Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients. Objective To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19. Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021. Intervention Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days. Main outcomes and measures The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points. Results The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes. Limitations Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population. Conclusion Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes. Trial registration ClinicalTrials.gov NCT04529525.

Objectives To assess the efficacy of ivermectin in addition to standard treatment compared to standard treatment alone in reducing hospitalizations in the COVID-19 patient population. Trial design IVERCOR-COVID19 will be a single-center, prospective, randomized, double-blind, parallel group (1:1 ratio), placebo-controlled study. Participants Patients who meet the following criteria will be invited to participate: Inclusion criteria: (1) Over 18 years of age who reside in the province of Corrientes at the time of diagnosis. (2) Confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test for detection of SARS-CoV2 in the last 48 h. (3) In the case of women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study and for the entire period of time for the duration of the study and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study). (4) Weight at the time of inclusion greater than 48 kg. (5) That they sign the informed consent for participation in the study. Exclusion criteria: (1) pregnant or breastfeeding women; (2) known allergy to ivermectin or some of the components of ivermectin tablets or placebo; (3) current use of home oxygen; (4) require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19; (5) presence of mal-absorptive syndrome; (6) presence of any other concomitant acute infectious disease; (7) known history of severe liver disease, for example liver cirrhosis; (8) need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19; (9) need or use of hydroxychloroquine or chloroquine; (10) use of ivermectin up to 7 days prior to randomization; (11) patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months; and (12) current participation or in the last 30 days in a research study that has included the administration of a drug (Table 1). Table 1 Ivermectin/placebo dose according to patient weight Patient weight Ivermectin/placebo dose Total dose (mg) Equal to or greater than 48 kg and less than 80 kg 2 tablets of 6 mg each at the time of inclusion and 2 tablets 24 h after the first intake 24 Equal or greater than 80 kg and less than 110 kg 3 tablets of 6 mg each at the time of inclusion and 3 tablets 24 h after the first intake 36 Equal or greater than 110 kg 4 tablets of 6 mg each at the time of inclusion and 4 tablets 24 h after the first intake 48 The study will be carried out by the Ministry of Public Health of the Province of Corrientes (Argentina) in coordination with the Institute of Cardiology of Corrientes in the Province of Corrientes, Argentina. Intervention and comparator Intervention group: patients who are randomized to ivermectin will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg ivermectin; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of ivermectin; patients weighing more than 110 kg will receive 4 tablets of 6 mg ivermectin) the day they enter the study and the same dose 24 h after the first dose. Control group: patients who are randomized to placebo will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg placebo; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of placebo; patients weighing more than 110 kg will receive 4 tablets of 6 mg placebo) on the day they enter the study and the same dose 24 h after the first dose (Table 2). Table 2 Inclusion and exclusion criteria Inclusion criteria Exclusion criteria 1. Over 18 years of age who reside in the province of Corrientes at the time of diagnosis 1. Pregnant or breastfeeding women 2.Confirmed diagnosis of COVID-19 by polymerase chain reaction test for detection of SARS-CoV2 in the last 48 h 2. Known allergy to ivermectin or some of the components of ivermectin tablets or placebo 3. In case of being women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study, during the entire period of time for the duration of the study, and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study) 3. Current use of home oxygen 4. Weight at the time of inclusion equal to or greater than 48 kg 4. That require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19 5. That they sign the informed consent for participation in the study 5. Presence of mal-absorptive syndrome 6. Presence of any other concomitant acute infectious disease 7. Known history of severe liver disease, for example liver cirrhosis 8. Need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19 9. Need or use of hydroxychloroquine or chloroquine 10. Use of ivermectin up to 7 days prior to randomization 11. Patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months 12. Current participation or in the last 30 days in a research study that has included the administration of a drug Main outcomes Primary outcome will be the percentage of hospitalizations in patients with COVID-19 in the intervention and control groups. Secondary outcomes: time to hospitalization in each of the arms of the study: number of days elapsed from the inclusion in the study until the hospitalization of the patient; percentage of use of invasive mechanical ventilation in each of the study arms: every patient who is connected to invasive mechanical ventilation after signing the informed consent and before the final study visit; time to invasive mechanical ventilation in each of the arms of the study: number of days elapsed from inclusion in the study to connection to invasive mechanical ventilation of the patient; percentage of patients requiring dialysis in each of the study arms: all patients who require renal replacement therapy of any kind, temporary or permanent, and which begins after signing the informed consent and before the final visit; mortality from all causes in each of the two trial groups: death of the patient, from any cause. Negative PCR swab at 3 ± 1 and 12 ± 2 days after entering the study. Ivermectin safety: it will be analyzed according to the incidence of adverse events that patients present in the intervention and control groups. The end of study (EOS) is recorded as the day the patient is discharged or death. Discharge will be granted according to the current recommendations of the Ministry of Public Health of the Province of Corrientes. A follow-up visit (EOF) will be made by phone 30 days after the EOS when vital status will be verified. Randomization Randomization will be done through a web system with randomly permuted blocks. Randomization will be carried out by one of the investigators who will not participate in the inclusion of patients or in the delivery of medication (Table 3). Table 3 EOS end of study, EOF end of follow-up Visit Basal and randomization, day 0 Day 3 ± 1 Day 12 ± 2 V#1 V#2 V#3 EOS EOF Informed consent X – – – – Inclusion/exclusion criteria X – – – – Demographic data and medical history X – – – – Concomitant medication X – – – – Vital signs* X X – – – Anthropometric data^ X – – – – Basal laboratory X – – – – PCR swab – X X – – Assessment of adverse events – X X X – Final objective evaluation – X X X X Randomization X – – – – Adherence to treatment X X – – – *Includes heart rate, temperature, and oxygen saturation by a digital saturometer ^Includes weight and height Blinding (masking) The participants, investigators, care providers, and outcome assessors will be blinded. Numbers to be randomized (sample size) We will include a total of 500 patients (250 patients in each group). Trial status This is version 1.0, 17 August 2020. The recruitment started on 19 August 2020, and we anticipate the trial will finish recruitment on 31 December 2020. Trial registration ClinicalTrials.gov NCT04529525. Registered on 26 August 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Background Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorization in Argentina. We studied its utility in a real world setting with a larger population. Methods We conducted a retrospective cohort study at “Hospital de Campaña Escuela-Hogar" (HCEH) in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all-cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach. Findings Subsequent clinical records of 446 non-exposed (Controls) and 395 exposed (EPIC) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years and 56.8% were males. Mortality at 28 days was 15.7% (EPIC) vs. 21.5% (Control). After IPTW adjustment the OR was 0.66 (95% CI: 0.46–0.96) P = 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n = 379), OR 0.58 (95% CI 0.39 to 0.85) P = 0.005. Overall and serious adverse events were not significantly different between groups. Conclusions In this retrospective cohort study, EPIC showed adequate safety and effectiveness in the treatment of hospitalized patients with severe SARS-CoV-2 disease.

Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorisation in Argentina. We studied its utility in a real world setting with a larger population. Methods: We conducted a retrospective cohort study at "Hospital de Campaña Escuela-Hogar" in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach. Results: Clinical records of 395 exposed (EPIC) and 446 non-exposed (Controls) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years, 56.8% males. Mortality at 28 days was 15.7% ( EPIC) vs 21.5% (Control). After IPTW adjustment the OR was 0.66 (95 % CI: 0.46 - 0.96) p= 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n=379), OR 0.58 (95% CI 0.39 to 0.85) p=0.005. Overall and serious adverse events were not significantly different between groups.