Ignite Creation Date:
2024-05-06 @ 4:02 PM
Last Modification Date:
2024-10-26 @ 2:02 PM
Study NCT ID:
NCT04845971
Status:
COMPLETED
Last Update Posted:
2021-09-08
First Post:
2020-11-17
Brief Title:
Efficacy and Safety of Oral Immunotherapy With GcMAF in Hospitalized Patients With COVID-19 Pneumonia
Sponsor:
Dr Spadera Lucrezia
Organization:
Ospedale del Mare
Study Overview
Official Title:
Phase II Clinical Trial Evaluating Efficacy and Safety of Oral Immunotherapy With Third Generation Gc Protein Derived Macrophage Activating Factor GcMAF in Hospitalized Patients With COVID-19 Pneumonia the COral-MAF1 Trial
Status:
COMPLETED
Status Verified Date:
2021-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
COral-MAF1
Brief Summary:
As of August 16 2020 the severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 has been responsible for more than 21 294 000 infections and about 760 000 deaths worldwide Accumulating evidence suggests that patients with severe acute COVID-19 pneumonia have a cytokine storm syndrome or unbalanced hyper-inflammatory response It is now well known that GcMAF plays a crucial role in immune system regulation as a primary defense against infections Thus this multifunctional protein released into the blood stream acts as a systemic immune modulator without pro-inflammatory activities In an animal study IL-6 level was shown to be dramatically decreased after 21 days of oral administration colostrum MAF Indeed data from previous studies and clinical practice have been reported its effectiveness and safety in the treatment of many pathologies such as infectious diseases some types of cancer juvenile osteopetrosis immunological and neurological diseases These observations suggest that oral immunotherapy with colostrum-MAF is potentially an effective and well-tolerated treatment for COVID-19 pneumonia In addition gastrointestinal involvement is well known in coronavirus infections of animals and humans The angiotensin-converting enzyme II ACE2 the entry receptor for SARS-CoV is highly expressed in proximal and distal enterocytes that are directly exposed to foreign pathogens It considers the mechanism of SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract SARS-CoV-2 indirectly damages the digestive system through a chain of inflammatory responses Delivered topically to the small intestine by an acid-resistant enteric-coated capsule colostrum MAF can directly activate a large number of gut mucosal macrophages for virus control localizing intestinal inflammation and resolving through driven phagocytic scavenger function Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body which besides the local functions are directing the systemic immune response
Detailed Description:
Over the last five months there have been increasing numbers of reports that struggle to understand the pathogenesis of the coronavirus disease 2019 COVID-19 pandemic To date the most commonly investigated hypothesis about the underlying mechanisms of multi-organ failure may be summarized into three main targets microcirculation dysfunction overwhelming inflammation and abnormal coagulation Clinical radiologic and laboratory findings as well as preliminary autopsy studies seem to support this hypothesis As widely suggested the systemic cytokine storm could play a key role in the virus-induced tissue damage Being the knowledge of this issue very scarce lessons learned from other human pathogenic viruses with specific reference to human immunodeficiency virus HIV could be diriment Unfortunately no drug or vaccine has yet been approved to treat human coronaviruses and new interventions based on drugs directly active on the virus itself are likely to require months to years to develop The main targets of the pharmacologic approaches to COVID-19 especially for the complicated cases are addressed to modulate the immune system and counteract the overwhelming inflammation Notably the mechanisms the investigators have hypothesized about the possible pathogenesis of the cell and tissue damage induced by SARS-CoV-2 seem to provide a common denominator in explaining the effects of most drugs currently in use in the clinical trials these include antivirals immunomodulating andor anti-inflammatory drugs In particular based on their antiviral activity chloroquine and hydroxychloroquine initially conceived as antimalarial therapeutics were proposed to treat hospitalized patients with COVID-19 with or without azithromycin showing promising efficacy in inhibiting the exacerbation of pneumonia improving lung imaging findings promoting a virus negative conversion and shortening the disease course On the other hand hydroxychloroquine is the cornerstone