Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Antibiotic use during the first 6 months of COVID-19 pandemic in Iran: A large-scale multi-centre study.

WHAT IS KNOWN AND OBJECTIVE: Although antibiotics are ineffective against viral infections, epidemiological studies have revealed that the COVID-19 pandemic resulted in the overuse of antibiotics and disruption of antimicrobial stewardship programmes. We investigated the pattern of antibiotic use during the first 6 months of the COVID-19 pandemic in Iran. METHODS: A multi-centre retrospective study was designed to investigate the use of 16 broad-spectrum antibiotics in 12 medical centres. The rate of antibiotic use was calculated and reported based on the Defined Daily Dose (DDD) per 100 hospital bed-days. The bacterial co-infection rate was also reported. RESULTS AND DISCUSSION: Totally, 43,791 hospitalized COVID-19 patients were recruited in this study. It was found that 121.6 DDD of antibiotics were used per 100 hospital bed-days, which estimated that each patient received approximately 1.21 DDDs of antibiotics every day. However, the bacterial co-infections were detected only in 14.4% of the cases. A direct correlation was observed between the rate of antibiotic use and mortality (r[142] = 0.237, p = 0.004). The rate of antibiotic consumption was not significantly different between the ICU and non-ICU settings (p = 0.15). WHAT IS NEW AND CONCLUSION: In this study, widespread antibiotic use was detected in the absence of the confirmed bacterial coinfection in COVID-19 patients. This over-consumption of broad-spectrum antibiotics may be associated with increased mortality in hospitalized COVID-19 patients, which can be an alarming finding.

Comparing efficacy and safety of tocilizumab and methylprednisolone in the treatment of patients with severe COVID-19.

OBJECTIVES: This study was designed to compare the efficacy and safety of methylprednisolone and tocilizumab in the treatment of patients with severe COVID-19. METHODS: During a prospective cohort study, hospitalized patients with severe COVID-19 received intravenous methylprednisolone (250-500 mg daily up to three doses), weight-based tocilizumab (maximum 800 mg, one or two doses as daily interval) or dexamethasone (8 mg daily). The primary outcome was time to onset of clinical response. Secondary outcomes were improvement rate of oxygen saturation and CRP, need for ICU admission, duration of hospitalization and 28-day mortality. During study, adverse events of the treatments were recorded. RESULTS: Although the difference was not statistically significant (p = 0.090), clinical response occurred faster in the tocilizumab group than other groups (10 vs. 16 days). Clinical response was detected in 74.19%, 81.25%, and 60% of patients in the methylprednisolone, tocilizumab, and dexamethasone groups respectively (p = 0.238). Based on the Cox regression analysis and considering dexamethasone as the reference group, HR (95% CI) of clinical response was 1.08 (0.65-1.79) and 1.46 (0.89-2.39) in the methylprednisolone and tocilizumab groups respectively. Improvement rate of oxygen saturation and CRP was not significantly different between the groups (p = 0.791 and p = 0.372 respectively). Also need for ICU admission and 28-day mortality was comparable between the groups (p = 0.176 and p = 0.143 respectively). Compared with methylprednisolone, tocilizumab caused more sleep disturbances (p = 0.019). Other adverse events were comparable among patients in the groups. CONCLUSION: When or where access to tocilizumab is a problem, methylprednisolone may be considered as an alternative for the treatment of patients with severe COVID-19.

Serious events following COVID‐19 vaccination with ChAdOx1 nCoV‐19 vaccine (Vaxzevria): A short case series from Iran

In 2020, the SARS‐COV‐2 disease (COVID‐19) imposed huge challenges on the health, economic, and political systems, and by the end of the year, hope had been born with the release of COVID‐19 vaccines aimed at bringing the pandemic to an end. However, the COVID‐19 vaccination programs have sparked several concerns and ongoing debates over safety issues. Here, we presented three cases of patients with serious adverse events, encephalopathy, vaccine‐induced thrombotic thrombocytopenia, and leukocytoclastic vasculitis, after receiving the ChAdOx1 nCoV‐19 vaccine. Therefore, it is critical to investigate and report the occurrence of adverse reactions following vaccination, particularly serious ones, as it contributes to the growing body of research and assists clinicians in better diagnosing and managing them. Despite the crucial role of COVID‐19 vaccination in controlling the pandemic, occurring of the severe adverse effects following inoculation is also inevitable and should be considered

Serious events following COVID-19 vaccination with ChAdOx1 nCoV-19 vaccine (Vaxzevria): A short case series from Iran.

