key: cord-0872376-rh2jrojk authors: Shahbaznejad, Leila; Davoudi, Alireza; Eslami, Gohar; Markowitz, John S.; Navaeifar, Mohammad Reza; Hosseinzadeh, Fatemeh; Movahedi, Faeze Sadat; Rezai, Mohammad Sadegh title: Effect of ivermectin on COVID-19: A multicenter double-blind randomized controlled clinical trial date: 2021-05-06 journal: Clin Ther DOI: 10.1016/j.clinthera.2021.04.007 sha: 942008e2d5d0e047e757033f04334eec3e6857ab doc_id: 872376 cord_uid: rh2jrojk PURPOSE: : Given the coronavirus disease-2019 (COVID-19) pandemic, there is a global urgency to discover an effective treatment against this disease. This study aimed to evaluate the effect of the widely used antiparasitic drug ivermectin on COVID-19 patient outcomes. METHODS: In this randomized double-blind clinical trial, COVID-19 patients admitted to two referral tertiary hospitals of Mazandaran, north of Iran, were randomly divided into two groups of intervention and control. In addition to standard treatment for COVID-19, the intervention group received a single weight-based dose (0.2 mg/kg) of ivermectin. Demographic, clinical, laboratory and imaging data of participants were recorded at baseline. Patients were daily assessed for clinical complaints and disease progression. The primary clinical outcome measures were duration of hospital stay, fever, dyspnea, cough, and overall clinical improvement. FINDINGS: : Sixty-nine patients with the mean age of 47.6±22.2 and 45.2±23.1 years participated in intervention and control groups, respectively (p=0.6). Nineteen patients (54%) in the ivermectin group and 18(53%) in control group were male (p=0.9). The mean duration of dyspnea was 2.4±1.7 days in the ivermectin and 3.7±2.1 days in the control group (p=0.02). Also, persistent cough lasted for 3.1±1.9 days in the ivermectin group compared to 4.8±2.0 days in control group (p=0.00). The mean duration of hospital stay was 6.9±3.1 vs 8.3±3.3 days for the ivermectin and control group, respectively (p=0.01). Also, the frequency of lymphopenia decreased to 14.3% in the ivermectin group and did not change in the control group (p=0.00). IMPLICATIONS: A single dose of ivermectin was well-tolerated in symptomatic COVID-19 patients and improved important clinical features of COVID-19 patients including dyspnea, cough, and lymphopenia. Further studies with larger sample sizes, different drug dosages, dosing intervals and durations, especially in different stages of the disease, may help understanding ivermectin's potential clinical benefits. TRIAL REGISTRATION: The current controlled trial was registered in the Iranian Registry of Clinical Trials (code: IRCT20111224008507N3) on 2020-06-27. Coronavirus disease 2019 (COVID- 19) was declared a global pandemic following its first outbreak in Wuhan, China in December 2019. 1, 2 Until January 2021, more than tens of millions have been infected with more than one million reported deaths with COVID-19 worldwide. 3 Therefore, it is essential to develop effective treatment modalities for this public health emergency. 2 There are a number of ongoing clinical trials related to COVID-19, involving a wide array of medications, including interferon-α (IFN-α), lopinavir/ritonavir, chloroquine and hydroxychloroquine, ribavirin, and arbidol, among others. Until now, effective medications like remdesivir and dexamethasone have been introduced for COVID-19 treatment but they have side effects and should be applied in multiple doses for frequent days and need hospitalization. 4, 5 Ivermectin has been suggested as a potential medication for COVID-19 treatment. 6 It is a Food and Drug Administration (FDA)-approved broad-spectrum anti-parasitic agent, widely utilized in the treatment and control of several tropical diseases including strongyloidiasis and onchocerciasis. 7, 8 Moreover, ivermectin has antimicrobial, anti-cancer, and antiviral properties and may hold potential in the treatment of associated diseases. [7] [8] [9] First commercialized in 1981, ivermectin's low cost, high efficacy, established safety, and marked helminth tropism have led to its inclusion in the 21 st World Health Organization (WHO) list of essential medicine. 10 Ivermectin causes hyperpolarization and paralysis of the infesting organism and leads to the immunomodulation of the host response. 11 It has been suggested that the nuclear transport-inhibitory activity of ivermectin may be effective against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). 8 Considering the potential effect of ivermectin on viral replication, its highest efficacy may be achieved when used in the first stages of the disease. 12 An effective antiviral therapy for SARS-CoV-2, if administered early in infection, may help reduce the viral load, prevent the progression of the disease, and limit person-to-person transmission. 