of medical therapy in lupus where it acts as an immunomodulatory without immunosuppressive effects However because of the lack of evidence about the efficacy and safety of these drugs the Italian Medicines Agency on July 17 said it had withdrawn an emergency approval for use of the malaria drug hydroxychloroquine or antivirals as a Covid-19 treatment out of clinical trials Meanwhile the use of low-molecular-weight heparin for COVID-19 is restricted only to well selected hospitalized patients Tocilizumab an IL-6 antagonist approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis also had initial therapeutic application in critical COVID-19 patients providing encouraging results However the phase III clinical trial COVACTA for evaluating tocilizumab in hospitalized patients with severe COVID-19 pneumonia found no difference between tocilizumab versus placebo in intensive care requirements or mortality The rationale basis for the use of monoclonal antibodies in patients affected by SARS-CoV-2 seems to lie in the so-called systemic cytokine storm Taking into account the key role of VEGF in enhancing angiogenesis in acute lung injury and ARDS two trials evaluating the efficacy of bevacizumab as VEGF antagonist in the treatment of COVID-19 BEST-PC and BEST-RCT were also started In light of pathological findings of pulmonary inflammation with edema and hyaline membrane formation timely and appropriate use of drugs with understood safety profiles aimed at reducing inflammation microcirculatory dysfunction oxidative stress neoangiogenesis and microthrombotic occlusion in a targeted way together with ventilator support should be considered for the severe patients to prevent and treat ARDS development It is now well known that GcMAF plays a crucial role in immune system regulation as a primary defense against infections Based on the aforementioned findings and on documented analogies between SARS-CoV-2 and HIV the investigators hypothesized that the reduced conversion activity of the Gc protein into the macrophage activating factor MAF could have a key role in the dysregulate immune response induced by SARS-CoV-2 just like for HIV infected patients If this hypothesis is correct it might help to set a valid strategy of immunotherapy also based on an off-label use of GcMAF in critically ill COVID-19 patients Serum Gc protein also known as vitamin D-binding protein DBP is a multifunctional protein present in plasmaserum at concentrations of 300-600 mgL Stepwise hydrolysis of Gc protein by the inducible membranous β-galactosidase of stimulated B-lymphocytes and by the Neu-1 sialidase of T-lymphocytes converts it into the active GcMAFOn the contrary deglycosilation of Gc protein by action of the enzyme alpha-N-acetylgalactosaminidase named nagalase secreted from HIV-infected cells leads to lack of macrophage activation and to immunosuppression as a consequence It is remarkable that nagalase was demonstrated to be an intrinsic component not only of the envelope glycoproteins gp120 and gp160 of HIV but also of the hemagglutinin HE of influenza virus and even produced by neoplastic cells Indeed flu-like symptoms with serum nagalase activity similar to the influenza acute state were reported in the early stage of HIV-infection so that the serum enzyme activity may be detectable at all phases of HIV-infection Similarly most COVID-19 patients complained of flu-like symptoms in the early stages of the disease In addition to the storage and transport of active vitamin D3 GcMAFs effects include macrophage modulation osteoclast activation facilitation of neutrophil chemotaxis mediated by C5 derived peptide superoxide activity scavenging of circulating G-actin anti-angiogenetic and anti-tumor properties Thus this multifunctional protein released into the blood stream acts as a systemic immune modulator without pro-inflammatory activities This means that any function impairment of Gc-globulin could result in a state of both immunosuppression and uncontrolled inflammation just like in severe COVID-19 Interestingly HIV viremia was associated with higher level of biomarkers of inflammation measured by IL-6 monocyte activation soluble CD14 and coagulation D-dimer leading to increased mortality as compared with uninfected people Meanwhile in COVID-19 patients in addition to the reduced peripheral lymphocyte counts mainly CD4 T and CD8 T cells there were found significant high levels of pro-inflammatory cytokines and chemokines Indeed GcMAF is not only a simple potent activator for macrophages but more specifically is able to turn macrophage activity on at the sites of infectioninflammation and then to induce their apoptosis by upregulating caspase