Trial design and oversight
A randomized, double-blind, placebo-controlled study was conducted in the community between August 19, 2020 and February 22, 2021 in the province of Corrientes, Argentina. This trial was conducted by the Ministry of Public Health of the Province of Corrientes in coordination with the Corrientes Institute of Cardiology “Juana F. Cabral”. It was authorized by the Health Sciences Research Bioethics Committee (HSRBC) of the National University of the Northeast (UNNE) Faculty of Medicine, Argentina (Supplementary Appendix). The study has been supervised by a Steering Committee and a Safety Committee. The trial was performed in accordance with the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations. The trial was registered on ClinicalTrials.gov (NCT04529525) on 27/08/2020 and the protocol is available online.
The authors who have designed the protocol and written the manuscript are listed in the Supplementary Appendix. All the authors collected data and vouch for the accuracy and completeness of the data and the adherence of the trial to the protocol, available in the Supplement Appendix. One of the authors (RZ) analyzed the data, and one of the main co-authors (RZ) wrote the first draft of the manuscript. No one other than an author contributed to writing of the manuscript. The study was not sponsored by any industry and none of the authors received any remuneration for conducting this trial. The tablets (ivermectin and placebo) were manufactured at the Corrientes Drug Factory.
Individuals who met all the following inclusion criteria and none of the exclusion criteria were eligible for inclusion. Individuals were to be over 18 years of age residing in the province of Corrientes at the time of diagnosis with confirmed COVID-19 diagnosis by polymerase chain reaction test (RT-PCR) (CFX96 qPCR, Bio-Rad) for SARS-CoV2 detection in the last 48 h. If they are women of childbearing age, they should be using a contraceptive method of proven efficacy and safety. All individuals were to weigh at the time of inclusion equal to or greater than 48 kg.
Participants were excluded if they were they required current home oxygen use or required hospitalization for COVID-19 at the time of diagnosis or had a history of hospitalization for COVID-19. Other exclusions criteria were pregnant or breastfeeding women, known allergy to ivermectin or the components of ivermectin or placebo tablets, presence of mal-absorptive syndrome, presence of any other concomitant acute infectious disease, known history of severe liver disease, and recent or expected need for dialysis. Concomitant use of hydroxychloroquine or chloroquine or antiviral drugs due to a viral pathology other than COVID-19 at the time of admission was prohibited as was the use of ivermectin up to 7 days before randomization. Individuals with participation in a research study that involved the administration of a drug within the last 30 days were excluded. All participants provided written informed consent. Inclusion criteria are provided in detail in the protocol.
By order of the Ministry of Health of the Province of Corrientes, all patients with COVID-19 were contacted by for tracing purposes. During this telephone contact, eligible individuals were invited to participate in the trial.
Eligible participants were visited at their homes by the researcher to obtain informed consent and undergo randomization. At this visit, trial participants were provided with the treatment kit containing the randomized medication and indicated the corresponding dose and how to take it.
At the day of randomization (day 0), day 3 (± 1 day) and day 12 (± 2 days) an investigator went to the patient’s home where a nasal swab was performed for RT-PCR, vital signs were collected and treatment compliance was assessed. The final visit was considered to be the time at which the patient received the epidemiological discharge of COVID-19 according to the provisions of the Ministry of Health of the Argentine Nation, or the day of death. A follow-up visit was conducted 30 days after the final visit to assess the vital status.
Throughout the study, one of the researchers maintained daily telephone contact with the participants in addition to collecting data related to the patient’s medical history and adverse events.
Randomization and intervention
Randomization was performed by one of the investigators through the web-based system using randomly permuted blocks in a 1:1 ratio (Supplementary Appendix). The investigator who performed the randomization was not involved in the dispensing of the medication, inclusion, and follow-up of the patients. The rest of the investigators were blinded to the treatment received, as were the patients. Patients were consecutively assigned to the treatment kit in ascending order at inclusion.
