key: cord-283903-e20v88ge authors: Davoodi, Lotfollah; Abedi, Seyed Mohammad; Salehifar, Ebrahim; Alizadeh‐Navai, Reza; Rouhanizadeh, Hamed; Khorasani, Ghasemali; Hosseinimehr, Seyed Jalal title: Febuxostat therapy in outpatients with suspected COVID‐19: A clinical trial date: 2020-06-30 journal: Int J Clin Pract DOI: 10.1111/ijcp.13600 sha: doc_id: 283903 cord_uid: e20v88ge BACKGROUND: The aim of this clinical trial was to evaluate the effects of febuxostat (FBX) in comparison with hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings in outpatients with moderate symptoms of COVID‐19 infection. METHODS: We conducted a clinical trial involving adult outpatients with the moderate respiratory illness following COVID‐19 infection. Patients were randomly assigned to receive either FBX or HCQ for 5 days. The measured variables were needs to hospitalization, clinical and laboratory data including fever, cough, breathing rate, C‐Reactive Protein level, lymphocytes count at onset of admission and was well as at 5 days of treatments. In addition, CT findings were evaluated on admission and 14 days after initiation of treatment. RESULTS: Sixty subjects were enrolled in the study with a 1 to 1 ratio in FBX and HCQ groups. On admission, fever (66.7%), cough (87%), tachypnea (44.4%), dyspnea (35%), elevated CRP value (94.4%) and lung involvement according to chest CT (100%) were documented in enrolled patients with insignificant difference between FBX and HCQ groups. Fever, cough and tachypnea were significantly mitigated in both groups after five days of treatments without any significant differences between groups. The mean percentages of lung involvement were significantly reduced to 7.3% and 8% after 14 days of treatment with FBX and HCQ, respectively. In adult outpatients with moderate COVID‐19 infection, the effectiveness of FBX and HCQ was not different in terms of resolution of clinical manifestations, laboratory tests and lung CT findings. CONCLUSION: This trial suggests that FBX is as an alternative treatment to HCQ for COVID‐19 infection and may be considered in patients with a contraindication or precaution to HCQ. novel non-purine xanthine oxidase (XO) approved for treating hyperuricemia in patients with gout. Several studies have already demonstrated the anti-inflammatory [7] , anti-oxidant [8] and antiapoptosis effects of FBX [9] . Several preclinical studies showed that FBX inhibits inflammatory responses through reducing the levels of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and NF-κB [10] [11] [12] . It protects animal against toxic-induced lung inflammation through downstream inflammatory mediators and oxidative stress [13] [14] [15] . FBX markedly accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis [16] . This clinical trial was conducted to assess the effects of FBX and hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings of patients with COVID-19 infection. IRCT2019072704434N1, the full trial protocol can be accessed at: http://www.irct.ir). The study was performed in accordance with declaration of Helsinki. All patients signed the informed consent form. Sample size was determined 30 patients in both group based on effect size = 0.3 for difference in response rate as a primary endpoint, power = 80% and alpha = 0.05 for this study, as a two-sided superiority trial [17, 18] . Inclusion criteria were as following 1; chest CT finding compatible with COVID-19 infection along with other symptoms of coronavirus infection. Bilateral and peripheral ground-glass and consolidative pulmonary opacities were the hallmarks of CT findings. 2; any symptoms of respiratory tract Accepted Article involvement including cough, dyspnea or tachypnea along with a history of contact with a known case of COVID-19 3; creatinine clearance greater than 60 ml/min. The exclusion criteria include: 1; Suspicious patients for COVID-19 pneumonia who had severe underlying diseases such as cardiovascular, lung and kidney diseases, 2; patients with severe pneumonia needing hospitalization, 3; patient who were unable to take oral medications and 4; concurrent use of azathioprine, didanosine, mercaptopurine or pegloticase (due to drug interaction with FBX). Patients were randomized using the balance block method to receive HCQ (30 patients) or FBX (30 patients). HCQ were administered one tablet of HCQ 200 mg twice daily (Amin Pharmaceutical Company, Iran). Patients in FBX group took one tablet of FBX 80 mg per day (Jalinus Pharmaceutical Company, Iran). All patients were taken acetaminophen 325 mg, as needed, for controlling the fever. The pharmaceutical companies were neither involved in the design nor in the financial