Conv. Plasma
Nigella Sativa

All vitamin C studies
Meta analysis
study COVID-19 treatment researchVitamin CVitamin C (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

Statistical Analysis Methods Applied to Early Outpatient COVID-19 Treatment Case Series Data

Gkioulekas et al., COVID, doi:10.3390/covid2080084
Aug 2022  
  Source   PDF   All Studies   Meta AnalysisMeta
Vitamin C for COVID-19
7th treatment shown to reduce risk in September 2020
*, now known with p = 0.000000098 from 67 studies, recognized in 10 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Retrospective analysis of case series data from 3,164 high-risk COVID-19 outpatients treated with early multidrug protocols similar to the McCullough protocol, including hydroxychloroquine, ivermectin, zinc, azithromycin, vitamin C, vitamin D, etc., administered in a sequenced approach customized to each patient's risk factors and phase of illness. Authors present a statistical framework to rigorously analyze such real-world evidence, calculating efficacy thresholds for mortality rate and hospitalization rate reduction that the expected rates without early treatment must exceed in order to confidently establish treatment efficacy by preponderance of evidence or clear and convincing evidentiary standards. When compared against CDC estimates and other studies, the efficacy thresholds are exceeded, indicating strong evidence for mortality rate and hospitalization rate reduction with early multidrug treatment protocols for high-risk patients.
Study covers HCQ, ivermectin, zinc, vitamin C, and vitamin D.
Gkioulekas et al., 18 Aug 2022, peer-reviewed, 3 authors. Contact: (corresponding author).
This PaperVitamin CAll
Statistical Analysis Methods Applied to Early Outpatient COVID-19 Treatment Case Series Data
Eleftherios Gkioulekas, Peter A Mccullough, Vladimir Zelenko
COVID, doi:10.3390/covid2080084
When confronted with a public health emergency, significant innovative treatment protocols can sometimes be discovered by medical doctors at the front lines based on repurposed medications. We propose a statistical framework for analyzing the case series of patients treated with such new protocols, that enables a comparison with our prior knowledge of expected outcomes, in the absence of treatment. The goal of the proposed methodology is not to provide a precise measurement of treatment efficacy, but to establish the existence of treatment efficacy, in order to facilitate the binary decision of whether the treatment protocol should be adopted on an emergency basis. The methodology consists of a frequentist component that compares a treatment group against the probability of an adverse outcome in the absence of treatment, and calculates an efficacy threshold that has to be exceeded by this probability, in order to control the corresponding p-value and reject the null hypothesis. The efficacy threshold is further adjusted with a Bayesian technique, in order to also control the false positive rate. A random selection bias threshold is then calculated from the efficacy threshold to control for random selection bias. Exceeding the efficacy threshold establishes the existence of treatment efficacy by the preponderance of evidence, and exceeding the more demanding random selection bias threshold establishes the existence of treatment efficacy by the clear and convincing evidentiary standard. The combined techniques are applied to case series of high-risk COVID-19 outpatients that were treated using the early Zelenko protocol and the more enhanced McCullough protocol.
Conflicts of Interest: The authors declare no conflict of interest. Abbreviations The following abbreviations are used in this manuscript: Appendix A. Exact Fisher Test in the Limit of an Infinite Control Group Let N be the total number of patients in the treatment group, let a be the number of patients with an adverse outcome (hospitalization or death) in the treatment group, let M be the total number of patients in the control group, and let b be the number of patients in the control group with an adverse outcome. In this appendix we will show that in the limit of an infinite control group (M, b) with x = b/M, the p-value p(N, a, M, b) obtained from the two-tail exact Fisher test converges to p(N, a, x). In the exact Fisher test, we assume that N, M, and a + b, are fixed numbers, and under the null hypothesis, we also assume that the distribution of the total a + b patients with an adverse outcome between the treatment group and control group is random, with equal probability for every possible combination. It follows that under the null hypothesis, the probability of seeing a particular event (N, a, M, b) is given by pr The corresponding p-value is the probability of observing the event (N, a, M, b) or any other less probable event, and it is given by We note that the summation variable n is restricted by both the total size N of the treatment group and the total number a + b of the patients with an adverse outcome, so the permissible range for all possible events is..