In 2020, the SARS-COV-2 disease (COVID-19) imposed huge challenges on the health, economic, and political systems, and by the end of the year, hope had been born with the release of COVID-19 vaccines aimed at bringing the pandemic to an end. However, the COVID-19 vaccination programs have sparked several concerns and ongoing debates over safety issues. Here, we presented three cases of patients with serious adverse events, encephalopathy, vaccine-induced thrombotic thrombocytopenia, and leukocytoclastic vasculitis, after receiving the ChAdOx1 nCoV-19 vaccine. Therefore, it is critical to investigate and report the occurrence of adverse reactions following vaccination, particularly serious ones, as it contributes to the growing body of research and assists clinicians in better diagnosing and managing them.

Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial.

BACKGROUND AND OBJECTIVES: Corticosteroids are commonly used in the treatment of hospitalized patients with COVID-19. The goals of the present study were to compare the efficacy and safety of different doses of dexamethasone in the treatment of patients with a diagnosis of moderate to severe COVID-19. METHODS: Hospitalized patients with a diagnosis of moderate to severe COVID-19 were assigned to intravenous low-dose (8 mg once daily), intermediate-dose (8 mg twice daily) or high-dose (8 mg thrice daily) dexamethasone for up to 10 days or until hospital discharge. Clinical response, 60-day survival and adverse effects were the main outcomes of the study. RESULTS: In the competing risk survival analysis, patients in the low-dose group had a higher clinical response than the high-dose group when considering death as a competing risk (HR = 2.03, 95% CI: 1.23-3.33, p = 0.03). Also, the survival was significantly longer in the low-dose group than the high-dose group (HR = 0.36, 95% CI = 0.15-0.83, p = 0.02). Leukocytosis and hyperglycemia were the most common side effects of dexamethasone. Although the incidence was not significantly different between the groups, some adverse effects were numerically higher in the intermediate-dose and high-dose groups than in the low-dose group. CONCLUSIONS: Higher doses of dexamethasone not only failed to improve efficacy but also resulted in an increase in the number of adverse events and worsen survival in hospitalized patients with moderate to severe COVID-19 compared to the low-dose dexamethasone. (IRCT20100228003449N31).

Predictors of the chest CT score in COVID-19 patients: a cross-sectional study.

BACKGROUND: Since the COVID-19 outbreak, pulmonary involvement was one of the most significant concerns in assessing patients. In the current study, we evaluated patient's signs, symptoms, and laboratory data on the first visit to predict the severity of pulmonary involvement and their outcome regarding their initial findings. METHODS: All referred patients to the COVID-19 clinic of a tertiary referral university hospital were evaluated from April to August 2020. Four hundred seventy-eight COVID-19 patients with positive real-time reverse-transcriptase-polymerase chain reaction (RT-PCR) or highly suggestive symptoms with computed tomography (CT) imaging results with typical findings of COVID-19 were enrolled in the study. The clinical features, initial laboratory, CT findings, and short-term outcomes (ICU admission, mortality, length of hospitalization, and recovery time) were recorded. In addition, the severity of pulmonary involvement was assessed using a semi-quantitative scoring system (0-25). RESULTS: Among 478 participants in this study, 353 (73.6%) were admitted to the hospital, and 42 (8.7%) patients were admitted to the ICU. Myalgia (60.4%), fever (59.4%), and dyspnea (57.9%) were the most common symptoms of participants at the first visit. A review of chest CT scans showed that Ground Glass Opacity (GGO) (58.5%) and consolidation (20.7%) were the most patterns of lung lesions. Among initial clinical and laboratory findings, anosmia (P = 0.01), respiratory rate (RR) with a cut point of 25 (P = 0.001), C-reactive protein (CRP) with a cut point of 90 (P = 0.002), white Blood Cell (WBC) with a cut point of 10,000 (P = 0.009), and SpO2 with a cut point of 93 (P = 0.04) was associated with higher chest CT score. Lung involvement and consolidation lesions on chest CT scans were also associated with a more extended hospitalization and recovery period. CONCLUSIONS: Initial assessment of COVID-19 patients, including symptoms, vital signs, and routine laboratory tests, can predict the severity of lung involvement and unfavorable outcomes.

