Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients
F A Cadegiani, A Goren, C G Wambier, J Mccoy
New Microbes and New Infections, doi:10.1016/j.nmni.2021.100915
In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo controlled studies in early-stage COVID-19. The present analysis aimed to elucidate, through a comparative analysis with two control groups, whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable. The Active group (AG) consisted of patients enrolled in the Pre-AndroCoV-Trial (n = 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5-36.5% in viral shedding (p < 0.0001), 70-85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilation, deaths and post-COVID manifestations (p < 0.0001 for all). For every 1000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with the well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19.
Transparency declaration The authors declare no conflict of interest with any of the pharmacological interventions proposed by the present study.
Authorship statement Dr. Cadegiani was the principal investigator and contributed to the study conception and design, compiled and analyzed the data, and helped write the manuscript. Dr Goren contributed with the study design, analysis of the data, and review of the manuscript. Dr. Wambier performed the statistical analysis, analyzed the data, and helped write the manuscript. Dr. McCoy helped with the study design, helped to analyze the data, and reviewed the last version of the manuscript.
References
Afrin, Weinstock, Molderings, Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome, Int J Infect Dis,
doi:10.1016/j.ijid.2020.09.016Almubark, Memish, Tamim, Alenazi, Alabdulla et al., Natural history and clinical course of symptomatic and asymptomatic COVID-19 patients in the Kingdom of Saudi arabia, Saudi J Med Med Sci,
doi:10.4103/sjmms.sjmms_853_20Amdal, Pe, Falk, Piccinin, Bottomley et al., Healthrelated quality of life issues, including symptoms, in patients with active COVID-19 or post COVID-19; a systematic literature review, Qual Life Res,
doi:10.1007/s11136-021-02908-zAxfors, Schmitt, Janiaud, Van't Hooft, Abd-Elsalam et al., Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials, Nat Commun,
doi:10.1038/s41467-021-22446-zBansal, Goyal, Cusick, Lahan, Dhaliwal et al., Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019, Ann Med,
doi:10.1080/07853890.2020.1839959Bartoszko, Siemieniuk, Kum, Qasim, Zeraatkar et al., Prophylaxis against covid-19: living systematic review and network meta-analysis, BMJ,
doi:10.1136/bmj.n949Blum, Nitazoxanide superiority to placebo to treat moderate COVID-19 A Pilot prove of concept randomized double-blind clinical trial, EClinicalMedicine,
doi:10.1016/j.eclinm.2021.100981Booth, Reed, Ponzo, Yassaee, Aral et al., Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis, PLoS One,
doi:10.1371/journal.pone.0247461Bryant, Lawrie, Dowswell, Fordham, Mitchell et al., Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines, Am J Ther,
doi:10.1097/MJT.0000000000001402Burton, Fort, Seoane, Hospitalization and mortality among black patients and white patients with covid-19, N Engl J Med
Cadegiani, Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?, Am J Physiol Endocrinol Metab
Cadegiani, Goren, John, Wambier, Azithromycin with nitazoxanide, hydeoxychloroquine 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
Cadegiani, Goren, Mccoy, Wambier, Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head515 comparison of the Pre-AndroCoV Trial
Cadegiani, Goren, Wambier, Spironolactone may provide protection from SARS-CoV-2: targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS), Med Hypotheses,
doi:10.1016/j.mehy.2020.110112Cadegiani, Lim, Goren, Mccoy, Situm et al., Clinical symptoms of hyperandrogenic women diagnosed with COVID-19, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17004Cadegiani, Lin, Goren, Wambier, Potential risk for developing severe COVID-19 disease among anabolic steroid users, BMJ Case Rep,
doi:10.1136/bcr-2021-241572Cadegiani, Mccoy, Wambier, Goren, 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), Cureus,
doi:10.7759/cureus.13047Cadegiani, Mccoy, Wambier, Vaño-Galván, Shapiro et al., Proxalutamide significantly accelerates viral clearance and reduces time to clinical remission in patients with mild to moderate COVID-19: results from a randomized, double-blinded, placebo-controlled trial, Cureus,
doi:10.7759/cureus.13492Cadegiani, Wambier, Goren, Spironolactone: an antiandrogenic and anti-hypertensive drug that may provide protection against the novel coronavirus (SARS-CoV-2) induced acute respiratory distress syndrome (ARDS) in COVID-19, Front Med,
doi:10.3389/fmed.2020.00453Castelnuovo, Costanzo, Cassone, Cauda, Gaetano et al., Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials, Pathog Glob Health,
doi:10.1080/20477724.2021.1936818Chen, Zhou, Dong, Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet
Cohen, Hall, John, Rapoport, The 566 early natural history of SARS-CoV-2 infection: clinical observations from an urban, ambulatory COVID-19 clinic, Mayo Clin Proc
Fernández-De-Las-Peñas, Palacios-Ceña, Gómez-Mayordomo, Florencio, Cuadrado et al., Prevalence of post-COVID-19 symptoms in hospitalized and nonhospitalized COVID-19 survivors: a systematic review and metaanalysis, Eur J Intern Med,
