Efficacy of Hemoperfusion in Severe and Critical Cases of COVID-19.

INTRODUCTION: Uncontrolled overproduction of inflammatory mediators is predominantly observed in patients with severe COVID-19. The excessive immune response gives rise to multiple organ dysfunction. Implementing extracorporeal therapies may be useful in omitting inflammatory mediators and supporting different organ systems. We aimed to investigate the effectiveness of hemoperfusion in combination with standard therapy in critically ill COVID-19 patients. METHOD: We conducted a single-center, matched control retrospective study on patients with confirmed SARS-CoV-2 infection. Patients were treated with hemoperfusion in combination with standard therapy (hemoperfusion group) or standard treatment (matched group). Hemoperfusion or hemoperfusion and continuous renal replacement therapies were initiated in the hemoperfusion group. The patients in the matched group were matched one by one with the hemoperfusion group for age, sex, oxygen saturation (SPO2) at the admission, and the frequency of using invasive mechanical ventilation during hospitalization. Two types of hemoperfusion cartridges used in this study were Jafron© (HA330) and CytoSorb® 300. RESULT: A total of 128 COVID-19-confirmed patients were enrolled in this study; 73 patients were allotted to the matched group and 55 patients received hemoperfusion. The median SPO2 at the admission day in the control and hemoperfusion groups was 80% and 75%, respectively (p value = 0.113). The mortality rate was significantly lower in the hemoperfusion group compared to the matched group (67.3% vs. 89%; p value = 0.002). The median length of ICU stay was statistically different in studied groups (median, 12 days for hemoperfusion group vs. 8 days for the matched group; p < 0.001). The median final SPO2 was statistically higher in the hemoperfusion group than in the matched group, and the median PaCO2 was lower. CONCLUSION: Among critically ill COVID-19 patients, based on our study, the use of hemoperfusion may reduce the mortality rate and improve SPO2 and PaCO2.

Study of the effects of interferon ß-1a on hospitalized patients with COVID-19: SBMU Taskforce on the COVIFERON study.

Interferons are an essential part of the innate immune system and have antiviral and immunomodulatory functions. We studied the effects of interferon ß-1a on the outcomes of severe cases of coronavirus disease 2019 (COVID-19). This retrospective study was conducted on hospitalized COVID-19 patients in Loghman-Hakim hospital from February 20, 2020 to April 20, 2020, Tehran, Iran. Patients were selected from two groups, the first group received interferon ß-1a in addition to the standard treatment regimen, and the second group received standard care. The clinical progression of two groups during their hospital admission was compared. We studied a total number of 395 hospitalized COVID-19 patients. Out of this number, 111 patients (33.5%) died (31.3% of the interferon ß-1a group and 34.1% of the control group). The mortality rate indicated no statistically significant difference between groups (p-value = 0.348), however for patients who were hospitalized for more than a week, the rate of mortality was lower in the interferon ß-1a group (p-value = 0.014). The median hospital stay was statistically longer for patients treated by interferon ß-1a (p-value < 0.001). The results of this study showed that interferon ß-1a can improve the outcomes of hospitalized patients with severe COVID-19, but more adequately-powered randomized controlled trials should be conducted.

Evaluation of the effect of sofosbuvir and daclatasvir in hospitalized COVID-19 patients: a randomized double-blind clinical trial (DISCOVER).

BACKGROUND: The combination of sofosbuvir and daclatasvir has shown preliminary efficacy for hospitalized patients with COVID-19 in four open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir/daclatasvir to standard care improved clinical outcomes in hospitalized patients with COVID-19. METHODS: This was a placebo-controlled, double-blind, randomized clinical trial in adults hospitalized with COVID-19 at 19 hospitals in Iran. Patients were randomized to oral sofosbuvir/daclatasvir 400/60 mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O2 saturation <95% and compatible symptoms. The primary outcome was hospital discharge within 10 days of randomization. Secondary outcomes included mortality and time to clinical events. The trial is registered on the Iran Registry of Clinical Trials under IRCT20200624047908N1. RESULTS: Between July and October 2020, 1083 patients were randomized to either the sofosbuvir/daclatasvir arm (n = 541) or the placebo arm (n = 542). No significant difference was observed in the primary outcome of hospital discharge within 10 days, which was achieved by 415/541 (77%) in the sofosbuvir/daclatasvir arm and 411/542 (76%) in the placebo arm [risk ratio (RR) 1.01, 95% CI 0.95-1.08, P = 0.734]. In-hospital mortality was 60/541 (11%) in the sofosbuvir/daclatasvir arm versus 55/542 (10%) in the placebo arm (RR 1.09, 95% CI 0.77-1.54, P = 0.615). No differences were observed in time to hospital discharge or time to in-hospital mortality. CONCLUSIONS: We observed no significant effect of sofosbuvir/daclatasvir versus placebo on hospital discharge or survival in hospitalized COVID-19 patients.