support of the study. Study drugs were purchased from an official Iranian pharmacy. Amin and Jalinus pharmaceutical companies did not access to the data of the study during trial and prior publication. The treatment duration was five days. Both patients and physician did not know the contents of tables. The primary outcome of this study was the rate of hospitalization. Secondary outcomes were clinical improvements (e.g., resolution of fever, cough and dyspnea) and improvement of CT findings at days 14 after initiation of the treatment. Patients were assessed clinically (e.g., temperature, respiratory rate, cough, and dyspnea) and paraclinically (e.g., CBC-diff and C-Reactive Protein) at onset of admission and 5 th day of treatment. In addition, the chest CT scans were done at first and 14 days after the onset of treatment. For each patient, the chest CT scan was evaluated for the presence of groundglass opacities and/or consolidation. Each five lobe of the lung was assessed and the overall lung involvement was reached by summing the five lobe scores (range of possible scores, 0 -20 for each lobe and total lung involvement of possible score of 0-100 percent). The Chest CT was repeated in day 14 and compared with the initial finding. Reduced lung CT involvement; not adjusted" values were computed according to this equation: Reduced Lung CT involvement, not adjusted = Day 14 total long involvement -Initial total lung involvement Reduced lung CT involvement; adjusted values was computed with the following equation that included the initial total lung involvement in the denominator: Reduced lung CT involvement; adjusted value = (Initial total long involvement -Day 14 total long involvement) Initial total lung involvement × 100 Normality of data was checked with Shapiro-Wilk Test. Independent sample t-test and Mann-Whitney U test (comparison of continuous variables between two groups), Wilcoxon matched-pair signed-rank test (comparison of continuous variables before and after treatment), and Chi 2 test (comparing the qualitative data) were used for analysis. The method of analysis was intention-to-treat. The SPSS software version 21.0 (SPSS, Inc., Chicago, IL) was applied for statistical analysis. Sixty subjects were enrolled including FBX (N = 30) and HCQ groups (N = 30) ( Figure 1 ). Six patients (1 patient in FBX group and 5 patients in HCQ group) were excluded, because patients were not interest to continue the treatment ( Figure 1 ). This article is protected by copyright. All rights reserved documented by clinical manifestations and CT findings. There were not between-group significant differences in baseline demographic characteristics, laboratory data (e.g., CRP, WBC and lymphocytes counts) and CT scores of lung lesions (Table 1) . The rate of hospitalization, the primary endpoint of the study, was nor different among groups. Six patients (11%, 3 patients in each group) were hospitalized because of developing more severe symptoms. The rate of intensive care unit (ICU) care and also mortality rate was not different between patients received FBX or HCQ. All hospitalized patients were released from hospitals between 1 to 7 days of hospitalization. Patients were re-evaluated at five days after admission and using FBX or HCQ. Fever, cough and tachypnea significantly mitigated in patients treated with either FBX or HCQ after five days of treatment (P<0.01 compared to baseline of each group) ( This article is protected by copyright. had severe disease and 5% needed critical care [19] . In Italy, approximately 40% of patients have been hospitalized, whereas nearly 7% admitted to ICU [20] . There is significant variation in the rate of hospitalization of patients with Covid-19 in the world. However, sample size of our clinical trial was smaller and patients with significant comorbidities such as sever cardiovascular and renal diseases were excluded in our trial. Clinical symptoms such as fever, cough and shortness of breath were observed in a large proportion of patients at admission, but these manifestations markedly reduced or resolved (e.g., fever and dyspnea) after 5 days following use of FBX or HCQ. It was not observed any statistically difference in mitigating of clinical symptoms between FBX and HCQ treatments. Low lymphocyte count has been consistently reported in patients with COVID-19 infection (in 80% of cases) and may indicate the severity of disease and serve as a predictor of prognosis [21] . More than half of patients show elevated values of CRP. Patients with severe disease had more prominent laboratory abnormalities than those with non-severe disease [22] . In our study, lymphopenia was observed in 81.5% of