Balakrishnan, Price, Luu, Shaul, Wartchow et al., Biochemical Characterization of Respiratory Syncytial Virus RNA-Dependent RNA Polymerase Complex, Acs Infect. Dis, doi:10.1021/acsinfecdis.0c00554
Barda, Riesel, Akriv, Levy, Finkel et al., Developing a COVID-19 mortality risk prediction model when individual-level data are not available, Nat. Commun, doi:10.1038/s41467-020-18297-9
Battineni, Sagaro, Chintalapudi, Amenta, Tomassoni et al., Impact of Obesity-Induced Inflammation on Cardiovascular Diseases (CVD), Int. J. Mol. Sci, doi:10.3390/ijms22094798
Benjamin, Berger, Three Recommendations for Improving the Use of p-Values, Am. Stat, doi:10.1080/00031305.2018.1543135
Berger, Could Fisher, Jeffreys, and Neyman have agreed on testing?, Stat. Sci, doi:10.1214/ss/1056397485
Biancatelli, Berrill, Marik, The antiviral properties of vitamin C, Expert Rev. Anti-Infect. Ther, doi:10.1080/14787210.2020.1706483
Biancatelli1, Berrill, Catravas, Marik, Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19), Front. Immunol, doi:10.3389/fimmu.2020.01451
Brown, Cai, Dasgupta, Interval Estimation for a Binomial Proportion, Stat. Sci, doi:10.1214/ss/1009213286
Bryant, 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.0000000000001402
Burrows, The abortive treatment of influenza with quinine dihydrochloride, Med. Rec
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antivir. Res, doi:10.1016/j.antiviral.2020.104787
Chetty, Elucidating the pathogenesis and Rx of COVID reveals a missing element, Mod. Med
Clopper, Pearson, The use of confidence or fiducial limits illustrated in the case of the binomial, Biometrika, doi:10.1093/biomet/26.4.404
Collins, Bowman, Landray, Peto, The Magic of Randomization versus the Myth of Real-World Evidence, N. Engl. J. Med, doi:10.1056/NEJMsb1901642
Colquhoun, The False Positive Risk: A Proposal Concerning What to Do About p-Values, Am. Stat, doi:10.1080/00031305.2018.1529622
Dabbagh-Bazarbachi, Clergeaud, Quesada, Ortiz, O'sullivan et al., Zinc Ionophore Activity of Quercetin and Epigallocatechin-gallate: From Hepa 1-6 Cells to a Liposome Model, J. Agric. Food Chem, doi:10.1021/jf5014633
Dashti, Roche, Bates, Mora, Demler, SARS-2 simplified scores to estimate risk of hospitalization and death among patients with COVID-19, Nat. Sci. Rep, doi:10.1038/s41598-021-84603-0
Deaton, Cartwright, Understanding and misunderstanding randomized controlled trials, Soc. Sci. Med, doi:10.1016/j.socscimed.2017.12.005
Derwand, Scholz, Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?, Med. Hypotheses, doi:10.1016/j.mehy.2020.109815
Dubee, Roy, Vielle, Parot-Schinkel, Blanchet et al., Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: A placebo-controlled double blind trial, Clin. Microbiol. Infect, doi:10.1016/j.cmi.2021.03.005
Fonseca, Sousa, Wolkoff, Moreira, Pinto et al., Risk of hospitalization for COVID-19 outpatients treated with various drug regimens in Brazil: Comparative analysis, Travel Med. Infect. Dis, doi:10.1016/j.tmaid.2020.101906
Frieden, Evidence for Health Decision Making -Beyond Randomized, Controlled Trials, N. Engl. J. Med, doi:10.1056/NEJMra1614394
Galvez, Zanni, Galvez-Llompart, Benlloch, Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation, J. Chem. Inf. Model, doi:10.1021/acs.jcim.0c01394
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.105949
Gavriilaki, Anyfanti, Gavriilaki, Lazaridis, Douma et al., Endothelial Dysfunction in COVID-19: Lessons Learned from Coronaviruses, Curr. Hypertens. Rep, doi:10.1007/s11906-020-01078-6
Gkioulekas, Mccullough, Zelenko, Frequentist and Bayesian Analysis Methods for Case Series Data and Application to Early Uutpatient COVID-19 Treatment Case Series of High Risk Patients, Authorea, doi:10.22541/au.164745391.17821933/v3.