13 Due to the lack of supporting clinical evidence, especially human studies on ivermectin, clinical trials are necessary on a larger scale. Therefore, many clinical studies are underway to provide more information in this area and few studies are published until now. 11, [14] [15] [16] In this study, we report the effect of ivermectin on outcomes of patients hospitalized with COVID-19 in a double-blind randomized clinical trial. The exclusion criteria were as follows: patients with a history of chronic liver and/or renal disease; receiving treatment with warfarin, angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin II receptor antagonists; and acquired immunodeficiency. Pregnant women and lactating mothers were also excluded from the study. The patients were randomly divided into two intervention and control groups by simple randomization method with a table of random numbers. The total sample size consisted of 70 patients, 35 participants per group. Neither the participants nor the evaluators were aware of the randomization process or group allocation. After admission to the hospital and obtaining written informed consent, a package containing oral medications was given to the patients of both groups. Besides supportive medical treatment for COVID-19 according to the national protocols of Iran at the time of this study (hydroxychloroquine and/or lopinavir/ritonavir) in the control group, the intervention group received a single (0.2 mg/kg) oral dose of ivermectin utilizing 3 mg oral tablets (Europhartech, France) or a multiple thereof. 18 On the first day of admission at the following weight-based doses: weight: 15-24 kg, 3 mg; weight: 25-30 kg, 6 mg; weight: 36-50 kg, 9 mg; weight: 51-80 kg, 12 mg; and weight, >80 kg, 0.2 mg/kg. All of the participants received appropriate antibiotics and/or supplementary oxygen as indicated. Demographic, clinical, laboratory, and imaging data of all participants were recorded at baseline on the first day of admission. Also, the patients were evaluated regarding the severity of the disease and moderate and severe COVID-19 patients who needed hospitalization enrolled the study. The severe form of the disease was defined as tachypnea (respiratory rate ≥24 breaths per minute), needing mechanical ventilation, requiring supplemental oxygen, and oxygen saturation (SpO2) <94% in the ambient air. 19 Other patients were considered as moderates. Patients were assessed once daily by nurses, using a checklist that included the primary outcome variables such as clinical complaints, including fever, chills, sore throat, cough, dyspnea, loss of appetite, abdominal pain, dizziness, insomnia, itching, joint pain, joint swelling, headache, nausea, vomiting, diarrhea, malaise, conjunctivitis, tachycardia, wheezing, rhonchi, retraction, hypotension, rash, and other symptoms from baseline until discharge. Moreover, respiratory rate, oxygen saturation, complete blood count with differential (CBC diff), erythrocyte sedimentation rate (ESR), sodium (Na), potassium (K), blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were measured. The laboratory measures were repeated after 48 hours. Additionally, a chest CT scan was performed prior to the intervention. Patients were evaluated daily in terms of disease progression or any new complaints for seven days. The need for supplementary oxygen, route of oxygen administration, invasive mechanical ventilation, and outcomes were also recorded. Moreover, potential drug-induced adverse events, including wheezing, itching, skin rash, edema, and hypotension, were assessed daily. The primary outcome was clinical improvement after baseline defined as resolving patients' baseline status on persistent and continuous cough (coughing a lot for more than an hour, or ≥3 coughing episodes in 24 hours that interferes with daily life and ability to work) and tachypnea in addition to increasing oxygen saturation >94%. Other secondary outcomes included the time to improvement of chief complaints, hospitalization duration, duration of days with supplemental oxygen, with noninvasive ventilation, mortality, druginduced adverse events and changes in assessed laboratory values over time. The ethics committee of Mazandaran University of Medical Sciences approved the study protocol Data were analysed by SPSS software, version 20.0 by mean±SD (standard deviation) used for reporting quantitative data and frequency and percent for qualitative variables. For comparison of differences between intervention and control group, t-test and chi-square tests were used. The Kaplan-Meier Breslow estimate was done for duration of hospitalization and symptoms in both groups. A p-value of less than 0.05 was considered being statistically significant. The patient recruitment process was initiated on May 23, 2020 and ended on July 31, 2020 (date of enrollment of the last patient). Seventy COVID-19 positive patients were enrolled in the study and one patient from the control group withdrew ( Figure 1 ). The patients' age ranged between 5-86 years. Also, the mean age of the intervention and control groups were 47.6±22.2 and 45.2±23.1 years, respectively (P=0.6). Nine (13%) patients were <18 years old (n=4 in the ivermectin group and n=5 in the control group) (P=0.7). Eighteen (51.4%) patients in the ivermectin group and 17 (48.6%) patients in the control group were males (P=0.9). Table 1 presents the patients' demographics and disease characteristics at baseline. No significant difference was found between the two groups regarding the duration of symptoms before admission, place of residence, or comorbidities. The prescription of antibiotics, hydroxychloroquine, and lopinavir/ritonavir were not significantly different between the two groups. On admission, 13 (37.1%) patients in the intervention group and 18 (52.9%) patients in the control group presented with the severe form of the disease (P=0.2). Overall, 53 (76.8%) patients had dyspnea upon admission, 50 (72.5%) patients had persistent cough, 40 (57.8%) patients had fever, and 37 (53.6%) patients experienced loss of appetite. The frequency of symptoms and signs was not significantly different between the two groups at baseline, except for the loss of appetite, insomnia, rales, and arthralgia, which were higher in the intervention group (Table 1) . Also, both groups were similar in terms of baseline laboratory markers and the rate of positive RT-PCR. Chest CT-scan was performed for all patients, and COVID-19 compatible abnormalities were found in all of them except for one patient with normal chest CT-scan in the control group. Table 2 presents the duration of clinical recovery , symptoms, and hospital stay in both groups in detail. Ten patients in the ivermectin group and nine patients in the control group required supplementary oxygen (P=0.8). Three patients underwent invasive mechanical ventilation (two in the ivermectin group and one in the control group). A 78-year-old woman with a history of diabetes mellitus, and heart failure died in the ivermectin group. She was critically ill at the time of admission and died within the first 24 hours. The laboratory test results were not significantly different between the two groups upon admission. Although lymphopenia was detected in 7 (22.6%) and 13 (40.6%) patients in the intervention and control groups, two days after the intervention, the frequency of lymphopenia decreased to 3 (14.3%) in the ivermectin group and did not change in the control group (n=13, 52%) (P=0.007). No potential adverse events including wheezing, itching, skin rash, edema, and hypotension were observed in patients of both groups. To date, few therapies has shown adequate efficacy for the treatment of COVID-19. In this study, we evaluated the effect of ivermectin on the treatment of COVID-19. With spread of the COVID-19 pandemic, researchers have attempted to find drugs that can be potentially effective against this disease. 13 In this study, both groups were matched regarding age, gender, the severity of the disease, and comorbidities. Most of the participants were middle-aged, and the male-to-female ratio was almost equal. Since this study was performed on hospitalized patients and the intervention included a single oral dose of the medication, the likelihood of missing participants was very low. Based on the results of the current study, we found significant effects of ivermectin on clinical parameters and reduction of hospital stay, dyspnea (as an easily assessed symptom), cough, and lymphopenia. Although in in vitro studies, the dose of ivermectin for inducing antiviral effects is higher than the approved usual dose for humans, the concentration of ivermectin in the lung tissues was found to be three times higher than its plasma concentration in animal models. 7 Patients with COVID-19 develop dyspnea, which can progress rapidly to acute respiratory distress syndrome and even death. 20, 21 Cough, fever, and dyspnea are the most common clinical presentations of COVID-19 22 , which can represent the progression of the disease. 23 In the present study, faster significant improvements in clinical complaints and a shorter duration of hospital stay were detected in the ivermectin group. The mean time to hospital stay was significantly lower in ivermectin group compared with the controls (7.6±2.7 vs 13.2±5.9 days, p=0.00005) in Gorial et al.'s study. 24 Rajter and colleagues did not observe a significant difference in length of hospital stay between the ivermectin and control groups and patients received one dose of ivermectin at any time during the hospitalization. Possible explanation could be delay in offering the ivermectin to patients due to lag in obtaining required repeat COVID-19 testing results. 16 There are trials on the efficacy of other drugs, such as remdesivir, dexamethasone and lopinavir/ritonavir in COVID-19. 5 19 A similar study on lopinavir/ritonavir reported adverse gastrointestinal effects in the intervention group, compared to the standard care controls. 