key: cord-0949923-o78kp25r authors: Babalola, O E; Bode, C O; Ajayi, A A; Alakaloko, F M; Akase, I E; Otrofanowei, E; Salu, O B; Adeyemo, W L; Ademuyiwa, A O; Omilabu, S title: Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double-blind, dose-response study in Lagos date: 2021-02-18 journal: QJM DOI: 10.1093/qjmed/hcab035 sha: 634119ef5a07e506d6b522ff077f942a967d1404 doc_id: 949923 cord_uid: o78kp25r INTRODUCTION: 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. METHODS: We conducted a translational proof of concept (PoC) randomized, double blind placebo controlled, dose response, parallel group study of IV efficacy in RT - PCR proven COVID 19 positive patients. 62 patients were randomized to 3 treatment groups. (A) IV 6mg regime, (B)IV 12 mg regime (given Q84hrs for 2weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care. RESULTS: 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 . 2 Way repeated measures ANOVA of ranked COVID 19 +/- scores at 0, 84, 168, 232 hours showed a significant IV treatment effect (p = 0.035) and time effect (p < 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 × 10(3)/ml. The platelet count increase was inversely correlated to DTN (r = -0.52, p = 0.005). No SAE was reported. CONCLUSIONS: 12 mg IV regime may have superior efficacy. IV should be considered for use in clinical management of SARS-Cov-2, and may find applications in community prophylaxis in high-risk areas. The Corona Virus Disease 2019 (COVID 19) pandemic caused by the Severe Acute Respiratory Syndrome Corona virus -2 (SARS-CoV-2) 1 led to a World Health Organization declared global pandemic on March 11, 2020 2 . As of as of February 8, 2021, more than 106.7 million people on all continents had been infected and more than 2.3 million people had died globally 3 . Prolonged morbidity after recovery from acute COVID 19 4 and astronomical hospital costs 5 , has left hospitals swamped and health workers exhausted. In addition, the global economy is in a depression 6 with massive job losses, furloughing and social movement restrictions. There have been concerted attempts to seek preventive and interventional modalities to arrest the spread of the contagion by public health measures such as masking, social distancing, self isolation and hygiene, or more recently by vaccines 7, 8 There are also pharmaceutical/ therapeutic agents with antiviral properties, being repurposed to urgently treat or serve as chemoprevention for COVID 19. One such drug is Ivermectin, which has exhibited broad spectrum anti-parasitic, anti-bacterial and antiviral properties against many RNA viruses 9, 10 . Ivermectin is extensively used, with good safety profile in Nigeria and other African nations in treating ocular onchocerciasis 11 . Of more current import, Ivermectin was shown to exhibit a 5000-fold reduction in SARS-C0V-2 viral RNA in vitro in Vero-h/SLAM cells in a study from Australia. 12 There are several mechanisms by which Ivermectin may inhibit SARS-CoV-2 in COVID 19 patients, including by inhibition of RNA -dependent RNA polymerase (RdRP) required for viral replication, 13 abolition of importin-α/β1 heterodimer nuclear transport of SARS-CoV-2 from the cytosol to the nucleus, and inhibition of viral mRNA and viral protein translation 14 . However, there has been skepticism as to whether the virucidal IC50 of Ivermectin against SARS-CoV-2 of 2.4uM (obtained in vitro) could be feasible or attainable in humans or patients with COVID 19. This is because a 10-fold dose of Ivermectin (120mg) simulations-based kinetics in cattle still did not yield peak drug levels (Cmax) approaching the IC50 for in vitro SARS-CoV-2 inhibition 15 . In yet another simulation, based on human pharmacokinetics of different potential antiviral SARS-CoV-2 repurposed drugs, Ivermectin was one of the drugs predicted to have 10-fold concentrations higher than their reported 50% effective concentration [EC50] . 16 There is thus conflicting report on simulations from cattle and human pharmacokinetics in the effective anti-SARS-CoV-2 concentration attainable by Ivermectin dosing. Ivermectin has a long half life (t 1/2 ) of 81-91 hours, and is highly lipophilic with a high volume of distribution (Vd), indicating preferential lung and tissue accumulation. 17 Pharmacodynamically, Ivermectin dose-dependently inhibits lipopolysaccharide (LPS) induced release of inflammatory cytokines (interleukins) in mice and improved LPSinduced survival. 18 Collectively, there are multiple pharmacodynamic and pharmacokinetic indicators that suggest a potential utility and efficacy of Ivermectin in COVID 19. We therefore tested the hypothesis that Ivermectin will exert a clinically and therapeutically beneficial effect in mild to moderate COVID 19 patients in a randomized double blind controlled clinical trial in Nigerian COVID 19 patients with RT-PCR proven SARS-CoV-2 positivity. METHODOLOGY. Routine biochemistry, hematology, arterial oxygen saturation (Pa02) temperature and clinical data were gathered, and prognostic ones were recorded at the aforementioned times. This study was undertaken between May and November 2020. A general description of the study population and the spread over three arms is found in Table 1 . Sixty-three patients with positive PCR result were randomised into three arms of the study. There was one withdrawal, thus sixty-two patients completed the study. The average age was 44.1years (SD14.7), ranging from 20-82. There were 43 males and 19 females. The patients had mild to moderate clinical symptoms and none of them required ventilator, although five required intranasal oxygen, 3 in the 12mg arm (B) and two in the control arm (C). One third of the patients reported with a fever and cough, while 44% and 18% respectively reported with headache and difficulties with breathing. 