Gkioulekas, Supplementary material: Statistical Analysis Methods Applied to Early Outpatient COVID-19 Treatment Case Series Data, doi:10.6084/m9.figshare.19364699.v5
Goodman, Toward evidence-based medical statistics. 1: The P value fallacy, Ann. Intern. Med, doi:10.7326/0003-4819-130-12-199906150-00008
Goodman, Toward evidence-based medical statistics. 2: The Bayes factor, Ann. Intern. Med, doi:10.7326/0003-4819-130-12-199906150-00019
Grant, Lahore, Mcdonnell, Baggerly, French et al., Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients, doi:10.3390/nu12040988
Harbi, Kaabi, Nuaimi, Abdalla, Khan et al., Clinical and laboratory characteristics of patients hospitalized with COVID-19: Clinical outcomes in Abu Dhabi, United Arab Emirates, BMC Infect. Dis, doi:10.1186/s12879-022-07059-1
Hatfill, The Intentional Destruction of the National Pandemic Plan, J. Am. Physicians Surg
Hazan, Dave, Gunaratne, Dolai, Clancy et al., Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients, Front. Med, doi:10.2217/fmb-2022-0014
Heras, Garibaldi, Boix, Valero, Castillo et al., COVID-19 mortality risk factors in older people in a long-term care center, Eur. Geriatr. Med, doi:10.1007/s41999-020-00432-w
Hill, The Environment and Disease: Association or Causation?, Proc. R. Soc. Med, doi:10.1177/003591576505800503
Hong, On computing the distribution function for the Poisson binomial distribution, Comput. Stat. Data Anal, doi:10.1016/j.csda.2012.10.006
Iuliano, Chang, Patel, Threlkel, Kniss et al., Estimating under-recognized COVID-19 deaths, United States, March 2020-May 2021 using an excess mortality modelling approach, Lancet Reg. Health Am, doi:10.1016/j.lana.2021.100019
Jeffreys, The Theory of Probability
Jehi, Ji, Milinovich, Erzurum, Merlino et al., Development and validation of a model for individualized prediction of hospitalization risk in 4,536 patients with COVID-19, PLoS ONE, doi:10.1371/journal.pone.0237419
Kass, Raftery, Bayes, Factors, None, J. Am. Stat. Assoc, doi:10.1080/01621459.1995.10476572
Khan, Karim, Cele, San, Lustig et al., Omicron infection enhances neutralizing immunity against the Delta variant, Nature, doi:10.1038/s41586-022-04830-x
Klaschka, Reiczigel, On matching confidence intervals and tests for some discrete distributions: Methodological and computational aspects, Comput. Stat, doi:10.1007/s00180-020-00986-0
Kompaniyets, Goodman, Belay, Freedman, Sucosky et al., Body Mass Index and Risk for COVID-19-Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death-United States, Morb. Mortal. Wkly. Rep, doi:10.15585/mmwr.mm7010e4
Kory, Meduri, Gianfranco, Varon, Iglesias et al., Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, Am. J. Ther, doi:10.1097/MJT.0000000000001377
Kory, Meduri, Iglesias, Varon, Cadegiani et al., MATH+ Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale, J. Clin. Med. Res, doi:10.14740/jocmr4658
Leemis, Luckett, Powell, Vermeer, Univariate Probability Distributions, J. Stat. Educ, doi:10.1080/10691898.2012.11889648
Leemis, Mcqueston, Univariate Distribution Relationships, Am. Stat, doi:10.1198/000313008X270448
Lei, Zhang, Schiavon, He, Chen et al., SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2, Circ. Res, doi:10.1161/CIRCRESAHA.121.318902
Lopez-Blazquez, Mino, Binomial approximation to hypergeometric probabilities, J. Stat. Plan. Inference, doi:10.1016/S0378-3758(99)00187-1
