COVID-19 Clinical Trials and Expanded Access

This is a PET/CT study using the 18F-αvβ6-binding-peptide.The goal of this study is toevaluate this peptide in patients after infection with SARS CoV2.

The coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) has caused considerable morbidity andmortality in over 170 countries. Increasing age and burden of cardiovascularcomorbidities are associated with a worse prognosis among patients with COVID-19. Inaddition, serologic markers of more severe disease including coagulation abnormalitiesand thrombocytopenia, are not uncommon among patients hospitalized with severe COVID-19infection and are more common in patients who died in-hospital. As the COVID-19 pandemiccontinues to grow, there is a pressing need to identify safe, effective, and widelyavailable therapies that can be scaled and rapidly incorporated into clinical practice.Understanding the putative mechanism of increased mortality risk associated with abnormalcoagulation function and cardiac injury is critical to guide studies of promisingtherapeutic interventions. Published and anecdotal reports indicate that endothelialdysfunction and thrombosis are common in critically ill patients with COVID-19, includingreports of diffuse microvascular thrombosis in the lungs, heart, liver, and kidneys.Patients with cardiovascular disease (CVD) and CVD risk factors are known to haveendothelial dysfunction and a heightened risk of thrombosis. A recent study of COVID-19inpatients from Wuhan, China observed that an elevated D-dimer level greater than 1 ug/mLwas associated with an 18 times higher risk of in-hospital death, underscoring theimportance of increased coagulation activity as a potential modifiable risk marker thatmay drive end-organ injury. Given the established link between endothelial dysfunctionand thrombosis in patients with cardiovascular disease, and the association betweencoagulopathy and adverse outcomes in patients with sepsis, the association betweenincreased coagulation activity, end-organ injury, and mortality risk may represent amodifiable risk factor among COVID-19 patients with critical illness. Therefore, wepropose to conduct a randomized, open-label trial of therapeutic anticoagulation inCOVID-19 patients with an elevated D-dimer to evaluate the efficacy and safety.

The COVID-19 pathology is frequently associated with diabetes mellitus and metabolicsyndrome. In the epidemic outbreak that exploded at the beginning of 2020 in the LombardyRegion, about two thirds of the patients who died from COVID-19 were affected by diabetesmellitus. COVID-19 occurs in 70% of cases with an inflammatory pathology of the airwaysthat can be fed by a cytokine storm and result in severe respiratory failure (10% cases)and death (5%). The pathophysiological molecular mechanisms are currently not clearlydefined. It is hypothesized that the transmembrane glycoprotein type II CD26, known forthe enzyme activity Dipeptilpeptidase 4 of the extracellular domain, may play a main rolein this condition. It is in fact considerably expressed at the level of parenchyma andpulmonary interstitium and carries out both systemic and paracrine enzymatic activity,modulating the function of various proinflammatory cytokines, growth factors andvasoactive peptides in the deep respiratory tract. Of particular interest is the factthat Dipeptilpeptidase 4 has been identified as a cellular receptor for S glycoprotein ofMERS-COV. In the case of the SARS-COV 2 virus, the main receptor is theAngiotensin-Converting Enzyme 2 protein, but a possible interaction withDipeptilpeptidase 4 also cannot be excluded. The selective blockade of Dipeptilpeptidase4 could therefore favorably modulate the pulmonary inflammatory response in the subjectaffected by COVID-19. This protein is also known for the enzymatic degradation functionof the native glucagon-like peptide 1, one of the main regulators of insulin secretion.This is why it is a molecular target in the treatment of diabetes (drugs that selectivelyinhibit Dipeptilpeptidase 4 are marketed with an indication for the treatment of type 2diabetes). It is believed that the use of a Dipeptilpeptidase 4 inhibitor in people withdiabetes and hospitalized for Covid-19 may be safe and of particular interest for anevaluation of the effects on laboratory and instrumental indicators of inflammatory lungdisease. Among the drugs that selectively block Dipeptilpeptidase 4, the one with thegreatest affinity is Sitagliptin.

This is a randomized, double-blinded, placebo-controlled study of AVM0703 administered asa single intravenous (IV) infusion to patients with moderate or severe immediatelylife-threatening Acute Respiratory Distress Syndrome (ARDS) due to COVID-19 or influenza(A or B). The study is designed to evaluate the safety, tolerability, andpharmacokinetics of single dose of AVM0703 in these ARDS patients.

Some authors have proposed the use of the flu vaccine to reduce the severity of COVID-19cases, while some have proposed the use of ACE Inhibitors (ACEI) or Angiotensin Receptorblockers (ARB), since this virus shares hemagglutinin as a transmission mechanism andacts on the ACE2 enzyme during infection.Other authors described how none of the elderly patients receiving antihistamines andazythromycin in two nursing homes in Toledo -Spain- during the first wave died or neededhospital admission, even considering that 100% of residents had a positive serologicaltest after that wave. Other authors have described a positive evolution in patientsreceiving amantadine for their Parkinson's disease.The aim is to evaluate whether the admitted patients who are previously vaccinated orthose who were already receiving these treatments showed a better evolution.