12% reported with anosmia/ageusia. The commonest comorbidities were Diabetes Mellitus (DM) (2) and Hypertension (9), while some had combined hypertension and DM. Some patients required concomitant medications such as dexamethasone, enoxaparin, and supplemental oxygen. The effectiveness of randomization was assessed, and the results are displayed in Table 1 . In all, twenty-one patients were each randomised into the 6mg (A) and 12mg (B) Ivermectin arms while twenty went into the control arm (C). There was no significant difference in the distribution of the age, sex and symptoms, comorbidities, blood counts, prothrombin time, liver function and kidney function tests. There were however slight differences in the baseline Cycle threshold (Ct) values, being lower in the A arm than the other two arms with regards to the ORF and N genes, but similar for the EN gene. The distribution of other supplemental medications taken by participants, aside from Ivermectin, was broadly similar. These included Zinc, ascorbic acid, vitamin D and Azithromycin. The time to SARS-CoV-2 negativity is described in Figures 1A and B Mean days-to-negative for the 12mg arm was however shortened by 4.5 days, and by 3.15 days for the 6mg arm compared to controls. These differences were significant by ANOVA P>F =0.0179. The distribution of the days-to-negative are depicted in Figure 1A . Figure 1B Changes in clinical and laboratory parameters at baseline and at seven days (or as otherwise stated) were observed for the three arms and recorded in Table 3 . Day seven was used as a midway point in the trial. Of note was that there was a moderate increase in SpO2 in the Ivermectin arm, although this did not attain significance (P=0.098). The difference from baseline to highest attained SpO2 during the study for each participant is also depicted in Figure 3A , There were also no significant differences in changes in kidney function tests such as Blood Urea Nitrogen and Creatinine between the three groups. There was a notable significant increase in platelet counts in the ivermectin arm relative to the control arm (P=0.037). See Figure 3B . There was also a moderate but not significant relative increase in lymphocyte count. The overall Platelet Lymphocyte Ratio (PLR) was not significantly changed (Table 2 ). In Figure 3C , we note a statistically significant (P=0.0055) negative correlation between days-to-negative and increase in platelet count. The higher the change in platelet count, the fewer the days-to-negative. Pearson's r= -0.53, R 2 =0.28 There were slight increases in prothrombin time across all arms, more so in the control arm. There were no significant changes over time, across the three groups in clinical parameters such as Respiratory rate, Heart rate, Temperature, and symptoms such as cough and dyspnea as assessed by Likert scales. There was no significant overall effect of age on days-to-negative by linear regression analysis (r =0.046 p = 0.728). However, those in the 30-40-year age band had a lower time to negative relative to others. No adverse effects of Ivermectin was reported in response to questioning or spontaneous report. Symptomatic improvement was seen in all patients, with resolution of fever dypnea and other signs. There was no mortality and the patients remained well on follow up. at the doses that were initially considered inadequate based on pharmacokinetic simulations 15, 17 The progressive reduction in COVID 19 positivity in the Ivermectin-treated group over time, as well as the treatment effect were sustained with no time-treatment interactions ( Figure 2 . Table 2 ). This was associated both with symptomatic improvements as well as Ivermectininduced reversal of abnormal COVID 19 prognostic parameters. Ivermectin treatment was associated with a strong trend to an increase in arterial oxygen saturation (SPO2%) compared to controls (See Figure 3A ) p= 0,073 and 95% CI of -0.39 to 2.59. Pulse oximetry at the finger digits, has recently been shown to exhibit racial divergences with a higher likelihood of overrating SPO2% and leading to "occult hypoxemia" occurring more in black people in comparison to whites 23 thus, the real change in SPO2 with Ivermectin may have been masked. Platelet count is another prognostic index in COVID 19 with thrombocytopenia reflecting platelet consumption in SARS-CoV-2 as part of sepsis-induced coagulopathy, even before frank Disseminated Intravascular Coagulation (DIC) manifests as hemorrhage or thrombosis 24 . Ivermectin treatments (combined 6mg and 12 mg dose) caused an increase in platelet count relative to the control group patients with a 95% CI for the difference of 5.55 to 162.55 x 10 9 /L p= 0.037 ANOVA, F =4,88, df -24. (See Table 3 Tests were not completed in two cases. The one-way ANOVA P>F= 0.017. T-test comparing "Any Ivermectin" and control P=0.0066 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet WHO Declares COVID-19 a Pandemic Number of coronavirus (COVID-19) cases, recoveries and deaths worldwide as of For the Gemelli Against COVID-19 Post-Acute Care COVID-19 and the Financial Health of US Hospitals Global Economic Effects of COVID-19 Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer Lohmer LRL. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19 Prioritisation of Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg Tablet in healthy adult volunteers Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic Racial Bias in Pulse Oximetry Measurement Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study Use of Ivermectin Is Associated with Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The ICON Study Cytokine release syndrome in severe COVID-19 Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. Open Heart Cellular and Molecular Pathways of COVID-19 and Potential Points of Interleukin-6 and severe COVID-19: a systematic review and meta-analysis List of Abbreviations 1. DTN. Days To Negative 2. RCT. Randomised Controlled Trial 3. LPS. Lipopolysaccharides 4. RT-PCR. Reverse Transcriptase Polymerase Chain Reaction 5. SARS-Cov2 Proof of Concept Standard of Care 8. ANOVA. Analysis Of Variance 9. RAMOVA. Two-Way Repeat Measures Analysis Of Variance SPO2. Peripheral Capillary Oxygen Saturation National Agency for Food and Drug Administration and Control 13. Ct. Cycle Threshold 14. LFT. Liver Function Tests 15. KFT. Kidney Function Tests 16 We wish to acknowledge the contributions of the following: