key: cord-0974582-n92ho1a6 authors: Beltran-Gonzalez, J. L.; Gonzalez-Gamez, M.; Mendoza-Enciso, E.-A.; Esparza-Maldonado, R. J.; Hernanez-Palacios, D.; Duenas-Campos, S.; Ovalle-Robles, I.; Macias-Guzman, M. J.; Garcia Diaz, A. L.; Gutierrez Pena, C. M.; Martinez-Medina, L.; Monroy Colin, V. M.; Arreola Guerra, J. M. A. title: Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial date: 2021-02-23 journal: nan DOI: 10.1101/2021.02.18.21252037 sha: 2e9e6eaa6db3bc187998ecee9c72faf1409e8fd4 doc_id: 974582 cord_uid: n92ho1a6 Background In the search for active drugs against COVID19, the indications of many have been redirected. Ivermectin and Hydroxychloroquine are drugs that inhibit viral replication in vitro and that have been used in several medical centers. Objectives: This clinical trial analyzes the efficacy of Ivermectin and Hydroxychloroquine in patients with moderate COVID19 and in need of hospitalization. Methods. This a controlled, clinical, randomized, double blind trial that included patients with COVID-19-induced pneumonia and hospitalization criteria, but no severe respiratory failure. Patients were randomized to one of three groups: Group1 hydroxychloroquine, 400 mg every 12 hours on the first day and subsequently, 200 mg every 12 hours for 4 days, Group 2 ivermectin, 12 mg or 18 mg, according to patient weight and, Group 3 placebo. At inclusion, blood samples for arterial blood gases and biochemical markers associated with a poor prognosis were obtained. The primary outcome was established as the duration of hospitalization until discharge due to patient improvement, the total duration of hospitalization, and the safety outcomes were either respiratory deterioration or death. Results. During the month of August, the admission of patients requiring hospitalization mostly encompassed cases with severe respiratory failure, so we ended the recruitment process and analyzed the data that was available at the time. One hundred and six (106) patients with an average age of 53 yrs. (plus-or-minus sign 16.9) were included, with a greater proportion of males (n=66, 62.2 %). Seventy-two percent (72%) (n= 76) had an associated comorbidity. Ninety percent (90 %) of patients were discharged due to improvement (n=96). The average duration of hospitalization was 6 days (IQR, 3 to 10). No difference in hospitalization duration was found between the treatment groups (Group1: 7 vs Group 2: 6 vs Group 3: 5, p =0.43) nor in respiratory deterioration or death (Group 1: 18 % vs Group 2: 22.2 % vs Group 3: 24.3 %, p =0.83). Conclusions. In non-critical hospitalized patients with COVID-19 pneumonia, neither ivermectin nor hydroxychloroquine decreases the number of in-hospital days, respiratory deterioration, or deaths. according to patient weight and, Group 3-placebo. At inclusion, blood samples for arterial blood gases and biochemical markers associated with a poor prognosis were obtained. The primary outcome was established as the duration of hospitalization until discharge due to patient improvement, the total duration of hospitalization, and the safety outcomes were either respiratory deterioration or death. Results. During the month of August, the admission of patients requiring hospitalization mostly encompassed cases with severe respiratory failure, so we ended the recruitment process and analyzed the data that was available at the time. One hundred and six (106) patients with an average age of 53 yrs. (±16.9) were included, with a greater proportion of males (n=66, 62.2 %). Seventy-two . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) On January 30, 2020, the World Health Organization declared a global health emergency due to SARS-Cov-2 infections (COVID- 19) . (1) Since then, the outbreak has spread to all continents and the number of confirmed cases continues to increase. To date, there is no commercially available vaccine or approved treatment, and the management of patients that develop symptoms and require hospitalization is mostly supportive. clinical presentations; however, they have not been shown to improve clinical outcomes. (3) (4) (5) In the search for active drugs against COVID-19, the indications of several drugs have been redirected. One of the most studied is ivermectin, a macrolide obtained from We aim to evaluate the efficacy and safety of ivermectin and hydroxychloroquine patients with pneumonia secondary to COVID-19. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) This is a controlled, randomized, double-blind, clinical trial of patients with pneumonia secondary to SARS-CoV-2 infection and that fulfilled hospitalization criteria. These criteria were defined according to the attending physician in the emergency department and included the following parameters: severity of clinical presentation (determined with the CURB-65 scoring system), need for supplemental oxygen, the presence of comorbidities and, laboratory markers suggesting a poor prognosis. Patients were excluded if they required high oxygen volumes (face mask > 10 L/ min), if they had predictors of a poor response to high-flow oxygen nasal prong therapy or if they required mechanical ventilation. (9) Patients were classified as high-or low-risk for the development of QT interval prolongation due to hydroxychloroquine, according to their electrocardiogram. The QT interval was measured with Bazett´s formula. Patients with an interval ≥ 500 ms were randomized to ivermectin or placebo, while those with an interval < 500 ms were . