COVID-19 Clinical Trials and Expanded Access

The study is a randomized controlled, open-label trial comparing subcutaneous Zilucoplan® with standard of care to standard of care alone. In the active group, Zilucoplan® will be administered subcutaneously once daily for 14 days or till discharge from the hospital, whichever comes first. The hypothesis of the proposed intervention is that Zilucoplan® (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury. Eligible patients include patients with confirmed COVID-19 infection suffering from hypoxic respiratory failure defined as O2 saturation below 93% on minimal 2l/min O2 therapy and/or ratio PaO2/FiO2 below 350.

Neuromuscular electrical stimulation (NMES) has been considered as a promising approach for the early rehabilitation of patients in and/or after the intensive care unit (ICU). Aim of this study is to evaluate the NMES effect on physical function of COVID-19 patients.

Novel therapies are desperately needed for treatment of COVID-19 patients. At present, there are no proven interventions to prevent progression of the disease or to rapidly treat patients with COVID-19 related respiratory failure. Data on the original coronavirus -SARS pneumonia suggested that high dose (>160ppm) inhaled Nitric Oxide could have beneficial effects also on COVID-19, due to the genomic similarities between these two coronaviruses (1-3). This study will test whether high dose inhaled nitric oxide is safe and can reverse virus burden and respiratory failure in patients on mechanical ventilation.

Background: On December 2019, a new human coronavirus infection (COVID-19) was detected in China. Its infectivity and virulence characteristics caused a rapid spread, being declared pandemic on March 2020. The mortality attributed to the infection ranges between 3 and 10%. Main risk factors are age, male sex, and chronic degenerative comorbidities. Due to the absence of therapeutic options, potential alternatives such as human immunoglobulin or plasma from convalescent patients have been administered. Due to the severity of the disease and the associated mortality, it is urgent to find therapeutic alternatives. Objective: To assess the safety and efficacy of the administration of Convalescent plasma vs human immunoglobulin in critically ill patients with COVID-19 infection. Material and methods: Randomized Controlled trial of patients diagnosed with respiratory infection by COVID-19, with severe respiratory failure without indication of mechanical ventilation, or those who due to their severity are intubated upon admission. Randomization will be performed 2:1 to receive plasma from convalescent patients or human immunoglobulin. Outcomes: The primary outcome will be time to discharge from hospital for improvement. The safety outcomes will be: Kirby index (PaO2/FiO2) evolution and dead.

Treatment of patients with Covid-19 associated pneumonia using intravenous injection of allogenic pooled olfactory mucosa-derived mesenchymal stem cells

Patients who are critically ill with COVID-19 requiring life support in an intensive care unit (ICU) have increased risk of morbidity and mortality. Currently the ICU community does not know what effect the disease, the ICU admission, physiotherapy interventions and life support have on their long-term quality of life and whether they can return to their pre-illness level of function following ICU. COVID-Recovery will describe the physiotherapy interventions delivered to critically ill patients with COVID-19. In survivors, COVID-Recovery will utilise telephone follow-up of ICU survivors to assess disability-free survival and quality of life at 6 months after ICU admission. Additionally, COVID-Recovery will identify if there are predictors of disability-free survival. COVID-Recovery will aim to select up to 300 patients diagnosed with COVID-19 from ICUs in Australia. If they survive to hospital discharge, patients will be invited to receive a telephone questionnaire at 6 months after the ICU admission that aims to assess their long-term outcomes, including physical, cognitive and emotional function, quality of life, and whether they have been able to return to work following ICU discharge. To describe the experience of critical illness in survivors of COVID-19 and their family members. To explore and describe functional recovery, respiratory system function and respiratory health morbidity up to 6 months after ICU admission in persistently critically ill adults with COVID-19