A phase II clinical trial will be carried out with the objective of studying the impactof the administration of Tocilizumab on the evolution of the acute respiratory distresssyndrome (ARDS) in patients with severe or critical SARS-CoV-2 infection. Due to the highmortality of severe forms of SARS-CoV-2 and for ethical reasons, a control arm will notbe included. Patients will be recruited by signing an informed consent and the baselinevariables of interest will be recorded. Tocilizumab will be administered in one or twodoses, depending on the case, and will be followed up for 30 days. The response totreatment, survival and evolution will be studied. Factors associated with improvement ofARDS and survival will be identified through multivariate analyzes. The results will becompared with those reported internationally.

Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatmentof COVID-19Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Abedelaziz Elsayed(4) ,YousryAbo-amer(5), Hesham Attia(6), Quan Liu(7)' Tim Duong(8) and Heba Sahyon(9) 1. Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt. 2. Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt 3. Department of Cardiothoracic Surgery, Faculty of Medicine, Kafrelsheikh University, Egypt 4. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt. 5. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt 6. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt. 7. School of Life Sciences and Engineering, Foshan University, Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China. 8. Montefiore Health System and Albert Einstein College of Medicine, New York, United States of America. 9. Chemistry Department, Faculty of Science, Kafrelsheikh University, Egypt. - This clinical study is the first clinical study in literature (submitted on 20 April, 2020) which demonstrated that Isotretinoin will provide complete protection against COVID-19AbstractThe COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths overthe world, and it is still expanding. There is an urgent need for targeted and effectiveCOVID-19 treatments which has put great pressure on researchers across the world fordeveloping effective drugs. In this clinical study we attempt to demonstrate Isotretinoincould be an effective and promising treatment for SARS-CoV-2 based on the intracellularmechanism of SARS-CoV-2 transmission and consequences caused. Isotretinoin could stronglyinhibit both inflammation and viral entry in severe acute respiratory syndromecoronavirus 2 infection via decreasing the overproduction of early responseproinflammatory cytokines (interleukin-6 ) which are over expressed in COVID-19 andcontributed to disease progression, poor outcomes, vascular hyper permeability andmultiorgan failure in patients infected with COVID-19. It could also block the entry ofCOVID-19 by inhibiting androgenic factors that induce serine 2 transmembrane protease(TMPRSS2) expressions.. In addition to inhibiting of Angiotensin-converting enzyme-2(ACE2), Angiotensin T1 protein and Angiotensin II-mediated intracellular calcium releasepathway which is responsible for COVID-19 cell fusion and entry, ACE2-expressing cellsare prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry andinvasion. Moreover, isotretinoin is a potential repressor and inhibitor of papain-likeprotease (PLpro), which is a lethal protein expressed by COVID-19 genes and is an enzymeof dubiquitination which facilitates virus replication in patients with COVID-19.Thegenome of Middle East Respiratory Syndrome Coronavirus is recognized by melanomadifferentiation-associated protein-5 (MDA5), retinoic acid inducible gene-1 (RIG-1) andendosomal toll-like receptor 3 (TLR3) as pathogen-associated molecular patterns. Thisrecognition resulted in the formation of type-1 interferon (IFN1). As an evasionmechanism, virus synthesize proteins that hinder the production IFN1 in the pathway.13-cis retinoic acid induced significant upregulation of toll-like receptor 3 (TLR3),mitochondrial antiviral-signaling protein (MAVS) and IFN regulatory factor 1 expressionin a time-dependent. Furthermore, 13 cis Retinoic Acid (13 cis RA) could be an effectiveand promising treatment for SARS-CoV-2 owing to its ability to increase CD4 cells andinduce mucosal IgA antibodies that are less prone to Antibody Dependent Enhancementprocess (ADE) and responsible for passive mucosal immunity in the respiratory tract. ADEis a phenomenon in which antiviral antibodies facilitate viral infection of target immunecells and, in some cases, make a second infection worse, such as dengue fever (denguevirus), By inducing IgA antibodies, 13 cis retinoic acid enhances mucosal immunity and isknown to be a potent IgA isotype.13 Cis retinoic acid induced significant upregulation oftoll-like receptor 3 an immune boosting action that may result in an immune response todsRNA intermediate leading to the production of type I IFNs which is important to enhancethe release of antiviral proteins for the protection of uninfected cells. Isotretinointherapy has furthermore proven anti-platelet and fibrinolytic activities which mayprotect patients infected with covid-19 from widespread blood clots. From this point, wesuggest that isotretinon will be the Immunity passport" in the context of COVID-19

RACONA is a prospective trial that will test the hypothesis that nafamostat can lowerlung function deterioration and need for intensive care admission in COVID-19 patients.Design: Adult hospitalized COVID-19 patients will be randomized in a prospectivedouble-blind randomized placebo-controlled study to test the clinical efficacy ofnafamostat mesylate (administered intravenously) on top of best standard of care.Primary outcome measures: the time-to-clinical improvement, defined as the time fromrandomization to an improvement of two points (from the status at randomization) on aseven category ordinal scale or live discharge from the hospital, whichever comes first.

The study investigators are interested in learning more about how drugs, that are givento children by their health care provider, act in the bodies of children and young adultsin hopes to find the most safe and effective dose for children. The primary objective ofthis study is to evaluate the PK of understudied drugs currently being administered tochildren per SOC as prescribed by their treating provider.

Efficacy of Ivermectin in larger doses in COVID-19 treatment