Famotidine's Possible Cutaneous Rash in COVID-19 Patients: An Adverse Effect Case Series.

BACKGROUND: Various cutaneous manifestations have been observed in patients with COVID-19 infection. However, the side effects on skin of the medications used for COVID-19, such as famotidine, have not been studied. OBJECTIVE: This case series aims to present challenges in defining cutaneous manifestations of famotidine in the context of COVID-19. CASE PRESENTATION: We identified patients from Imam Khomeini hospital complex who were admitted to the ward due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), were taking famotidine and having cutaneous rash. Clinical data were obtained through observation and intervention. DISCUSSION: We found 4 SARS-CoV-2 patients with cutaneous manifestations. The mean (±SD) age of the patients was 57±2 years, 3 patients were men, and their COVID-19 symptoms appeared 10±3 days before admission. The most common symptoms were cough and shortness of breath. All the patients were admitted for hypoxemic respiratory failure. Patients received famotidine for gastrointestinal prophylaxis, and all 4 patients developed Acral macular mountainous skin lesions in the upper and lower extremities, then we discontinued famotidine and lesions were recovered completely in all patients. CONCLUSION: These cases prompted us to inform clinicians about cutaneous complications of famotidine in COVID-19 patients.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Clinical outcomes of patients with mild COVID-19 following treatment with hydroxychloroquine in an outpatient setting.

The role of hydroxychloroquine (HCQ) in early outpatient management of mild coronavirus disease 2019 (COVID-19) needs further investigation. This study was a multicenter, population-based national retrospective-cohort investigation of 28,759 adults with mild COVID-19 seen at the network of Comprehensive Healthcare Centers (CHC) between March and September 2020 throughout Iran. The baseline characteristics and outcome variables were extracted from the national integrated health system database. A total of 7295 (25.37%) patients who presented with mild COVID-19 within 3-7 days of symptoms onset received HCQ (400 mg twice daily on day 1 followed by 200 mg twice daily for the next four days and were then followed for 14 days). The main outcome measures were hospitalization or death for six months follow-up. COVID-19-related hospitalizations or deaths occurred in 523 (7.17%) and 27 (0.37%) respectively, in HCQ recipients and 2382 (11.10%) and 287 (1.34%) respectively, in non-recipients. The odds of hospitalization or death was reduced by 38% (odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.56-0.68, p = < 0.001) and 73% (OR = 0.27; 95% CI: 0.18-0.41, p = < 0.001) in HCQ recipients and non-recipients. These effects were maintained after adjusting for age, comorbidities, and diagnostic modality. No serious HCQ-related adverse drug reactions were reported. In our large outpatient national cohort of adults with mild COVID-19 disease who were given HCQ early in the course of the disease, the odds of hospitalization or death was reduced significantly regardless of age or comorbidities.

Predictors of the prolonged recovery period in COVID-19 patients: a cross-sectional study.

BACKGROUND: The clinical course of COVID-19 may vary significantly. The presence of comorbidities prolongs the recovery time. The recovery in patients with mild-to-moderate symptoms might take 10 days, while in those with a critical illness or immunocompromised status could take 15 days. Considering the lack of data about predictors that could affect the recovery time, we conducted this study to identify them. METHODS: This cross-sectional study was implemented in the COVID-19 clinic of a teaching and referral university hospital in Tehran. Patients with the highly suggestive symptoms who had computed tomography (CT) imaging results with typical findings of COVID-19 or positive results of reverse transcriptase-polymerase chain reaction (RT-PCR) were enrolled in the study. Inpatient and outpatient COVID-19 participants were followed up by regular visits or phone calls, and the recovery period was recorded. RESULTS: A total of 478 patients were enrolled. The mean age of patients was 54.11 ± 5.65 years, and 44.2% were female. The median time to recovery was 13.5 days (IQR: 9). Although in the bivariate analysis, multiple factors, including hypertension, fever, diabetes mellitus, gender, and admission location, significantly contributed to prolonging the recovery period, in multivariate analysis, only dyspnea had a significant association with this variable (p = 0.02, the adjusted OR of 2.05; 95% CI 1.12-3.75). CONCLUSION: This study supports that dyspnea is a predictor of recovery time. It seems like optimal management of the comorbidities plays the most crucial role in recovery from COVID-19.