doi:10.1016/j.ejim.2021.06.009Goren, Wambier, Herrera, Mccoy, Vaño-Galván et al., Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.16953Goyal, Choi, Pinheiro, Clinical characteristics of covid-19 in New York city, N Engl J Med
Grasselli, Pesenti, Cecconi, Critical care utilization for the COVID-19 outbreak in lombardy, Italy: early experience and forecast during an emergency response, JAMA
Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Imai, Halfmann, Yamayoshi, Iwatsuki-Horimoto, Chiba et al., Characterization of a new SARS-CoV-2 variant that emerged in Brazil, Proc Natl Acad Sci,
doi:10.1073/pnas.2106535118Iqbal, Lam, Sounderajah, Clarke, Ashrafian et al., Characteristics and predictors of acute and chronic post-COVID syndrome: a systematic review and meta-analysis, EClinicalMedicine,
doi:10.1016/j.eclinm.2021.100899Kim, Kim, Ra, Lee, Bae et al., Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19, Clin Microbiol Infect,
doi:10.1016/j.cmi.2020.04.040Kragholm, Andersen, Gerds, Association between male sex and outcomes of Coronavirus Disease 2019 (Covid-19) -a Danish nationwide, register553 based study, Clin Infect Dis
Li, Zhao, Zhan, Quantitative proteomics reveals a broadspectrum antiviral property of ivermectin, benefiting for COVID-19 treatment, J Cell Physiol,
doi:10.1002/jcp.30055Lyngbakken, Berdal, Eskesen, Kvale, Olsen et al., A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics, Nat Commun,
doi:10.1038/s41467-020-19056-6Mahmoud, Shitu, Mostafa, Drug repurposing of nitazoxanide: can it be an effective therapy for COVID-19?, J Genet Eng Biotechnol,
doi:10.1186/s43141-020-00055-5Massimo, Stefano, Elena, Vittorio, Nicolò et al., The humanitas COVID-19 task force, the humanitas gavazzeni COVID-19 task force, rodolfo hurle, alessandro nobili, maurizio cecconi, paolo casale, rosanna asselta impact of antiandrogen therapies on COVID-19 susceptibility: a case-control study in male population from two COVID-19 regional centers of lombardy,
doi:10.1101/2020.04.20.20068056Mccoy, Cadegiani, Wambier, Herrera, Vaño-Galván et al., 5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17021Mccoy, Wambier, Herrera, Vaño-Galván, Gioia et al., Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.16956Meyerowitz-Katz, Merone, A systematic review and meta-analysis of published research data on COVID-19 infection-fatality rates, Int J Infect Dis
Novak, Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report, eNeurologicalSci,
doi:10.1016/j.ensci.2020.100276O Murchu, Spillane, Byrne, Neill, Harrington et al., Interventions in an ambulatory setting to prevent progression to severe disease in patients with COVID-19: a systematic review, Ann Pharmacother,
doi:10.1177/10600280211028242Onder, Rezza, Brusaferro, Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy, JAMA
Petrilli, Jones, Yang, Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study, BMJ
Rakedzon, Neuberger, Domb, Petersiel, Schwartz, From hydroxychloroquine to ivermectin: what are the anti-viral properties of anti-parasitic drugs to combat SARS-CoV-2?, J Travel Med,
doi:10.1093/jtm/taab005Rocco, Silva, Cruz, Junior, Tierno et al., Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial, Eur Respir J,
doi:10.1183/13993003.03725-2020Roman, Burela, Pasupuleti, Piscoya, Vidal et al., Ivermectin for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials, Clin Infect Dis,
doi:10.1093/cid/ciab591Sawadogo, Dighero-Kemp, Ouédraogo, Hensley, Sakandé, How NETosis could drive "Post-COVID-19 syndrome" among survivors, Immunol Lett,
doi:10.1016/j.imlet.2020.09.005Son, Huang, Zeng, Bricker, Case et al., cell culture and coronavirus pathogenesis in a pig model
Stokes, Zambrano, Anderson, Coronavirus disease 2019 case surveillance -United States, january 22-may 30, 2020, MMWR Morb Mortal Wkly Rep
Subramanian, Anand, Adderley, Okoth, Toulis et al., Increased COVID-19 infections in women with polycystic ovary syndrome: a population-based study, Eur J Endocrinol,
doi:10.1530/EJE-20-1163Tolba, Omirah, Hussein, Saeed, Assessment and characterization of post-COVID-19 manifestations, Int J Clin Pract,
doi:10.1111/ijcp.13746Verity, Okell, Dorigatti, Estimates of the severity of coronavirus disease 2019: a model-based analysis, Lancet Infect Dis
Wambier, Mehta, Goren, Cadegiani, COVID-19, androgens, and androgenic alopecia, Dermatol Rev,
doi:10.1002/der2.50Wang, Hu, Hu, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA
Wijeratne, Crewther, 589 Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community, J Neurol Sci,
doi:10.1016/j.jns.2020.117179Woolf, Chapman, Sabo, Excess deaths from COVID-19 and other causes, march-april 2020, JAMA
Wortham, Lee, Althomsons, Characteristics of persons who died with COVID-19 -United States, february 12-may, MMWR Morb Mortal Wkly Rep
Wu, Chen, Cai, Xia, Zhou et al., Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.0994Young, Ong, Kalimuddin, Low, Tan et al., Singapore 2019 novel coronavirus outbreak research team. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore, JAMA,
doi:10.1001/jama.2020.3204Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective NMNI Cadegiani et al. Early drug therapy improves COVID-19 outcomes. cohort study, Lancet
Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet
