key: cord-0827913-xms5su6w authors: Rahmani, Hamid; Davoudi-Monfared, Effat; Nourian, Anahid; Khalili, Hossein; Hajizadeh, Nooshin; zarei Jalalabadi, Narjes; Reza Fazeli, Mohammad; Ghazaeian, Monireh; Saeed Yekaninejad, Mir title: Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial date: 2020-08-24 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2020.106903 sha: f3794bcd8b1e9be2e9f953aecff3b5b2797f8534 doc_id: 827913 cord_uid: xms5su6w In this study, efficacy and safety of interferon (IFN) β-1b in the treatment of patients with severe COVID-19 were evaluated. Among an open-label, randomized clinical trial, adult patients (≥ 18 years old) with severe COVID-19 were randomly assigned (1:1) to the IFN group or the control group. Patients in the IFN group received IFN β-1b (250 mcg subcutaneously every other day for two consecutive weeks) along with the national protocol medications while in the control group, patients received only the national protocol medications (lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine for 7-10 days). The primary outcome of the study was time to clinical improvement. Secondary outcomes were in-hospital complications and 28-daymortality. Between April 20 and May 20, 2020, 80 patients were enrolled and finally 33 patients in each group completed the study. Time to clinical improvment in the IFN group was significantly shorter than the control group ([9(6-10) vs. 11(9-15) days respectively, p=0.002, HR= 2.30; 95% CI: 1.33-3.39]). At day 14, the percentage of discharged patients was 78.79% and 54.55% in the IFN and control groups respectively (OR= 3.09; 95% CI: 1.05-9.11, p=0.03). ICU admission rate in the control group was significantly higher than the IFN group (66.66% vs. 42.42%, p = 0.04). The duration of hospitalization and ICU stay were not significantly different between the groups All-cause 28-day mortality was 6.06% and 18.18% in the IFN and control groups respectively (p = 0.12). IFN β-1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19. Furthermore, admission in ICU and need for invasive mechanical ventilation decreased following administration of IFN β-1b. Although 28-day mortality was lower in the IFN group, further randomized clinical trials with large sample size are needed for exact estimation of survival benefit of IFN β-1b. 4 Coronavirus disease 2019 (CoVID- 19) was reported from Wuhan for the first time in late December 2019. Causing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) [1] , it rapidly spread throughout the world to the extent that the World Health Organization (WHO) stated it as pandemic in March 2020 [2] . Until July 5, 2020, more than 15 million confirmed cases of CoVID-19 were reported worldwide. Furthermore, more than 600.000 deaths were recorded [3] . Until now, there is no definite antiviral treatment for CoVID-19 and attempts continue for finding effective treatments worldwide. However, from the beginning of the pandemic, various treatments such as antiretrovirals, anti-malaria agents, favipiravir, remdesivir, and corticosteroids, immunoglobulin and cytokine blockers as adjunctive therapies were suggested for the treatment of CoVID-19 [4] . Except for the remdesivir which has had acceptable results, the efficacy of other drugs has not been significant on the outcomes of the patients with CoVID-19 [5] [6] [7] [8] [9] . Interferons (IFNs) have a key role in defense against viral infections as a component of innate immune system [10] . Invitro activity of IFN β has been shown against severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) [10] [11] [12] [13] . Although IFN β was used less than IFN α for the treatment of SARS-COV and MERS-CoV in human studies, it was effective in the treatment of MERS-CoV in retrospective studies and case series [14] [15] . The efficacy of IFN β-1b is being assessed in the treatment of MERS in a randomized clinical trial [16] . According to the presence of this evidence, IFN β was considered as a promising option for the treatment of In this open-label, randomized clinical trial, efficacy and safety of IFN β-1b in the treatment of patients with severe CoVID-19 were assessed. 5 This open-label, randomized clinical trial was designed to evaluate the efficacy and safety of IFN β-1b in the treatment of patients with CoVID- 19 Adult patients (≥ 18 years old) with positive PCR and clinical symptoms/signs of pneumonia (including dyspnea, cough and fever), peripheral oxygen saturation (SPO 2 ) ≤ 93 % in ambient air or arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) < 300 or SPO 2 /FiO 2 < 315 and lung involvement in chest imaging were included. These criteria indicated severe form of the disease [17] . At baseline, patients with serious allergic reactions to IFN, history of suicide 6 thoughts and attempts, alanine amino transferase (ALT)> 5× the upper limit of the normal range, uncontrolled underlying diseases such as neuropsychiatric disorders, thyroid disorders, cardiovascular diseases and also pregnant and lactating women were not included. Recruitment was considered during the first 48-hour of the hospital admission. During the study period, patients who received less than 4 doses of IFN β-1b were excluded. If patients were discharged before fulfilment of the treatment course, the treatment was applied at home. Eligible patients were recruited in the IFN group or the control group according to the permuted block randomization. Patients in the IFN group received IFN β-1b along with the national protocol medications, while in the control group, patients received only the