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 23, 2021. ; randomized to ivermectin, hydroxychloroquine, or placebo. The dose of ivermectin was 12 mg in patients weighing less than 80 kg and 18 mg in those above 80 kg. (10) In the hydroxychloroquine group, patients were administered 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours for another 4 days. Due to the physical appearance of hydroxychloroquine, calcium citrate was chosen as a placebo and was administered as 2 tablets every 12 hours on the first day, followed by one tablet every 12 hours on the following 4 days. Blinding was assured with amber-colored vials. Each patient had a vial for the initial dose in order to blind the ivermectin and a second vial for subsequent doses. All patients received two vials, one with the initially prescribed dose and a second one, with the indication to take two tablets 12 hours after the initial dose followed by one tablet every 12 hours until all tablets were finished. On admission, blood samples were obtained to determine arterial blood gases, a complete blood count, blood chemistry, and prognostic markers such as fibrinogen, Ddimer, ferritin, troponin I, procalcitonin, C reactive protein, prothrombin and activated partial thromboplastin times. If available, a high-resolution chest CT scan was also obtained and if not, only a chest X-ray. The diagnostic probability of pneumonia due to SARS-CoV-2 was established following the CO-RADS classification. (11) All hospitalized patients received pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin according to local and international guidelines.(12,13) During the last week of June and based on the RECOVERY trial, we initiated the administration of dexamethasone, 6 mg IV every 24 hours, for 10 days or until discharge, in patients requiring oxygen therapy.(14) . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 23, 2021. ; https://doi.org/10.1101/2021.02.18.21252037 doi: medRxiv preprint All included patients were under continuous cardiac monitoring and protocolized therapy was withdrawn in patients that developed any arrhythmia or acute coronary syndrome. Safety outcomes were established as death due to any cause or respiratory deterioration. Respiratory deterioration was defined as a respiratory frequency above 30 breaths per minute, a required inspired oxygen fraction delivered by face mask or high-flow nasal prongs of 60% or above, a PaO2/Fio2 ratio <200, or a ROX index at 12 hours <3.85 points. (9, 15) Hospital discharge was considered when the patient fulfilled the following criteria: absence of neurologic complications, no fever, hemodynamic stability over at least, the previous 72 hours, minimal oxygen requirements (nasal prongs at 1-2 liters per minute), and the availability of a well-established social support network. The main outcome was determined as the hospitalization duration until discharge due to clinical improvement, the total duration of hospitalization, and the safety outcomes were duration of hospitalization until respiratory deterioration (previously defined) or death. This study was conducted at the Hospital Centenario Miguel Hidalgo in the state of Aguascalientes (Mexico), a tertiary care institution for the population lacking social security. The study protocol was approved by the Ethics Committee of the Hospital Centenario Miguel Hidalgo on April 15, 2020, with the assigned number 2020-R-24. It was also included in the ClinicalTrials website with the identifier NCT04391127. Depending on the measurement level, descriptive statistics were used. The distribution of continuous variables was determined with the Kolmogorov Smirnov test. Continuous . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Considering a mean hospitalization stay of 20 to 30 days and standard deviation of 7 days, if we want a reduction of 4 days of hospitalization, taking into account the mean differences formula, we calculate 47 patients per group of treatment. During the past month of August, we observed a very significant decrease in the number of potential candidates that could be included in the study, since practically all hospital admissions required therapy with high oxygen concentrations or invasive mechanical ventilation. Based on the Ethics Committee´s recommendations, we decided to end recruitment and conduct an analysis with the data obtained as of August 15, 2020. At the time of analysis, 108 patients had been recruited, two of which were eliminated because they were transferred to another hospital. The patients´ average age was 53 years (±16.9), and there was a greater proportion of males (n=66, 62.2 %). Comorbidities were present in 72% of cases (n= 76). Type 2 diabetes mellitus and systemic arterial . