Umifenovir in hospitalized moderate to severe COVID-19 patients: A randomized clinical trial.

INTRODUCTION: The effectiveness of umifenovir against COVID-19 is controversial; therefore, clinical trials are crucial to evaluate its efficacy. METHODS: The study was conducted as a single-center, randomized, open-label clinical trial. Eligible moderate-severe hospitalized patients with confirmed SARS-Cov-2 infection were randomly segregated into intervention and control groups. The intervention group were treated with lopinavir/ritonavir (400 mg/100 mg bid for 10-14 days) + hydroxychloroquine (400 mg single dose) + interferon-ß1a (Subcutaneous injections of 44 µg (12,000 IU) on days 1, 3, 5) + umifenovir (200 mg trice daily for 10 days), and the control group received lopinavir/ritonavir (same dose) + hydroxychloroquine (same dose) + interferon-ß1a (same dose). RESULTS: Of 1180 patients with positive RT-PCRs and positive chest CT scans, 101 patients were finally included in the trial; 50 were assigned to receive IFNß1a + hydroxychloroquine + lopinavir/ritonavir group and 51 were managed to treat with IFNß1a + hydroxychloroquine + lopinavir/ritonavir + umifenovir. Since all patients received the intended treatment as scheduled, the analysis just included as the ITT population. Time to clinical improvement (TTCI) did not hold a statistically significant difference between intervention and control groups (median, 9 days for intervention group versus 7 days for the control group; P: 0.22). Besides, Hazard Ratio for TTCI in the Cox regression model was 0.75 (95% CI: 0.45-1.23, P:0.25) which also confirmed that there was no statistically significant difference between the treatment group and the control group. The mortality was not statistically significant between the two groups (38% in controls vs 33.3% treatment group). CONCLUSIONS: Our findings shed new lights on the facts that additional umifenovir has not been found to be effective in shortening the duration of SARS-CoV-2 in severe patients and improving the prognosis in non-ICU patients and mortality. TRIAL REGISTRATION: The trial was confirmed by the Ethics in Medical Research Committee of the Shahid Beheshti University of Medical Sciences. signed informed consents were obtained from all the participants or their legally authorized representatives. This trial has been registered as ClinicalTrials.gov, NCT04350684.

Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial.

Type 1 Interferons (IFNs) have been associated with positive effects on Coronaviruses. Previous studies point towards the superior potency of IFNß compared to IFNα against viral infections. We conducted a three-armed, individually-randomized, open-label, controlled trial of IFNß1a and IFNß1b, comparing them against each other and a control group. Patients were randomly assigned in a 1:1:1 ratio to IFNß1a (subcutaneous injections of 12,000 IU on days 1, 3, 6), IFNß1b (subcutaneous injections of 8,000,000 IU on days 1, 3, 6), or the control group. All three arms orally received Lopinavir/Ritonavir (400 mg/100 mg twice a day for ten days) and a single dose of Hydroxychloroquine 400 mg on the first day. Our utilized primary outcome measure was Time To Clinical Improvement (TTCI) defined as the time from enrollment to discharge or a decline of two steps on the clinical seven-step ordinal scale, whichsoever came first. A total of 60 severely ill patients with positive RT-PCR and Chest CT scans underwent randomization (20 patients to each arm). In the Intention-To-Treat population, IFNß1a was associated with a significant difference against the control group, in the TTCI; (HR; 2.36, 95% CI 1.10-5.17, P-value = 0.031) while the IFNß1b indicated no significant difference compared with the control; HR; 1.42, (95% CI 0.63-3.16, P-value = 0.395). The median TTCI for both of the intervention groups was five days vs. seven days for the control group. The mortality was numerically lower in both of the intervention groups (20% in the IFNß1a group and 30% in the IFNß1b group vs. 45% in the control group). There were no significant differences between the three arms regarding the adverse events. In patients with laboratory-confirmed SARS-CoV-2 infection, as compared with the base therapeutic regiment, the benefit of a significant reduction in TTCI was observed in the IFNß1a arm. This finding needs further confirmation in larger studies.Trial Registration Number: ClinicalTrials.gov, NCT04343768. (Submitted: 08/04/2020; First Online: 13/04/2020) (Registration Number: NCT04343768).

Post-mortem Histopathologic Findings of Vital Organs in Critically Ill Patients with COVID-19.

BACKGROUND: The scientific evidence concerning pathogenesis and immunopathology of the coronavirus disease 2019 (COVID-19) is rapidly evolving in the literature. To evaluate the different tissues obtained by biopsy and autopsy from five patients who expired from severe COVID-19 in our medical center. METHODS: This retrospective study reviewed five patients with severe COVID-19, confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and imaging, to determine the potential correlations between histologic findings with patient outcome. RESULTS: Diffuse alveolar damage (DAD) and micro-thrombosis were the most common histologic finding in the lung tissues (4 of 5 cases), and immunohistochemical (IHC) findings (3 of 4 cases) suggested perivascular aggregation and diffuse infiltration of alveolar walls by CD4+ and CD8+ T lymphocytes. Two of five cases had mild predominantly perivascular lymphocytic infiltration, single cell myocardial necrosis and variable interstitial edema in myocardial samples. Hypertrophic cardiac myocytes, representing hypertensive cardiomyopathy was seen in one patient and CD4+ and CD8+ T lymphocytes were detected on IHC in two cases. In renal samples, acute tubular necrosis was observed in 3 of 5 cases, while chronic tubulointerstitial nephritis, crescent formation and small vessel fibrin thrombi were observed in 1 of 5 samples. Sinusoidal dilation, mild to moderate chronic portal inflammation and mild mixed macro- and micro-vesicular steatosis were detected in all liver samples. CONCLUSION: Our observations suggest that clinical pathology findings on autopsy tissue samples could shed more light on the pathogenesis, and consequently the management, of patients with severe COVID-19.