patients at onset of admission and significantly increased after This article is protected by copyright. All rights reserved carriage of SARS-CoV-2 in COVID-19 patients were evaluated. The clinical symptoms, laboratory tests and lung CT features were reported to be similar in both groups of patients [17] . In other study, Gautret, et al conducted an uncontrolled non-comparative observational study in a cohort of 80 mildly infected inpatients treated with a combination of HCQ and AZT over a period of at least three days. A rapid fall of nasopharyngeal viral load tested by qPCR was noted, with 83% negative at Day 7, and 93% at Day 8. Authors concluded that they have provided evidence of a beneficial effect of coadministration of HCQ with AZT in the treatment of COVID-19 and its potential effectiveness in the early stages of contagiousness [27] . To date, despite some promising results associated with efficacy and safety of HCQ in COVID-19, the evidence regarding its effect remains limited [28] . Infrequent and rare side effects include retinal toxicity, cardiac toxicity, QT interval prolongation and agranulocytosis have been reported in patients receiving HCQ or CQ. Life threatening arrhythmias following use of CQ and HCQ appear to be rare but cardiac monitoring is necessary if the drug is being used more extensively [29, 30] . HCQ inhibits IL-6, TNF-α, IL-1β and NF-κB [31] [32] [33] [34] [35] , and it has immunomodulatory and anti-inflammatory effects [32, 36, 37] , which may be beneficial in patients with COVID-19 who inflammatory response and storm cytokine production plays a major role in damaging the lung tissue [37] . There are complex interactions between inflammation and thrombosis, that inflammation is causing a thrombotic tendency. The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients, it is recommended to use medicine with anti-inflammatory and antithrombotic properties for prevention or management of thrombosis in COVID-19 [38] . Recently in the recovery trial found that use of dexamethasone was associated with mortality benefit in patients with severe form of COVID-19 infection [39] . NF-κB plays a central role in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and autoimmunity. NF-κB is activated through microbial products and also pro-inflammatory cytokines, as well as endogenous ligands that function as its trigger during tissue injury, the latter of which may promote inflammation in the absence of infection [40] [41] [42] . In addition, viral infections cause NF-κB overexpression, which plays a crucial role in the production of pro-inflammatory cytokine storms and triggers various cellular responses including cell phagocytosis, dendritic cell maturation, chemotaxis and lipopolysaccharide-induced pulmonary inflammation [6, 43, 44] . It seems that downregulation of NF-κB results in the attenuation of inflammatory cytokine signaling and This article is protected by copyright. All rights reserved may be a promising target for lung protection [45] . FBX is in a class of medications called xanthine oxidase (OX) inhibitors leading to decrease in uric acid production. Beside decreasing serum uric acid in gout by FBX, there are well documents demonstrating FBX suppresses pro-inflammatory cytokines such as IL-1β, IL-6 MCP-1 and TNF-α as well as inhibits the oxidative stress and inflammatory responses through NF-κB pathway in animal models [10, 12, 46, 47] . FBX is able to improve lung damage induced by toxic agents through down-regulation of oxidative stress pathway and suppression of inflammatory mediators [8, 16, 48, 49] . To date, there is not any report associated to anti-viral activity of FBX. Xanthine oxidase, which is responsible for the generation of oxygen free radicals, was elevated in serum and lung tissue of mice infected with influenza virus [50] [51] [52] . Due to the crucial roles of cytokines and pro-inflammatory mediators in severe acute respiratory syndrome induced by COVID-19, with respect to beneficial effects of FBX in blockading the activation of cytokines and NF-κB pathway, this medicine seems to be an effective drug for the prevention and treatment of lung inflammation in patients with COVID-19 insignificant efficacy with HCQ. However, further studies are needed to find the exact mechanism of FBX in treatment of COVID-19 infection. The adverse effects associated with FBX therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels, rash and cardiovascular problems. These side effects were not observed in our study, which may be due to the short time consuming of FBX. It is also notable that we excluded patients with cardiovascular and chronic kidney diseases. The limitation of our