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 2) The ratio between the Arterial Oxygen pressure (PaO2) and the Inspired Oxygen fraction (PaO 2 /FiO 2 ) was greater than 200 mmHg in 64 patients; 42 patients had severe respiratory deterioration (Table 3) . Patients included in the study had characteristics considered significantly severe: in 77%, the Neutrophil / Lymphocyte index was (Table 4) During hospitalization, 52.3% of patients received some form of antibiotic, 92.2% were on thromboprophylaxis and 55.7% received dexamethasone as ancillary therapy (Table 5) . Follow-up during hospitalization did not reveal thrombotic complications and no arrhythmias developed in patients on hydroxychloroquine. Only 3 patients developed septic shock, one in each treatment arm. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 23, 2021. ; https://doi.org/10.1101/2021.02.18.21252037 doi: medRxiv preprint The average duration of hospitalization was 6 days (IQR 3 -10). Ninety percent (90 %) of patients were discharged after clinical improvement (n=96). Twenty-three (23) patients developed respiratory deterioration, 13 (12.2%) of whom died during follow-up, all as a result of respiratory failure, and three with sepsis due to bacterial coinfection. No differences in outcome were detected between the treatment groups ( Table 6 ). The time until death or respiratory deterioration was also not different between groups (figure 1). In this study of non-critically ill patients with pneumonia secondary to COVID-19 and fulfilling hospitalization criteria, treatment with hydroxychloroquine or ivermectin was not superior to placebo, neither in terms of hospitalization duration nor in progression to severe respiratory failure or death. In the first weeks of the COVID-19 pandemic, there was in vitro evidence on the efficacy of hydroxychloroquine as well as case series and non-controlled comparative studies supporting its use. This led various medical centers and health systems to recommend it based on compassionate use. This strategy fostered panic purchases and prescriptions leading to drug shortages for patients with well-established indications. As months went by, its inefficacy was suspected and reports from the SOLIDARITY study finally proved its therapeutic futility in decreasing mortality, and patient recruitment was stopped.(16) Our analysis further confirms that study´s findings. (4, 5) Although adverse events have been reported with the use of hydroxychloroquine, particularly QT interval prolongation, none of our patients developed cardiovascular . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The main strength of this clinical trial is the fact that it represents the response of a referral hospital in the management of patients with COVID-19. In a controlled manner, patients were offered two therapeutic alternatives that at the beginning of the pandemic appeared to be potentially effective. Although the patient number is not sufficient to reach . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 23, 2021. ; categorical conclusions, the study´s design certainly suggests that both drugs are ineffective. We hope it will contribute to meta-analyses that may yield more robust conclusions. The study´s main weakness is the limited number of patients per group; also, among the pre-established outcomes, we were unable to determine whether the SARS-CoV-2 PCR tests became negative, due to the lack of reactants and the minimal usefulness of proving its negativity from a clinical-practical viewpoint. In conclusion, in non-critically ill, hospitalized patients with pneumonia secondary to COVID-19, the use of hydroxychloroquine or ivermectin did not decrease the number of hospitalization days, respiratory deterioration, or deaths. Table 1 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 23, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 23, 2021. ; https://doi.org/10.1101/2021.02.18.21252037 doi: medRxiv preprint on the second meeting of the Emergency Committee of the International Health Regulations (2005) on the outbreak of the new coronavirus (2019-nCoV). Accessed Effects of chloroquine on viral infections: an old drug against today's diseases Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 World Health Organization. Coronavirus Disease (COVID-19) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Diagnosis and Treatment of Adults With Community-Acquired Pneumonia An Index Combining Respiratory Rate and Oxygenation to Predict Outcome of Nasal High-Flow Therapy Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens Spanish Society of Thrombosis and Haemostasis. Recommendations for thromboprophylaxis and antithrombotic treatment in COVID-19 patients Prevention and Treatment of Venous Thromboembolism Associated with Coronavirus Disease 2019 Infection: A Consensus Statement before Guidelines Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report Predictors of success of high-flow nasal cannula in the treatment of acute hypoxemic respiratory failure Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study Lohmer LRL. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19 Embrace of Unproven COVID-19 Treatment Hinders Drug Trials No conflict of interest are declared by the authors.