27 In the RECOVERY Collaborative Group's study, the use of oral or intravenous dexamethasone for up to 10 days resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone but not among those receiving no respiratory support. 5 Although Remdesivir was approved for COVID-19 treatment by FDA, it is not specific for it. Despite Ivermectin has some advantages including single-dose, oral nature, shorter recovery time and no side effects in adults hospitalized with COVID-19, but it needs further investigations to be considered for approval as COVID-19 specific treatment. In the current study, two days after the intervention, Ivermectin significantly decreased the frequency of lymphopenia. The potential mechanisms for lymphopenia in COVID-19 patients include lymphocyte apoptosis; destruction of lymphatic organs, such as thymus and spleen directly by the virus; lymphocyte apoptosis by disturbed inflammatory cytokines; and inhibition of lymphocytes following metabolic disorders, such as hyperlactic acidemia. 28, 29 Low lymphocyte counts are consistently associated with severe COVID-19. 30 In other words, lymphopenia can be used as a marker of poor prognosis in COVID-19, especially in younger patients. 28, 31 Therefore, an increased lymphocyte count is a valuable finding of our study, which can be considered in the treatment of COVID-19 patients. It is worth noting that we used Ivermectin in combination with hydroxychloroquine, azithromycin, and antivirals, such as lopinavir/ritonavir. Lopinavir/ritonavir, as a potent inhibitor of cytochrome P450, which is the main metabolic pathway for ivermectin 7 day-1 followed by 100mg 12hrly for next 4 days) compared with placebo in their study and virological clearance was earlier in the 5-day ivermectin treatment arm versus the placebo group. 14 Therefore, a treatment regimen with ivermectin can be considered due to its lower cost, availability, the oral route of administration, and fewer adverse effects in comparison with other available drugs. 11 Although remdesivir showed few side effects in clinical trials, it was not FDA-approved to be administered for children under 12 years of age. 25, 33 There are some concerns regarding the neurotoxicity of ivermectin, as the drug targets glutamate-gated chlorine channels in the invertebrates and may cross-react with GABA-gated chlorine channels in mammalians. 34 This concern diminishes in an intact blood-brain barrier, while in a hyperinflammatory state, this barrier may become permeable in more severe forms of COVID-19, and the drug penetrates the central nervous system. 7 Therefore, in severe forms of the disease, ivermectin should be prescribed with extreme caution. For this reason, in our study, a single dose of the drug was used on the first admission day before progression of the disease to severe central nervous system involvement. This study had a number of limitations. First, the sample size was small and effect of the drug on mortality could not be evaluated. Therefore, further studies with a larger sample size are warranted. A further limitation of this study was the assessment of patients with moderate to severe forms of the disease, who needed to be hospitalized. Regarding the mechanism of action of this drug, its application during the first days of symptoms' onset may be associated with higher clinical response. Although good benefits of Ivermectin were achieved in this study, but due to its small sample size, generalizing its effect and optimization of its use needs further studies with larger sample size, different drug dosages, dosing intervals and durations, especially in different stages of the disease. A single weight-based dose (0.2 mg/kg) of ivermectin could improve important clinical symptoms of COVID-19 patients, such as dyspnea, cough, and lymphopenia in this study. This drug is well-tolerated by patients and has a good safety profile with few adverse effects and can be administered orally. 9 Declaration of Competing Interest The authors have declared that no competing interests exist. MSR and LSh contributed to study conception and design. ARD, MSR and LSh contributed to data collection and patient sampling. FH and MRN contributed to drafting and editing the manuscript. FSM performed the statistical analysis. MSR, LSh and FH revised the manuscript. MSR and GE provided study supervision. JSM assisted in the drafting and editing the manuscript All authors read and approved the submitted manuscript. Written informed consent was obtained from the patients or their parents prior to manuscript submission for their personal or clinical details in addition to any identifying images to be published in this study. Ethics approval and consent to participate All data generated or analyzed during this study are included in this published article. For additional data, please contact the corresponding author (drmsrezaii@yahoo.com). The authors received no specific funding for this work. 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