A randomized, double-blind, placebo-controlled, multicenter, phase 2 study was carried out to examine the effectiveness of oral ivermectin in hospitalized adults (age >18 years) with COVID-19. The trial was conducted at five hospitals (Velayat, Bu Ali, Taleghani, Razi, and Sina) in Qazvin and Khuzestan provinces of Iran. Ethical approval was in accordance with the ethical standards of the Helsinki Declaration (1964, amendment of 2008). The study protocol was approved by the medical ethics committee of Qazvin University of Medical Sciences (registration ID IR.QUMS.REC.1399.017).
Eligible patients with COVID-19 who met the following criteria were admitted: a) Age >18 years; b) signed the informed consent; c) clinical symptoms of suggestive of COVID-19 pneumonia: cough (with or without sputum), fever, pleuritic chest pain or dyspnea; d) mild to severe COVID-19 disease confirmed by chest computed tomography (CT) scan findings compatible with COVID-19 or positive real-time reverse transcription polymerase chain reaction (RT-PCR). Exclusion criteria included presence of severe immunosuppression (e.g., use of immune-suppressants and HIV positive), pregnant women, chronic kidney disease, malignancy, and indications that the patients were unable and/or unlikely to comprehend and/or follow the protocol. The primary endpoint of this trial was clinical recovery within 45 days of enrolment. Clinical recovery was defined as normal fever, respiratory rate, and oxygen saturation (>94) without oxygen therapy sustained for 24h. The patients would be discharged if this trend continued. During the process the criteria for discharge was changed over the course of study. Initially, patients with two successive negative nasopharyngeal samples based on PCR assay (CT value≥35) were separated. The study sample size was estimated based on a test of equivalence27. Using a two-sided test level of 0.05 and a desired statistical power of 90% and under the assumption that each treatment arm would yield a 75 % success rate, the number of patients in the study was obtained equal to 163 patients. Assuming an availability rate of 35%, 30 patients were enrolled per treatment arm.
The participants were randomly allocated to six arms including common regimen based on Iran health ministry (Hydroxychloroquine 200mg/kg twice per day), placebo plus common regime, single dose ivermectin (200mcg/Kg, 1 pill per day), three low interval doses of ivermectin (200, 200, 200 mcg/Kg , 3 pills in 1, 3 and 5 interval days ), single dose ivermectin (400mcg/Kg, 2 pills per day), and three high interval doses of ivermectin ( 400, 200, 200 mcg/Kg, 4 pills in 1, 3 and 5 interval days).
Randomization and masking
Eligible patients were randomly allocated to either the standard, Placebo and the ivermectin arms. Randomization according to the severity of the disease was as follows: mild, moderate, and sever. The transposed block randomization sequence, including stratification, was prepared by a statistician not involved in the trial using Random Allocation Software. The patients in six treatment arms enrolment were randomized after calling the central randomization telephone number and receiving randomization information and confirmation. Each patient received the unique patient numbers that were to be used on all study medication containers, case report forms, and to identify all specimens. Pharmacia generated the randomization list and provided the list to the central randomization service.
Laboratory and radiographic tests
The patients systematically underwent an unenhanced chest low-dose computed tomography (LDCT) at reception or soon after, using a single CT machine (16 slice Model Neusof, China). All images were analyzed by expert chest radiologists and classified as compatible or not compatible with pneumonia. Images were considered as compatible with circumferential multifocal ground-glass opacities, vesicular consolidation, or crazy paving template. Novel Coronavirus RNA was recognized by real-time reverse transcription PCR 28. Negative results for viral RNA detection were defined as a cycle threshold (CT) value≥35.
All patients were treated according to “Iranian guideline of hospitalized COVID-19 patients’ management (version 5)”. This comprised oral hydroxychloroquine (HCQ) 200mg/kg twice per day as standard regimen and a heparin prophylaxis in combination with supplemental oxygen. Tablet of ivermectin (14 mg) and placebo were formulated in Alborz Darou pharmaceutical Co., Tehran, Iran. The Participants received drug after signing the consent letter. For all arms, radiographic findings, hospitalization time, clinical outcomes such as mortality, and clinical parameters such as account oxygen saturation testing and blood sampling absolute lymphocyte count (ALC), C-reactive protein (CRP), white blood cells (WBC), lactate dehydrogenase (LDH), thrombocyte count (PLT), erythrocyte sedimentation rate (ESR), blood urea nitrogen (BUN), and creatinine (Cr) were examined on days zero and five. Assessment of gas exchange requires knowledge of fractional inspired oxygen tension (FiO2); unless the patient is breathing room air. Hence, all peripheral capillary oxygen saturation was measured in breathing room air at rest.
The SPSS version 20 (SPSS®, Armonk, NY, USA) software was used for statistical analyses. Shapiro-Wilk test was used to evaluate normality of numerical variables. The quantitative variables were expressed as mean ± SD (standard deviation) or Median ± IQR (Inter Quartile Range). The difference values for each quantitative variable on days zero and five (∆ 0/5) were calculated to check recovery process of patients between groups. Pair T-test / Wilcoxon signed-rank test were used on inter-group comparison. The analysis of variance (ANOVA) was used to compare the mean scores of the groups. To compare the proportions, Pearson chi-square or Fisher's exact test was used. Analyses were based on non-missing data. P-value less than 0.05 was considered statistically significant.