Abstract: Short Communication For reprint orders, please contact: reprints@futuremedicine.com Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients Sabine Hazan*,1 , Sonya Dave2 4 Peter A McCullough , Anoja W Gunaratne3 , Sibasish Dolai3 , Robert L Clancy3 , 3 & Thomas J Borody 1 ProgenaBiome, LLC, 1845 Knoll Dr., Ventura, CA 93003, USA 2 North End Advisory, 2451 Cumberland Pkwy SE Ste. 3152, Atlanta, GA 30339, USA 3 Centre for Digestive Diseases, 229 Great North Road, Five Dock, NSW, 2046, Australia 4 Truth for Health Foundation, Tucson, AZ 85728, USA *Author for correspondence: DrHazan@progenabiome.com Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04949230 (ClinicalTrial.gov) First draft submitted: 15 January 2022; Accepted for publication: 25 January 2022; Published online: 9 February 2022 Keywords: coronavirus • COVID • doxycycline • ivermectin • SARS-CoV-2 • zinc There is currently a lack of effective treatments for early or ambulatory patients with COVID-19. Patients testing positive are sent home to isolate without specific treatment prescribed. However, there is growing evidence that certain repurposed drugs with good safety profiles, taken early, can significantly improve outcomes and even avoid or delay the need for immune-modulators, antiplatelet/antithrombotic therapy and the administration of oxygen [1]. Among the most extensively studied of such COVID-19 therapeutics is ivermectin (IVM), a drug that has been used safely in 3.7 billion doses worldwide since 1987 [2–4]. Recently, Dr Satoshi Omura, the 2015 Nobel Prize co-laureate for the discovery of IVM, and colleagues comprehensively reviewed studies to date on IVM activity against COVID-19, concluding that the evidence demonstrated such efficacy [4]. IVM used alone has been tested in more than 20 randomized, controlled trials (RCTs) for COVID-19 treatment, with statistically highly significant clinical benefits in almost all of these and an average of 62% reduction in risk of death [5]. Five such studies for IVM treatment of COVID-19 recently published in top-tier medical journals have all shown multiple clinical benefits for IVM versus controls, most of these with high statistical significance on the order of p < 0.002 [6–10]. At much greater than the standard single antiparasite dose of 200 μg/kg, IVM is well tolerated [11,12] and has been used in RCTs for COVID-19 treatment at cumulative doses of 1500 μg/kg [13] and 3000 μg/kg [14,15] over 4 or 5 days either without or with mild and transient adverse..