COVID-19 Clinical Trials and Expanded Access

Study Design: This is a double-blind, placebo-controlled, Phase 3 clinical efficacy studyevaluating NONS in adult volunteers as a treatment for high-risk asymptomatic andsymptomatic individuals with mild COVID-19 infection. thru facility).

This study is aimed to investigate the treatment vitamin D3 as complementary therapy withroutine care for early mild symptoms of COVID-19 in outpatients setting.

Utilizing the crosstalk among aerosolized phenformin, methylene blue, photodynamictherapy , zinc and potassium for treating severe COVID-19 infection and its inflammatorycomplicationAmr Ahmed(1), Mahmoud Elkazzaz(2), Tamer Haydara(3), and Abdullah Alkattan(4) 1. Director of tuberculosis program Ghubera, public health department ,First health cluster ,Ministry of health ,Saudia Arabia. 2. Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt. 3. Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt. 4. Ministry of Health, Riyadh, Saudi Arabia.SARS-CoV-2 represents the largest current health challenge for the society. Moreover,numerous variants of the virus that causes COVID-19 are being tracked in the UnitedStates and globally during this pandemic. Here, we will use combination therapy whichinvolve agents with significant activity and different mechanisms of action againstcovid-19 and its inflammatory complication. Excessive activities of cysteinyl cathepsins(CysCts) contribute to the progress of many diseases. however, therapeutic inhibition hasbeen problematic. Cathepsin L are crucial in terms of the endocytosis by cleaving thespike protein, which permits viral membrane fusion with endosomal membrane, and succeededby the releasing of viral genome to the host cell. Thereby, inhibition of cathepsin L maybe advantageous in terms of decreasing infection caused by SARS-CoV-2. It is well knownthat zinc (Zn) possesses a variety of direct and indirect antiviral properties, which arerealized through different mechanisms. Administration of Zn supplement has a potential toenhance antiviral immunity and to restore depleted immune cell function, in particular inimmunocompromised patients. It has been found that Zn 2+ deficiency leads to anexaggerated activity of Cysteine cathepsin increasing the autoimmune/inflammatoryresponse. . Zn2+ is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa)triads. cysteine protease Cathepsin L (CatL) involvement with severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. At thispurpose Zn 2+ metal can be safely combined with phenformin a drug that increases theanti-proteolytic effect of endogenous Zn 2+ lowering the excessive activity of someCysCts.; A study found that phenformin-Zn2+ complex is identified as a modifiablepharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range ofpotencies and specificities. Phenformin stabilizes a "Zn2+ sandwich" between the drug andprotease active site. Additionally, phenformin was found to be potent inhibitor of IL-6R, with phenformin (100 µM) treatment for 48 h, decreased IL-6R expression in ANBL6,RPMI, U266, MM1S, and JJN3 was 5.51 (p = 0.0025), 3.03 (p = 0.0005), 1.55 (p < 0.05),2.09 (p = 0.0082) and 1.19-fold, respectively. Furthermore, phenformin was discovered topotentially and strongly bind to ACE2 receptors, according to a docking research beingconducted by the principle investigators of this clinical study therefore, Phenformin isexpected to potentially attach to ACE2 receptors and lead to its downregulation, aninhibitory mechanism which may combat and block COVID-19 infection in lung epithelialcells. Phenformin may induce lactic acidosis therefore according to the principalinvestigator The phenformin will be utilized as aerosolized by inhalation for COVID-19treatment and this may be an effective novel treatment strategy that would limit the riskof systemic side-effects associated with biguanides due to the low inhaled dose. Inaddition, we will use aerosolized phenformin in combination with methylene blue. A studyfound that a very marked improvement in lactate and pyruvate concentrations occurredwithin six hours of the beginning of méthylène blue administration in human . It has beenknown for some time that méthylène blue is a moderately efficient hydrogen acceptor inseveral enzyme sys¬ tems and significantly reduce oxidative stress by scavenging ROS.Moreover, Methylene Blue has antiviral activity and was found to Inhibit the Spike-ACE2Protein-Protein Interaction-a Mechanism that can contribute to its Antiviral ActivityAgainst COVID-19 For many reasons, methylene blue is a promising drug for an activetreatment against SARS-CoV-2 . Since methylene blue can work as a photosensitizer,photodynamic therapy as an antiviral treatment has great potential in the treatment ofCOVID-19.. This clinical study will investigate the effectiveness of SARS-CoV-2 infectedpeople treatment using methylene blue and the following photodynamic therapy after thatour clinically approved patients will receive phenformin and zinc . But methylene bluemay lead to lowering in potassium concentration.Therefore, we will add potassiumsupplement to this combination.