Patients who met the inclusion criteria were randomized to ivermectin plus standard of care (SOC) or placebo plus SOC. The SOC was in accordance with the recommendations of the Argentine Ministry of Health. The dose of ivermectin used was the approved dose in Argentina for the treatment of other diseases, such as parasitic diseases, and it was staggered according to weight. Those weighing up to 80 Kg received 2 tablets of 6 mg (mg) each at inclusion and another 2 tablets of 6 mg each 24 h after the first dose (total 24 mg). Those weighing more than 80 kg and up to 110 kg received 3 tablets of 6 mg each at inclusion and another 3 tablets of 6 mg each 24 h after the first dose (total 36 mg). Those weighing more than 110 kg received 4 tablets of 6 mg each at inclusion and another 4 tablets of 6 mg each 24 h after the first dose (total 48 mg). Individuals randomized to placebo received the equivalent number of placebo tablets to the ivermectin weight-based dosage, at baseline and again after 24 h.
The baseline characteristics, concomitant medication and progress of the patients were collected in the clinical history of the patients and then in the database through Google form.
Data related to the patients’ medical history, COVID-19-related symptoms, daily progress and adverse events during their study participation were collected by daily telephone contact. Vital signs, blood samples and nasal swabs were collected by one of the investigators at the patient’s home or at the hospital if the patient was hospitalized at the time of some of the corresponding visits.
In the event that any of the participants required hospitalization, this was performed in a single hospital in the entire province of Corrientes for patients with COVID-19. Hospitalization data were obtained from the digitized clinical history.
The primary outcome was hospitalization for any reason of patients with COVID-19. This was defined as a stay of at least 24 h in a health institution, in any of its services, at any point from randomization until the end of study visit.
Secondary objectives were time to hospitalization in those who required it, use of invasive mechanical ventilatory support (MVS), time to invasive MVS in those who required it, negative nasal swabs 3 days (± 1) and 12 days (± 2) from study inclusion, dialysis, ivermectin safety (frequency of adverse events), and all-cause mortality. All outcomes were measured from randomization to the EOS visit.
To calculate the sample size, it w as assumed that 10% of the patients required hospitalization, applying a statistical significance level of 0.05 and with a statistical power of 80%. When the trial was designed, there was not enough evidence of the potential benefit of ivermectin in these patients, therefore calculations were based on an estimated odds ratio in the ivermectin arm between 0.3 and 0.5 with the aim of including a total of 500 patients (250 patients in each group).
Continuous variables were expressed as means [± standard deviation (SD)] or medians [with interquartile range (IQR) 25–75] according to their distribution. Categorical variables were expressed as percentages and their 95% confidence interval (CI). Continuous variables were compared in both groups using Student’s t-test or the Mann-Whitney test according to their distribution. Categorical variables were compared across groups using the chi-square test.
For analysis of the primary outcome, logistic regression was used to present the odds ratio and the corresponding 95%CI. For secondary outcomes, the logistic regression was used if the secondary outcome was categorical. The Student’s t-test or the Mann-Whitney test was used if the variable was continuous and according to its distribution.
In addition, an analysis of hospitalization-free survival was performed using the log-rank test with its corresponding Kaplan-Meier curve and the Cox regression test. The safety point was analyzed using generalized estimating equations, considering that the same patient could have had more than one adverse event.
Subgroup analyses were prespecified according to whether patients were symptomatic or asymptomatic, according to age (< 65 years or ≥ 65 years), and in symptomatic patients according to duration of symptoms prior to inclusion in the study (< 7 days or ≥ 7 days). A prespecified multivariable analysis of the primary outcome was planned (Supplementary Appendix).
Pre-specified interim analyses including 125, 250 and 375 patients were performed to assess the eventual need for early termination of the study according the Haybittle-Peto boundary for which a p value < 0.001 was considered significant (Supplementary Appendix). The results of these analyses were reported to the Steering Committee, the Safety Committee and the HSRBC of the UNNE School of Medicine. In all cases, each committee advised continuation of the study as planned.
Patients were analyzed according to the group to which they were assigned during randomization regardless of whether they later received ivermectin or placebo or did not adhere to treatment compliance (intention-to-treat analysis).
Missing data from the primary endpoint were assigned to be considered as hospitalizations, but there were none. A p-value < 0.05 was considered significant. Stata software version 16.0 / SE (StataCorp) was used for the analysis.