study was the absence of placebo group. Considering ethical issues, we designed this study without a placebo group due to the life-threatening nature of COVID-19 infection. Our trial suggests a beneficial effect of administration of FBX in patients with suspected mild-tomoderate COVID-19 infection. The effects of FBX and HCQ was not different in terms of need to hospitalization, improvement in clinical symptoms and CT findings pointing out the lung involvement. FBX may be considered in patients who are not a good candidate of HCQ due to underlying cardiovascular diseases. This article is protected by copyright. All rights reserved This study was supported by a grant from Mazandaran University of Medical Science, Sari, Iran (ID#7294). We thank all patients who participated in this trial and their families. We thank Adel Heidari for assistance in data gathering. We appreciated the health care staffs who lost their lives in the care of patients with Covid-19. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. There were not any significant differences between two groups in baseline demographic and clinical characteristics &: indicate the Lung CT data on day 14 compared to Day 1; P-value for between groups differences were not significant for any of variables both on day 1 and day 14. Clinical Characteristics of 138 Hospitalized Patients With Evaluation and Treatment Coronavirus (COVID-19) Dysregulation of immune response in patients with COVID-19 in Wuhan, China Accepted Article This article is protected by copyright. All rights reserved Coronavirus infections and immune responses The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung Protective effects of febuxostat against paraquatinduced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades Febuxostat pretreatment attenuates myocardial ischemia/reperfusion injury via mitochondrial apoptosis Febuxostat attenuates ulcerative colitis by the inhibition of NF-kappaB, proinflammatory cytokines, and oxidative stress in mice Effects of febuxostat on serum cytokines IL-1 Febuxostat Modulates MAPK/NF-kappaBp65/TNF-alpha Signaling in Cardiac Ischemia-Reperfusion Injury Protective effects of febuxostat against paraquatinduced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades Xanthine oxidase contributes to sustained airway epithelial oxidative stress after scald burn Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner Accepted Article This article is protected by copyright. All rights reserved XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention COVID-19 in Italy: momentous decisions and many uncertainties Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study China Medical Treatment Expert Group for C. Clinical Characteristics of Coronavirus Disease 2019 in China Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus p Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review Chloroquine and Hydroxychloroquine in the Era of SARS -CoV2: Caution on Their Cardiac Toxicity Off-label prescribing in the midst of a pandemic: The case of hydroxychloroquine Increased Myeloid Dendritic Cells and TNF-alpha Expression Predicts Poor Response to Hydroxychloroquine in Cutaneous Lupus Erythematosus Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase Hydroxychloroquine alleviates 5-fluorouracil-induced enteritis in mice and its mechanism Accepted Article This article is protected by copyright. All rights reserved Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients Cholesterolmodified Hydroxychloroquine-loaded Nanocarriers in Bleomycin-induced Pulmonary Fibrosis The Pharmacological Mechanisms and Therapeutic Activities of Hydroxychloroquine in Rheumatic and Related Diseases Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials NF-kappaB, inflammation, and metabolic disease The nuclear factor NF-kappaB pathway in inflammation The Role of NF-kB Inhibitors in Cell Response to Radiation Accepted Article This article is protected by copyright. All rights reserved Barbaloin protects against lipopolysaccharide (LPS)-induced acute lung injury by inhibiting the ROSmediated PI3K/AKT/NF-kappaB pathway Osthole Protects against Acute Lung Injury by Suppressing NF-kappaB-Dependent Inflammation Acute induction of inflammatory cytokine expression after γ-irradiation in the rat: effect of an NF-κB inhibitor Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner Oxygen radicals in influenzainduced pathogenesis and treatment with pyran polymer-conjugated SOD Protective effect of n-acetylcysteine in a model of influenza infection in mice Accepted Article The authors declare no potential conflicts of interest with respect to authorship, and/or publication of this study.