national protocol medications. IFN β-1b (Ziferon®, Zist Daru Daneh Co., Iran) was administrated as 250 mcg subcutaneously every other day for two consecutive weeks. The national protocol consisted lopinavir/ritonavir (400/100 mg BD) or atazanavir/ritonavir (300/100 mg daily) plus hydroxychloroquine (400 mg BD in first day and then 200 mg BD) for 7-10 days. Other supportive cares such as fluid therapy, stress ulcer prophylaxis, deep vein thrombosis, treatment of electrolyte disorders and antibiotic therapy were considered according to the hospital protocols. The duration of the study was two weeks. A 4-week follow-up period was considered for all patients. Patients' demographic data, baseline diseases, symptoms at the time of disease presentation, vital signs and laboratory data at the time of hospital admission were recorded. Patients were daily monitored in terms of changes in the vital signs, hemodynamic parameters, oxygenation status, laboratory data and treatment strategies. Clinical status of the patients was assessed by the six-7 category ordinal scale at days 0, 7, 14 and 28 of the randomization [18] . Need for supplemental oxygen therapy and also invasive or non-invasive respiratory supports were evaluated regularly. Time to clinical improvement was considered as primary outcome of study. Clinical improvement was defined as improvement of at least two points from the baseline status on the six-category ordinal scale [18] . This scale contains the subsequent categories: (1) death (2) hospital admission requiring invasive mechanical ventilation (3) hospital admission, requiring non-invasive positive pressure ventilation (4) hospital admission, requiring oxygen (5) hospital admission, not requiring oxygen (6) discharge. Secondary outcomes were clinical status of patients at day 7, 14 and 28, ICU admission and intubation rates, length of hospitalization and ICU stay, and 28-day mortality. Side effects related to IFN therapy and other adverse events during the study period were monitored and recorded as the safety outcomes. Categorization of adverse events was done according to the common terminology criteria for adverse events (CTCAE), National Institutes of Health and National Cancer Institute, 2017. Also serious complications during the hospitalization course such as acute respiratory distress syndrome (ARDS), nosocomial infections, septic shock, acute kidney injury (AKI) and acute hepatic injury (AHI) were considered. Continuous variables are demonstrated as median (interquartile range (IQR)) and categorical variables as frequencies and percentages. Continuous variables were compared between the groups by Mann-Whitney U test. The Fisher's exact test was applied for comparison of categorical variables. 8 The Hazard Ratio (HR) and 95% CI for clinical improvement were estimated by Cox proportional hazards regression analysis. The effect of ischemic heart disease, lymphocyte count, Aspartate aminotransferase (AST) and C-reactive protein (CRP) on the primary outcome was evaluated by the adjusted Cox regression models as potential confounding factors. Time to clinical improvement was estimated by Kaplan-Meier plot and compared with a log-rank test. All statistical analysis was done by SPSS software (version 21.0). Time to clinical improvement was estimated to be approximately 10 days and sample size was calculated by following equation: Power= 0.85 According to the above equation, at least 28 patients in each group were expected to make a difference of 4 days in time to clinical improvement with power of 85%. Patients were randomly recruited (1:1) to the IFN group or the control group. The method of randomization was the permuted block randomization (6 patients per block). A biostatistician who was not involved in patients' care did this process. A total of 97 patients were screened. Of them, 15 patients did not have the eligibility criteria of study and 2 patients were referred from another hospital. Three and four patients withdrew the consent during the study in the IFN group and control groups, respectively. Four patients did not adhere to IFN injection after second or third dose. Also three patients in the control group were enrolled in another trial. Finally, 33 patients in each group completed the study ( Figure 1 ). The median (IQR) age of patients was 60(50-71) years and 59.09 % of them were male. No significant difference in terms of the patients' demographic data was detected between the groups. The most common comorbidities were hypertension, diabetes mellitus and ischemic heart disease. Dyspnea, fever and cough were the most frequent symptoms at the time of hospital admission. The median (IQR) time from onset of the symptoms to hospital admission was 7(5-9) and 7(4-8) days in the IFN group and control groups respectively. The time from onset of the symptoms to randomization was not statistically significant between the groups. All of patients required respiratory support at the time of randomization. Oxygenation through facemask was required for more than 80 percent of patients. None of the patients in both groups were intubated at baseline ( The EC 50 values for remdesivir and lopinavir were determined as 1.04 and 11.6 µM respectively. The CC50 values of IFNs, remdesivir and lopinavir were > 50.000 IU/ml, > 100 µM and 102 µM respectively. Among IFNs, the most reductive effects on viral load belonged to IFN β-1a and IFN β-1b. However, IFN β-1b showed highest potency and selectivity index against SARS-COV-2 [22] . In a randomized clinical trial, 86 and 41 patients were recruited in the