Evaluation of the prophylactic effect of hydroxychloroquine on people in close-contact with patients with COVID-19.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has caused significant mortality worldwide. The disease attacks the lung tissue and may lead to acute respiratory distress syndrome. An in vitro study showed that hydroxychloroquine (HCQ) has a prophylactic effect against COVID-19 due to its anti-inflammatory effects. The present study aimed to evaluate the prophylactic effect of HCQ on individuals in close contact with patients with COVID-19. METHOD: In this quasi-trial study, we prescribed HCQ for 7 days to all people who had close contact with a patient with COVID-19. All contacts underwent a nasal swab in two steps, and those positive for COVID-19 were excluded from the study. After 14 days of follow-up, the clinical and laboratory manifestations of COVID-19 were evaluated. RESULTS: A total of 113 participants completed the study. The HCQ group comprised 51 (45.13%) contacts, and 62 (54.86%) contacts were allocated to the control group. According to the results of clinical examination and real-time polymerase chain reaction test, 8 (12.90%) contacts in the control group were reported to have contracted COVID-19. In the HCQ group, 7 (13.72%) contacts were confirmed to have contracted COVID-19. There was no relationship between HCQ use and age, sex, underlying disorders, and laboratory data (all p > 0.05). In terms of HCQ side effects, five participants experienced gastrointestinal and cutaneous side effects that subsided on discontinuation of HCQ. CONCLUSION: The current study showed that HCQ had no prophylactic effect with regard to COVID-19 prevention.

An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a in severe COVID-19: The COVIFERON II randomized controlled trial.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been a serious obstacle in front of public health. Interferon-beta 1a (IFN-ß 1a) has been used to treat patients with COVID-19. We aimed to compare the effectiveness of high-dose IFN-ß 1a compared to low dose IFN-ß 1a in severe COVID-19 cases. METHODS: In this randomized, controlled, and clinical trial, eligible patients with confirmed SARS-CoV-2 infections were randomly assigned to receive one of the two following therapeutic regimens: The intervention group was treated with high-dose IFN-ß 1a (Recigen) (Subcutaneous injections of 88 µg (24 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally) and the control group was treated with low-dose IFN-ß 1a (Recigen) (Subcutaneous injections of 44 µg (12 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally). RESULT: A total of 168 COVID- 19 confirmed patients underwent randomization; 83 were assigned to the intervention group and 85 were assigned to the control group. Median Time To Clinical Improvement (TTIC) for cases treated with low-dose IFN-ß1a was shorter than that for cases treated with high-dose IFN-ß1a (6 vs 10 days; P = 0.018). The mortality rates in intervention and control group were 41% and 36.5%, respectively. CONCLUSION: The use of high-dose IFN-ß 1a did not improve TTCI in hospitalized patients with moderate to severe COVID-19. Also, it did not have any significant effect on mortality reduction compared with treating with low-dose IFN-ß 1a. TRIAL REGISTRATION: This trial has been registered as ClinicalTrials.gov, NCT04521400.

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).

An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a (the base therapeutic regimen) in moderate to severe COVID-19: A structured summary of a study protocol for a randomized controlled l trial.

