<jats:title>Summary</jats:title> <jats:sec> <jats:title>Introduction</jats:title> <jats:p>In vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS—CoV-2 viral replication, but questions remained as to in-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We conducted a translational proof of concept randomized, double blind placebo controlled, dose response and parallel group study of IV efficacy in RT—polymerase chain reaction proven COVID 19 positive patients. Sixty-two patients were randomized to three treatment groups. (A) IV 6 mg regime, (B) IV 12 mg regime (given Q84 h for 2 weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The Days to COVID negativity (DTN) was significantly and dose dependently reduced by IV (P = 0.0066). The DTN for Control were, = 9.1+/–5.2, for A 6.0 +/– 2.9 and for B 4.6 +/–3.2. Two way repeated measures ANOVA of ranked COVID 19 +/– scores at 0, 84, 168 and252h showed a significant IV treatment effect (P = 0.035) and time effect (P &lt; 0.0001). IV also tended to increase SPO2% compared to controls, P = 0.073, 95% CI—0.39 to 2.59 and increased platelet count compared to C (P = 0.037) 95%CI 5.55—162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = –0.52, P = 0.005). No SAE was reported.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>12mg IV regime given twice a week may have superior efficacy over 6mg IV given twice a week, and certainly over the non IV arm of the study. IV should be considered for use in clinical management of SARS-COV2, and may find applications in prophylaxis in high risk areas.</jats:p> </jats:sec>