Marik, Kory, Ivermectin, A Reanalysis of the Data, Am. J. Ther, doi:10.1097/MJT.0000000000001443
Marik, Kory, Varon, Iglesias, Meduri, MATH+ protocol for the treatment of SARS-CoV-2 infection: The scientific rationale, Expert Rev. Anti-Infect. Ther, doi:10.1080/14787210.2020.1808462
Maxima, Maxima, None, a Computer Algebra System
Mccullough, Alexander, Armstrong, Arvinte, Bain et al., Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19), Rev. Cardiovasc. Med
Mccullough, Innovative Early Sequenced Multidrug Therapy for SARS-CoV-2 (COVID-19) Infection to Reduce Hospitalization and Death, Int. J. Med. Sci. Clin. Invent, doi:10.18535/ijmsci/v7i12.02
Mccullough, Kelly, Ruocco, Lerma, Tumlin et al., Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection, Am. J. Med, doi:10.1016/j.amjmed.2020.07.003
Mercola, Grant, Wagner, Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity, Nutrients, doi:10.3390/nu12113361
Merritt, The Treatment of Viral Diseases: Has the Truth Been Suppressed For Decades?, J. Am. Physicians Surg
Million, Lagier, Tissot-Dupont, Ravaux, Dhiver et al., Early Treatment with Hydroxychloroquine and Azithromycin in 10,429 COVID-19 Outpatients: A Monocentric Retrospective Cohort Study, Rev. Cardiovasc. Med, doi:10.31083/j.rcm2203116
Morey, Romeijn, Rouder, The philosophy of Bayes factors and the quantification of statistical evidence, J. Math. Psychol, doi:10.1016/
Mucchielli, Behind the French controversy over the medical treatment of Covid-19: The role of the drug industry, J. Sociol, doi:10.1177/1440783320936740
Muhlberger, Filovirus replication and transcription, Future Virol, doi:10.2217/17460794.2.2.205
Onder, Rezza, Brusaferro, Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy, J. Am. Med. Assoc, doi:10.1001/jama.2020.4683
Palazzuoli, Ruberto, Ferrari, Forleo, Secco et al., Inpatient mortality according to level of respiratory support received for severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection: A prospective multicenter study, Crit. Care Explor, doi:10.1097/CCE.0000000000000220
Park, Leemis, Ensemble Confidence Intervals for Binomial Proportions, Stat. Med, doi:10.1002/sim.8189
Poly, Islam, Yang, Lin, Jian et al., Obesity and Mortality Among Patients Diagnosed With COVID-19: A Systematic Review and Meta-Analysis, Front. Med, doi:10.3389/fmed.2021.620044
Procter, Ross, Pickard, Smith, Hanson et al., Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection, Rev. Cardiovasc. Med
Procter, Ross, Pickard, Smith, Hanson et al., Early Ambulatory Multidrug Therapy Reduces Hospitalization and Death in High-Risk Patients with SARS-CoV-2 (COVID-19), Int. J. Innov. Res. Med. Sci, doi:10.23958/ijirms/vol06-i03/1100
Reese, Iuliano, Patel, Garg, Kim et al., Estimated Incidence of Coronavirus Disease 2019 (COVID-19) Illness and Hospitalization-United States, Clin. Infect. Dis, doi:10.1093/cid/ciaa1780
Reiczigel, Confidence intervals for the binomial parameter: Some new considerations, Stat. Med, doi:10.1002/sim.1320
Risch, Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis, Am. J. Epidemiol, doi:10.1093/aje/kwaa093
Risch, Hydroxychloroquine in Early Treatment of High Risk COVID-19 Outpatients: Efficacy and Safety Evidence
Risch, Murchu, Byrne, Carty, Gascun et al., Quantifying the risk of SARS-CoV-2 reinfection over time, Rev. Med. Virol, doi:10.1002/rmv.2260
Risch, The author replies, Am. J. Epidemiol, doi:10.1093/aje/kwaa152