OBJECTIVES: We will investigate the effectiveness of high dose Interferon Beta 1a, compared to low dose Interferon Beta 1a (the base therapeutic regimen) in COVID-19 Confirmed Cases (Either RT-PCR or CT Scan Confirmed) with moderate to severe disease TRIAL DESIGN: This is a single center, open label, randomized, controlled, 2-arm parallel group (1:1 ratio), clinical trial. PARTICIPANTS: The eligibility criteria in this study is: age ≥ 18 years, oxygen saturation (SPO2) ≤ 93% or respiratory rate ≥ 24, at least one of the following manifestation: radiation contactless body temperature ≥37.8, Cough, shortness of breath, nasal congestion/ discharge, myalgia/arthralgia, diarrhea/vomiting, headache or fatigue on admission. The onset of the symptoms should be acute (≤ 14 days). The exclusion criteria include refusal to participate, using drugs with potential interaction with lopinavir/ritonavir or interferon-ß 1a, blood ALT/AST levels > 5 times the upper limit of normal on laboratory results, pregnant or lactating women, history of alcohol or drug addiction in the past 5 years, the patients who be intubated less than one hours after admission to hospital. This study will be undertaken at the Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences. INTERVENTION AND COMPARATOR: COVID- 19 confirmed patients (using the RT-PCR test or CT scan) will be randomly assigned to one of two groups. The intervention group (Arms1) will be treated with lopinavir / ritonavir (Kaletra) + high dose Interferon-ß 1a (Recigen) and the control group will be treated with lopinavir / ritonavir (Kaletra) + low dose Interferon-ß 1a (Recigen) (the base therapeutic regimen). Both groups will receive standard care consisting of the necessary oxygen support, non-invasive, or invasive mechanical ventilation. MAIN OUTCOMES: Primary outcome: Time to clinical improvement is our primary outcome measure. This is an improvement of two points on a seven-category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization) or discharge from the hospital, whichever comes first. SECONDARY OUTCOMES: mortality from the date of randomization until the last day of the study which will be the day all of the patients have had at least one of the following outcomes: 1) Improvement of two points on a seven-category ordinal scale. 2) Discharge from the hospital 3) Death. Improvement of SPO2 during the hospitalization, duration of hospitalization from date of randomization until the date of hospital discharge or death, whichever comes first. The incidence of new mechanical ventilation uses from the date of randomization until the last day of the study and the duration of it will be extracted. Please note that we are trying to add further secondary outcomes and this section of the protocol is still evolving. RANDOMIZATION: Eligible patients with confirmed SARS-Cov-2 infections will be randomly assigned in a 1:1 ratio to two therapeutic arms using permuted, block-randomization to balance the number of patients allocated to each group. The permuted block (three or six patients per block) randomization sequence will be generated, using Package 'randomizeR' in R software version 3.6.1. and placed in individual sealed and opaque envelopes by the statistician. The investigator will enroll the patients and only then open envelopes to assign patients to the different treatment groups. This method of allocation concealment will result in minimum selection and confounding biases. BLINDING (MASKING): The present research is open-label (no masking) of patients and health care professionals who are undertaking outcome assessment of the primary outcome - time to clinical improvement. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Of the 100 patients randomised, 50 patients will be assigned to receive high dose Interferon beta-1a plus lopinavir/ritonavir (Kaletra), 50 patients will be assigned to receive low dose Interferon beta 1a plus lopinavir/ritonavir (Kaletra). TRIAL STATUS: Protocol version 1.2.1. Recruitment is finished, the start date of recruitment was on August 20th 2020, and the end date was on September 4th 2020. Last point of data collection will be the last day on which all of the 100 participants have had an outcome of clinical improvement or death, up to 14th days after hospitalization. TRIAL REGISTRATION: This study was registered with National Institutes of Health Clinical trials ( www.clinicaltrials.gov ; identification number NCT04521400, https://clinicaltrials.gov/ct2/show/NCT04521400 , registered August 18, 2020 and first available online August 20, 2020). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Iranian Society of Cardiac Surgeons COVID-19 task force version II, restarting elective surgeries.

Given the nature of heart disease and the importance of continuing heart surgery during the pandemic and its aftermath and in order to provide adequate safety for the surgical team and achieve the desired result for patients, as well as the optimal use of ICU beds, the medical team, blood, blood products, and personal protective equipment, it is essential to change the usual approach during the pandemic. There are still a lot of evidences and experiences needed to produce the perfect protocol. Some centers may have a special program for their centers during this period of epidemics that can be respected and performed. Generally, in pandemic conditions, the use of non-surgical approaches is preferred if similar outcomes can be obtained.