Investigating the potential role of Aerosolized retinoic acid, a potent Vitamin Ametabolite for treating COVID-19 Anosmia and retinoic acid insufficiency .A novelapproach for regaining Sense of Smell.Mahmoud ELkazzaz(1),Tamer Haydara(2), Abedelaziz Elsayed(3) ,Yousry Abo-amer(4), HeshamAttia(5), Quan Liu(6) and Amr Ahmed(7) 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 Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt. 4. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt 5. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt. 6. 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. 7. Director of tuberculosis program Ghubera, public health department ,First health cluster ,Ministry of health ,Saudia Arabia. - Very important Note: This clinical study is the first clinical study in literature (First posted August 12, 2021) which demonstrated depending on molecular findings that Vitamin A /Retinoic Acid will treat smell loss resulted by COVID-19Recent rapidly accumulating evidences and reports indicate that partial loss of the senseof smell or even total anosmia are early markers of SARS-CoV-2 infection and frequentlyreported symptoms associated with the COVID-19 pandemic (Lechien J. R et al., 2020)However, the cellular mechanisms of this phenomenon are unknown. The rates of insomniaand depression were 26.45% and 9.92% in the COVID-19 patients after recovery. Therefore,finding an effective treatment for COVID-19 Anosmia is a critical point. Although, ACE2has been identified as the principal host cell receptor of 2019-nCoV, and it is thoughtto play a critical role in the virus's entrance into the cell and subsequent infection,many cells can be infected by COVID-19 while also expressing little or no ACE2. Eventhough the COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is notexpressed in the receptor of olfactory neurons, or its synthesis is limited to to a minorfraction of these neurons.of these neurons, COVID-19 infection causes a loss of smell(anosmia) (Katarzyna Bilinska et al.,2021). Our recent findings showed that COVID-19binds directly to STRA6 receptors of retinol leading to retinol depletion and retinoicacid insufficiency (M Elkazzaz et al,. 2021) . Retinoic acid insufficiency in theolfactory epithelium, both in mouse and chick models, causes progenitor cell maintenancefailure and, consequently, olfactory neurons differentiation is not maintained . Anexplant system, showed that renewal of olfactory neurons is inhibited if retinoic acidsynthesis was failed in the olfactory epithelium (Paschaki M et al., 2013) . It's worthnoting that vitamin A shortage also causes olfactory and taste problems, In a study byGarrett-Laster et al., (1984), the patients had vitamin A deficiency because ofmalnutrition and alcoholic liver cirrhosis; they lost their sense of smell after thatdisorder. LaMantia and Rawson et al.,( 2007) reported that administration of retinoidacid after the damage of olfactory system motivates an immune response and produces amore quick recovery of olfactoryguided behavior. It was showed that Isotretinoin improvedthe significantly performance of patients in the olfactory test(Demet Kartal et al.,2017)Moreover, there is increasing evidence that retinoic acid (atRA) influences geneexpression of components of renin-angiotensin system (RAS), which plays a pivotal role inthe pathophysiology of essential hypertension. Retinoic acid induced ACE2 expression indifferent animal models. Moreover, a study suggests that topical retinoids may haveapplicability in promoting sinus regeneration and wound healing. In a study comparingtreated and untreated nasal mucosa ,untreated regenerated mucosa showed expected changesof submucosal gland loss, basal lamina and lamina propria fibrosis and loss of cilia.Reinoic acid treatment appeared to result in better mucosal regeneration marked by lesscellular atypia and fibrosis(Mendy S. Maccabee et al,. 2003).. Aerosolized retinoic acidwill have an effective role in treating post COVID-19 anosmia (loss of smell) viaupregulating ACE2, STRA 6 and regenerating of olfactory receptors and olfactory sensorycells and neurons.