Rudrapal, Khairnar, Jadhav, Drug Repurposing (DR): An Emerging Approach in Drug Discovery
Ruxton, Neuhauser, Review of alternative approaches to calculation of a confidence interval for the odds ratio of a 2 × 2 contigency table, Methods Ecol. Evol, doi:10.1111/j.2041-210x.2012.00250.x
Santi, Scheim, Mccullough, Yagisawa, Borody, Ivermectin: A multifaceted drug of Nobel prize-honoured distinction with indicated efficacy against a new global scourge, COVID-19, N. Microbes N. Infect, doi:10.1016/j.nmni.2021.100924
Scholz, Derwand, Zelenko, COVID-19 outpatients-Early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: A retrospective case series study, Int. J. Antimicrob. Agents
Sherman, Anderson, Pan, Gray, Gross et al., Real-World Evidence-What Is It and What Can It Tell Us?, N. Engl. J. Med, doi:10.1056/NEJMsb1609216
Siddiqi, Libby, Ridker, COVID-19-A vascular disease, Trends Cardiovasc. Med, doi:10.1016/j.tcm.2020.10.005
Sterne, Some remarks on confidence or fiducial limits, Biometrika
Stone, Ndarukwa, Scheim, Dancis, Dancis et al., Rapid increase of SpO2 on room air for 34 severe COVID-19 patients after ivermectin-based combination treatment: 55-62% normalization within 12-24 hours, doi:10.21203/
Strayhorn, Virtual controls as an alternative to randomized controlled trials for assessing efficacy of interventions, BMC Med. Res. Methodol, doi:10.1186/s12874-020-01191-9
Stricker, Fesler, A novel plan to deal with SARS-CoV-2 and COVID-19 disease, J. Med. Virol, doi:10.1002/jmv.25945
Tyson, Fareed, Overcoming the COVID Darkness. How Two Doctors Successfully Treated 7000 Patients
Ulhaq, Soraya, Interleukin-6 as a potential biomarker of COVID-19 progression, Med. Mal. Infect, doi:10.1016/j.medmal.2020.04.002
Vahidy, Drews, Masud, Schwartz, Askary et al., Characteristics and outcomes of COVID-19 patients during initial peak and resurgence in the Houston metropolitan area, J. Am. Med. Assoc, doi:10.1001/jama.2020.15301
Velthuis, Fodor, Influenza virus RNA polymerase: Insights into the mechanisms of viral RNA synthesis, Nat. Rev. Microbiol, doi:10.1038/nrmicro.2016.87
Verity, Okell, Dorigatti, Winskill, Whittaker et al., Estimates of the severity of coronavirus disease 2019: A model-based analysis, Lancet Infect. Dis, doi:10.1016/S1473-3099(20)30243-7
Vidgen, Yasseri, P-Values: Misunderstood and Misused, Front. Phys, doi:10.3389/fphy.2016.00006
Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol. J, doi:10.1186/1743-422X-2-69
Vollset, Confidence intervals for a binomial proportion, Stat. Med, doi:10.1002/sim.4780120902
Wasserstein, Lazar, The ASA's statement on p-values: Context, process, and purpose, Am. Stat, doi:10.1080/00031305.2016.1154108
Wessels, Rolles, Rink, The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis, Front. Immunol, doi:10.3389/fimmu.2020.01712
Woolf, On estimating the relation between blood group and disease, Ann. Hum. Genet, doi:10.1111/j.1469-1809.1955.tb01348.x
Yu, Weng, Wu, Wang, Lu et al., The lifecycle of the Ebola virus in host cells, Oncotarget, doi:10.18632/oncotarget.18498
Zaidi, Dehgani-Mobaraki, The mechanisms of action of ivermectin against SARS-CoV-2. An extensive review, J. Antibiot, doi:10.1038/s41429-021-00491-6
Zelenko, Correspondence from Dr Vladimir Zelenko on Treatment of COVID-19
Zelenko, Dr, Bar, Tov, None
Zelenko, To All Medical Professionals Around the World
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop