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

  1. Flavio A. Cadegiani
  2. Andy Goren
  3. Carlos G. Wambier
  4. John McCoy

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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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  1. ScreenIT

    SciScore for 10.1101/2020.10.05.20206870: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationThe choice between hydroxychloroquine, nitazoxanide, and/or ivermectin was based on an almost-random manner, i.e., randomly, except when clinical judgement considered otherwise.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableSubject selection: This specific study is an open label prospective observational study of the characterization and clinical outcomes of females with COVID-19 in response to specific therapeutic combinations.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Suspected females underwent rtPCR-SARS-CoV-2 (Abbott RealTime SARS-CoV-2 Assay, Abbott, USA; or Cobas SARS-CoV-2, Roche, Switzerland), and those confirmed for SARS-CoV-2 were included.
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    All statistical tests were performed using XLSTAT (Microsoft, USA).
    XLSTAT
    suggested: (XLSTAT, RRID:SCR_016299)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: As a prospective observational study conducted prior to a double-blind placebo-control RCT, aiming to better determine the selection process and parameters to be evaluated, as well as define the most plausible pharmacological approach between hydroxychloroquine, nitazoxanide, ivermectin, or none. As per the study deisgn, the lack of a placebo group initially hampers from conclusive findings. However, this has been overcome by the evident differences when compared to the well-established COVID-19 course and outcomes, which disallows us from performing the RCT as a full placebo-control. The replication of a highly sensitive case-detection guidance that include the occurrence of absolutely any symptom as being suspected for COVID-19 may find barriers that may preclude from a successful approach, including: 1. Lack of general and medical education regarding the unspecific pattern of COVID-19 clinical presentation; 2. Self-judgement of not being affected by COVID-19; 3. Inability to correlate non-obvious symptoms with COVID-19, losing the window of opportunity; and 4. Cultural focus on the severe patient, neglecting those are possibly preventable from COVID-19 complication. Although this may not necessarily occur with all patients, the larger number of patients treated early, the better clinical outcomes should be. Final discussion: Since COVID-19 is an extensive, diffuse, and largely unclarified disease, a thorough medical evaluation that encompasses questions for al...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04446429CompletedAnti-Androgen Treatment for COVID-19

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.10.05.20206870 on medRxiv