Randomized, open, single-center, controlled clinical trial, with 2 treatment arms thatseeks to demonstrate the effectiveness of tocilizumab against systemic corticosteroids,both treatments added to supportive treatment in patients admitted for COVID-19 withbilateral pneumonia and poor evolution

With the results of this study the investigators aim to identify an effective treatmentthat will reduce morbidity and mortality of patients with symptomatic COVID-19 infection,which would in turn reduce the burden on the healthcare system by decreasing the need forintensive care.Objectives: The main objective of this research is to determine if once weekly treatmentwith the GLP-1 agonist semaglutide for 4 doses will reduce cardiac as well as non-cardiaccomplications of COVID-19 infection.Study Plan: The study design is prospective randomized open-label blinded-evaluation(PROBE). Eligible patients with symptomatic COVID-19 infection and an enhanced riskprofile as described above, who have been admitted to hospital due to symptoms ofCOVID-19 infection but do not as yet require critical care will be approached toparticipate in this study. Provided there are no exclusion criteria and the participantsagree by means of documented written informed consent, The participants the participantswill be randomized to receive s.c. semaglutide 0.25 mg s.c. or control immediately afterrandomization and then 0.5 mg s.c. at Day 7, Day 14 and Day 21. Blood will be drawn atDay 7±2 and Day 14±2 for the cardiac troponin biomarker and safety parameters. ECG willbe obtained at Day 7±2 and Day 14±2. Primary outcome will be assessed on Day 28.Primary outcome measure: A composite of (1) death from any cause or (2) mechanicalventilation (invasive or non-invasive) at 28 days.Major secondary outcome measure:(1) an elevation to >99th percentile URL upper reference limit (URL) in those with abaseline cardiac troponin level ≤99th percentile URL; or 3x elevation from baseline inthose with a baseline cardiac troponin >99th percentile URL; measured at 1 week (7-days)post randomization.Other major secondary outcome measure:A composite of 1. Death from any cause, mechanical ventilation or vasopressor or ECLS support at 28 days 2. an elevation to >99th percentile URL in those with a normal baseline troponin level; or 3x elevation from baseline in those with a baseline troponin; measured at 1 and 2 weeks (7±2 and 14±2 days) post randomization.

Study population: Patients with fibrotic lung sequelae after recovery from acute phase ofsevere COVID19 pneumonia Objectives: To evaluate the effect of pirfenidone administeredfor 24 weeks in patients who have pulmonary fibrotic changes after suffering severeCOVID19 pneumonia, analysed by - % change in forced vital capacity (FVC) - % fibrosis in high resolution computed tomography (HRCT) of the lung

Phase 2 ,double blind, randomized study of therapy with Angiotensin 1-7 in COVID-19patients. 120 confirmed SARS-CoV-2 infected patients who exhibit moderate- clinicalsymptoms including dyspnea, cough and fever, hospitalized in the KETER department inseveral hospitals in Israel, will be enrolled. 60 patients will receive Ang 1-7subcutaneously 500 mcg/kg /day. 60 patients will receive placebo : NaCl 0.9% 2 ml-control arm .Treatment duration: 14 days or until clinical improvement that enables discharge fromhospital.(the shortest time will be the limiting factor in treatment duration). Follow-up-30 days.14-30 days after discharge from hospital: we will contact the patient via phone to askquestions related to any possible adverse reaction to the drug and general health.

The COVID-RASi study is an international randomized clinical trial that will evaluate thepotential benefit of angiotensin modulators on clinical outcomes, in COVID-19 patients.The purpose of this study is to determine if renin-angiotensin system inhibitors (RASi),with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers(ARB), has a beneficial effect in patients with COVID-19 infections, by reducing ICUadmission, ventilator requirement or death. We would also like to determine if there aredifferences between ACEi and ARB therapeutic treatments. With the increasing potential oflong COVID symptoms, at the 1 year follow up, a primary endpoint will be the quality oflife of study participants, as assessed by ongoing symptoms and/or the standardizedquestionnaires.

The Multi-arm trial of Inflammatory Signal Inhibitors for COVID-19 (MATIS) study is atwo-stage, open-label, randomised controlled trial assessing the efficacy of ruxolitinib(RUX) and fostamatinib (FOS) individually, compared to standard of care in the treatmentof COVID-19 pneumonia. The primary outcome is the proportion of hospitalised patientsprogressing from mild or moderate to severe COVID-19 pneumonia. Patients are treated for14 days and will receive follow-up assessment at 7, 14 and 28 days after the first studydose. Patients with mild or moderate COVID-19 pneumonia will be recruited. Initially,n=171 (57 per arm) patients will be recruited in Stage 1. Following interim analysis toassess the efficacy and safety of the treatments, approximately n=285 (95 per arm) willbe recruited during Stage 2.