A recent outbreak of coronavirus disease 2019 (COVID-19) caused by the novel coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan, China, at the end of 2019. The clinical characteristics of COVID-19 include respiratory symptoms, fever, cough, dyspnea, and pneumonia. As of 25 February 2020, at least 77 785 cases and 2666 deaths had been identified across China and in other countries; in particular, 977 and 861 cases were identified in South Korea and Japan, respectively. The outbreak has already caused global alarm. On 30 January 2020, the World Health Organization (WHO) declared that the outbreak of SARS-CoV-2 constituted a Public Health Emergency of International Concern (PHEIC), and issued advice in the form of temporary recommendations under the International Health Regulations (IHR).It has been revealed that SARS-CoV-2 has a genome sequence that is 75%-80% identical to that of SARS-CoV, and has more similarities to several bat coronaviruses. SARS-CoV-2 is the seventh reported human-infecting member of the family Coronaviridae, which also includes SARS-CoV and the Middle East respiratory syndrome (MERS)-CoV. It has been identified as the causative agent of COVID-19. Both the clinical and the epidemiological features of COVID-19 patients demonstrate that SARS-CoV-2 infection can lead to intensive care unit (ICU) admission and high mortality. About 16%-21% of people with the virus in China have become severely ill, with a 2%-3% mortality rate. However, there is no specific treatment against the new virus. Therefore, it is urgently necessary to identify effective antiviral agents to combat the disease and explore the clinical effect of antiviral drugs. One efficient approach to discover effective drugs is to test whether the existing antiviral drugs are effective in treating other related viral infections. Several drugs, such as ribavirin, interferon (IFN), Favipiravir (FPV), and Lopinavir (LPV)/ritonavir (RTV), have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. It has recently been demonstrated that, as a prodrug, Favipiravir (half maximal effective concentration (EC50) = 61.88 μmol·L-1, half-maximal cytotoxic concentration (CC50) > 400 μmol·L-1, selectivity index (SI) > 6.46) effectively inhibits the SARS-CoV-2 infection in Vero E6 cells (ATCC-1586). Furthermore, other reports show that FPV is effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μmol·L-1. Therefore, clinical studies are urgently needed to evaluate the efficacy and safety of this antiviral nucleoside for COVID-19 treatment. After enrollment of the patients (day 1) depending on inclusion and exclusion criteria and laboratory findings confirming the presence of the COVID-19 virus, 25 patients will receive Favipiravir plus standard treatment and the second group of 25 patients will receive standard treatment only. The comparison of the findings of the follow up studies on days 4, 7, and 10 in terms of clinical manifestations, chest X-ray and laboratory findings, such as Real Time Polymerase Chain Reaction (RT-PCR) results for viral presence will determine whether Favipiravir has safety and efficacy against COVID-19 infections. All ethical issues related to this trial including right of the participants to withdraw from the study should be maintained according to of guidelines of International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP).

COVID-19 patients who develop severe disease often develop acute respiratory distress syndrome (ARDS) as a result of a dysregulated immune response. This in turn stimulates a pro-inflammatory cascade ("cytokine storm") as well as emergency myelopoiesis. This proinflammatory cascade is activated when viral-mediated cell damage occurs in the lungs, resulting in the release of damage-signaling alarmin molecules such as S100A8/A9 (Calprotectin), HMGB1, Resistin, and oxidized phospholipids. These damage-associated molecular patterns (DAMPs) are recognized by the pattern recognition receptor Toll-Like Receptor 4 (TLR4) found on macrophages, dendritic cells and other innate immune cells and result in additional release of pro-inflammatory molecules. Several recent studies have shown that S100A8/A9 serum levels in hospitalized COVID-19 patients positively correlate with both neutrophil count and disease severity. Taken together the DAMP-TLR4 interaction forms a central axis in the innate immune system and is a key driver of the pathological inflammation observed in COVID-19. We hypothesis that targeting the initial step in the signalling pathways of these DAMPs in innate immunity offers the best hope for controlling the exaggerated host response to SARS-CoV-2 infection. EB05 has demonstrated safety in two clinical studies (>120 patients) and was able to block LPS-induced (TLR4 agonist) IL-6 release in humans. Given, this extensive body of evidence we believe EB05 could ameliorate ARDS due to COVID-19, significantly reducing ventilation rates and mortality.

Many of the patients hospitalized for a severe form of SARSCoV-2 respiratory impairment require prolonged intensive care that can be complicated in the short term, In the medium and long term, physical and psychological sequelae can affect patients' quality of life and prevent a return to normal working life. To date, there is little data on the fate of patients treated in Resuscitation for a severe form of COVID-19, both in terms of respiratory sequelae, as well as in terms of psychological sequelae and their quality of life. The objective of this study is to be able to describe and evaluate the possible physical and psychological sequelae and quality of life of patients hospitalized in Resuscitation for a severe form of COVID-19 in the short (3 and 6 months), medium (1 year) and long (5 years) End of their stay in ICU. To do this, we want to carry out a prospective, observational and monocentric study in the consultation department of the Nice CHU. All patients admitted to Resuscitation for a severe form of COVID-19 who have accepted the longitudinal medical follow-up proposed by the Nice CHU will be included in the study and data from the computerized medical record will be analyzed.

The purpose of this study is to investigate the prevalence of venous thromboembolism in a regional health care system (Region Östergötland, Sweden) before and during the SARS-COV-2 pandemic. In a retrospective observational study, we will review patient data, diagnostic data and treatment data over a three-month period since the onset of the SARS-COV-2 pandemic. This data will be compared with data from the corresponding time frame during the years 2015 to 2019.