combination and control groups respectively. Patients in the combination group received IFN β-1b, lopinavir/ritonavir and ribavirin while those in the control group received only lopinavir/ritonavir. The primary outcome was defined as the time to reach a negative RT-PCR of respiratory secretions for SARS-CoV-2. The time to resolution of the symptoms was considered as one of the secondary outcomes. The median time to achieving a negative RT-PCR was significantly shorter in the combination group compared to the control group (7 vs. 12 days). Moreover, resolution of the symptoms occurred notably faster in the combination group than the control group (4 vs. 8 days) [23] . Similar with our study, IFN β-1b was started in the viral phase of COVID-19 i.e. within first 7 days of onset of the symptoms. In our study median time from onset of the symptoms to randomization was 8 days. In both studies, first dose of IFN β-1b was administered within 24 to 48 hours of hospital admission. Initiation of antiviral agents as soon as possible following onset of the symptoms is critical in control of viral replication and prevention of tissue viral invasion. The efficacy of antivirals significantly decreased after establishment of the cytokines release phase in COVID-19 [24] [25] . Due to resource limitations, evaluation of viral clearance was not possible in our study. and 150 patients were assigned to the IFN and control groups respectively. In-hospital mortality was considered as the primary outcome of study. The mortality rate was statistically significant in the control group than the IFN group (20.8% vs. 27.3%) [26] . Retrospective design and lack of matching of the groups in terms of receiving other antivirals should be considered when interpreting the results. In a case series, characteristics and outcomes of five patients with severe COVID-19, who were treated with IFN β-1b, lopinavir/ritonavir and hydroxychloroquine, were described. The antiviral regimen applied for these patients was similar to our study. Treatment was successful in 3 patients while clinical status of 2 patients deteriorated during the treatment course. All patients received corticosteroids. Furthermore, all patients were initially admitted in another hospital and later transferred to the referral hospital [27] . 43.6%). Early administration of IFN β-1a significantly reduced the mortality rate compared with late administration [30] . Absence of follow-up PCR and chest imaging along with the small sample size were the major limitations of the study. Our study suffered from some limitations. Follow up chest imaging or virological assessment was not possible due to resources limitations, therefore the effect of IFN β-1b on viral clearance was not determined. Small sample size did not allow accurate estimation of survival benefit of IFN β-1b. In conclusion, IFN β-1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19. Furthermore, ICU admission rate and need for invasive mechanical ventilation significantly reduced by administration of IFN β-1b. Although compared with the control group, IFN β-1b reduced duration of hospitalization, length of ICU stay, intubation rate and 28-day mortality were not statistically different between the groups. Further randomized clinical trials with enough sample size are needed to accurately estimate survival benefit of IFN β-1b. In patients with severe COVID-19: -As Add-on therapy, IFN β-1b shortened the time to clinical improvement -IFN β-1b significantly increased the discharge rate at day 14 -IFN β-1b reduced overall 28-day mortality -IFN β-1b related adverse effects were mild and did not cause treatment interruptions Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence WHO Declares COVID-19 a Pandemic Johns Hopkins Coronavirus Resource Center Home Page Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19 Effectiveness and Safety of Glucocorticoids to Treat COVID-19: A Rapid Review and Meta-Analysis Clinical efficacy of intravenous immunoglobulin therapy in critical patients with COVID-19: A multicenter retrospective cohort study The antiviral effect of interferonbeta against SARS-coronavirus is not mediated by MxA protein Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) Interferon-beta 1a and SARS coronavirus replication inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study Treatment outcomes for patients with Middle Eastern respiratory syndrome coronavirus (MERS CoV) infection at a coronavirus referral center in the kingdom of Saudi Arabia And the MIRACLE trial group. 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Viruses Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial COVID-19: towards understanding of pathogenesis COVID-19 infection: the perspectives on immune responses Clinical evaluation of IFN beta1b in COVID-19 pneumonia: a retrospective study Five severe COVID-19 pneumonia patients treated with triple combination therapy with lopinavir/ritonavir, hydroxychloroquine, and interferon β-1b Interferon beta-1a as a Candidate for An Open-Label Single-Arm Clinical Trial Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial Efficacy and safety of interferon beta-1a in treatment of severe COVID-19: A randomized clinical trial Table 1-Baseline characteristics of patients Parameter; Median (IQR) or n (%) We would like to thank the nurses and other staffs of Imam Khomeini Hospital Complex for their kind supports and also Ms. Ava Khalili for English proofreading the manuscript. The authors did not receive any fund for this work. There is no conflict of interest for authors to declare.