Efficacy and safety of sofosbuvir/ ledipasvir in treatment of patients with COVID-19; A randomized clinical trial.

BACKGROUND: There is no study regarding the use of SOF/LDP in treatment of COVID-19.  Objectives: In this study, the efficacy and safety of SOF/LDP were assessed in treatment of patients with mild to moderate COVID-19. METHODS: Among an open-label randomized clinical trial, 82 patients with mild to moderated COVID-19 were assigned to receive either SOF/LDP 400/100 mg daily plus the standard of care (SOF/LDP group, n=42) or the standard of care alone (control group, n=40) for 10 days. Time to clinical response, rate of clinical response, duration of hospital and ICU stay and 14-day mortality were assessed. RESULTS: Clinical response occurred in 91.46% of patients. Although rates of clinical response were comparable between the groups but it occurred faster in the SOF/LDP group than the control group (2 vs. 4 days respectively, P= 0.02). Supportive cares were provided in the medical wards for most patients but 17.07% of patients were transferred to ICU during the hospitalization course. However, durations of hospital and ICU stay were comparable between the groups.  14--day mortality rate was 7.14% and 7.5% in the SOF/ LDP and control groups respectively. No adverse effects leading to drug discontinuation occurred. Gastrointestinal events (nausea, vomiting and diarrhea) were the most common side effects (15.85%). CONCLUSION: Added to the standard of care, SOF/LDP accelerated time to the clinical response. However, rate of clinical response, duration of hospital and ICU stay and 14-day mortality were not different. No significant adverse event was detected.  More randomized clinical trials with larger sample sizes are needed to confirm the efficacy and safety of SOF/LDP in the treatment of COVID-19.

CT-scan findings of COVID-19 pneumonia based on the time elapsed from the beginning of symptoms to the CT imaging evaluation: a descriptive study in Iran.

Background. Coronavirus disease 2019 (COVID-19) was initially detected in Wuhan city, China. Chest CT features of COVID-19 pneumonia have been investigated mostly in China, and there is very little information available on the radiological findings occurring in other populations. In this study, we aimed to describe the characteristics of chest CT findings in confirmed cases of COVID-19 pneumonia in an Iranian population, based on a time classification.Methods. Eighty-nine patients with COVID-19 pneumonia, confirmed by a real-time RT-PCR test, who were admitted to non-ICU wards and underwent a chest CT scan were retrospectively enrolled. Descriptive evaluation of radiologic findings was performed using a classification based on the time interval between the initiation of the symptoms and chest CT-scan.Results. The median age of patients was 58.0 years, and the median time interval from the onset of symptoms to CT scan evaluation was 7 days. Most patients had bilateral (94.4%) and multifocal (91.0%) lung involvement with peripheral distribution (60.7%). Also, most patients showed involvement of all five lobes (77.5%). Ground-glass opacities (GGO) (84.3%) and mixed GGO with consolidation (80.9%) were the most common identified patterns. We also found that as the time interval between symptoms and CT scan evaluation increased, the predominant pattern changed from GGO to mixed pattern and then to elongated-containing and band-like-opacities-containing pattern; on the other hand, the percentage of lung involvement increased.Conclusions. Bilateral multifocal GGO, and mixed GGO with consolidation were the most common patterns of COVID-19 pneumonia in our study. However, these patterns might change according to the time interval from symptoms.

Interferon ß-1b in treatment of severe COVID-19: A randomized clinical trial.

In this study, efficacy and safety of interferon (IFN) ß-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 ß-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 ß-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 ß-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 ß-1b.

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.