results:  A total of 305 males were enrolled, including 192 non-AGA, 71 AGA non-ARi and 52 AGA-5ARi. The prevailing symptoms were anosmia (68.9%), ageusia (61.2%), headache (37.5%), hyporexia (37.5%), fatigue (35.2%), dry cough (35.2%), fever or “feverish” (33.9%), thoracic pain (32.4%), conjunctival hyperemia (29.5%), weakness (29.5%), nasal congestion or rhinorrhea (28.6% and myalgia (26.3%). ARi users remained asymptomatic throughout COVID-19 treatment in 82.7% (43 of 52 males), and the only symptoms present in more than two AGA-5ARi patients were anosmia and ageusia. Thoracic, upper back, lower back pain, arthralgia affected a higher percentage of AGA no-5ARi than non-AGA males (all p < 0.01), but had similar durations (p = n/s). Anosmia, ageusia, headache, fatigue, myalgia and conjunctival hyperemia were more commonly present and lasted for longer periods in AGA no 5ARi patients (all p < 0.01). Self-reported perception of “sinusitis” and “sore throat”, dry cough and weakness were equally present (p = n/s) but had longer duration in AGA no-5ARi males (all p < 0.01).

The different drug combinations were equally distributed (p > 0.05). AGA males were more severely affected than non-AGA in terms of duration of clinical manifestations (9.4 ± 6.0 vs 14.2 ± 7.3 days, p < 0.0001) and viral shedding (14.0 ± 5.2 vs 17.8 ± 6.2 days; p < 0.0001), which has been fully mitigated by the chronic use of dutasteride (p < 0.0001 and < 0.0001 vs non-AGA and AGA no-5ARi, respectively, for both clinical manifestations and viral shedding duration. Non-AGA, AGA no-5ARi and AGA-5ARi achieved 95% clinical recovery in seven, 14, and two days, respectively. In regards functional capacity, AGA no -5ARi males at Days 30, 14, 7, and 3 after treatment initiation were similar than non-AGA at Days 14, 7, 3, and 0, respectively (all p > 0.9). None of the patients required hospitalization and mechanical ventilation, or progressed to more severe states.

Conclusion: The combination of more sensitive and earlier diagnosis of COVID-19 with  a variety of drug combinations with preliminary demonstration of direct or indirect antiviral activity against SARS-CoV-2 demonstrated indisputable improved COVID-19 related clinical outcomes compared to the extensively described COVID-19 clinical course, and avoided the progression to more severe state in all patients included in the present analysis, independently of risk factors, demonstrating that any additional risk factor can be completely mitigated by the combination of more sensitive clinical suspect with early pharmacological approaches.

The overwhelming differences indicate that full placebo control RCTs for early COVID-19 may be ethically questionable. Instead, double blind therapies with different options, or mixed open label placebo control for COVID-19 should be considered.

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How Was the Sars-Cov-2 Virus in The South of Brazil In The Beginning of 2021?


July 05, 2021

SARS-CoV-2 variants in Southern Brazil 

PREDOMINANCE OF THE SARS-COV-2 VARIANT P.1 AND SUBVARIANT P.1.2 IN THE SOUTH OF BRAZIL IN MARCH 2021 

In this study, we demonstrated that, as per March of 2021, almost all patients with COVID-19 were infected with the P.1 variant, a more transmissible and possibly pathogenic variant. In addition, we discovered the first cluster of patients with the P.1.2 subvariant, probably originated in the touristic city of Gramado, in the southern state of Rio Grande do Sul, Brazil. 

Link:
https://www.medrxiv.org/content/10.1101/2021.05.18.21257420v1 

Reference:

Vinícius Bonetti Franceschi, Gabriel

Dickin Caldana, Christiano Perin, Alexandre Horn, Camila Peter, Gabriela Bettella Cybis, Patrícia Aline Gröhs Ferrareze, Liane Nanci Rotta, Flávio Adsuara Cadegiani, Ricardo Ariel Zimerman, Claudia Elizabeth Thompson. Predominance of the SARS-CoV-2 lineage P.1 and its sublineage P.1.2 in patients from the metropolitan region of Porto Alegre, Southern Brazil in March 2021: a phylogenomic analysis.

medRxiv 2021.05.18.21257420; doi: https://doi.org/10.1101/2021.05.18.21257420 

Study abstract 

Almost a year after the COVID-19 pandemic had begun, The United Kingdom, South Africa, and Brazil became the epicenter of new lineages, the Variant of Concern (VOCs), B.1.1.7, B.1.351, and P.1, respectively. These VOCs are increasingly associated with enhanced transmissibility, immunity evasion, and mortality. The previous most prevalent lineages in the state of Rio Grande do South (Brazil), B.1.1.28 and B.1.1.33 were rapidly replaced by P.1 and P.2, two B.1.1.28-derived lineages harboring the E484K mutation. To perform a genomic characterization of SARS-CoV-2 samples from COVID-19 patients from the metropolitan region of Porto Alegre (Rio Grande do Sul, Southern Brazil), in this second pandemic wave, we sequenced viral samples from patients of this region to: (i) identify the prevalence of SARS-CoV-2 lineages in the region, the state and bordering countries/states, (ii) characterize the mutation spectra, and (iii) hypothesize possible viral dispersal routes by using phylogenetic and phylogeographic approaches. As results, we not only confirmed that 96.4% of the samples belonged to the P.1 lineage but also that approximately 20% of which could be assigned as the newer P.1.2 (a P.1 derived new sublineage harboring new signature substitutions recently described and present in other Brazilian states and foreign countries). Moreover, P.1 sequences from this study were allocated in several distinct branches (four clades and five clusters) of the P.1 phylogeny, suggesting multiple introductions of P.1 in Rio Grande do Sul still in 2020 and placing this state as a potential core of diffusion and emergence of P.1-derived clades. It is still uncertain if the emergence of P.1.2 and other P.1 clades are related to further virological, clinical, or epidemiological consequences. However, the clear signs of viral molecular diversification from recently introduced P.1 warrant further genomic surveillance.

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