activity via the p38 and JNK12 pathways when no longer needed Post-mortem lung observations of patients died of COVID-19 showed the presence of mononuclear cells and macrophages infiltrating air spaces by autopsy With regards to the anti-oxidant properties it was assessed that GcMAF promotes the superoxide generating capacity of activated macrophages and the production of nitric oxide NO It has been showed that the expression of extracellular superoxide dismutase EC-SOD mRNA and protein is cell- and tissue-specific and is prominent in lung heart blood vessels placenta and kidney In particular high levels of EC-SOD are present in lung macrophages alveolar type II cells fibroblasts vascular smooth muscle cells and endothelial cells EC-SOD limits oxidative stress and preserves NO bioactivity thus protecting against a number of lung and cardiovascular diseases Even though only in a minority of cases COVID-19 may progress to life-threatening complications including respiratory failure acute cardiac injury acute kidney injury septic shock disseminated intra-vascular coagulation DIC and multi-organ dysfunction Hypoxemia was found to be associated with interstitial pneumonia and in 10 to 20 of cases developed into acute respiratory distress syndrome ARDS In this connection it was documented that ARDS as well as organ dysfunction and septic shock is characterized by actin release which is involved in microvascular impairment DBP has an additional function in binding monomeric globular G-actin with high affinity Thereby rapidly removing polymeric actin fibrils from the blood stream it prevents actin polymers from clogging the micro vessels not unlike fibrinogenfibrin and consequently platelet aggregation and micro thrombi formation What the investigators postulated could also explain hypercoagulability with elevated concentrations of D-dimer fibrin degradation products increase PT and aPTT prolongation observed in COVID-19 patients It has been reported that 714 of the non survivors of COVID-19 matched the grade of overt-DIC according to the International Society on Thrombosis and Haemostasis ISTH diagnostic criteria for DIC Murine models deficient in DBP showed lung damage caused by actin polymerization developing severe acute lung inflammation with vascular leakage hemorrhage and thickening of the vascular wall after actin injection Interestingly the lung was the only organ that showed inflammatory injury after intravenous actin injection The observed lung inflammation was consistent with alterations to lung microvascular endothelial cells Indeed when lung endothelial cells were exposed to DBP-actin complexes in vitro showed enhanced cell death Reduced levels of DBP were even observed in sepsis and organ dysfunction of trauma patients as well as complete depletion of free DBP in those affected by septic shock These data could provide support for pathogenic explanations of cellular and tissue damage by SARS-CoV-2 and at the same time for the therapeutic use of DBP to bind extracellular actin and counteract microcirculatory alterations Whereas DBP also binds free fatty acids it was shown that the administration of GcMAF complexed with oleic acid OA via nebulisation or subcutaneous injection led to rapid decrease of blood pressure and increase in splenic blood flow as a result of a verisimilar synergistic NO release by OA-GcMAF-activated alveolar and splenic macrophages Severe or critically ill COVID-19 patients developed clinical typical manifestations of shock even in the absence of overt hypotension Furthermore it was found that GcMAF can inhibit the angiogenesis induced by pro-inflammatory prostaglandin E1 which serves roles in the promotion of VEGF expression A key role of VEGF in acute lung injury and ARDS was confirmed Reflecting the fact that clinical features and severity of symptoms vary widely between and within each COVID-19 patient with older males more likely to be affected and in a more severe manner the investigators sought to relate it with some special feature of DBP Several studies showed that the polymorphisms of DBP were associated with susceptibility or resistance to disease states including chronic obstructive pulmonary disease Moreover whereas androgens were not found to have any effect on circulating levels of DBP exposure to high levels of estrogens increased them by up to 50 suggesting a potential protective role of estrogens against COVID-19 On the other hand in relation to vitamin D status advanced age was recognized as one of the major risk factors for vitamin D deficiency Animal-based studies also demonstrated that deficiencies in both dietary protein- and energy-intake decreased the concentration of DBP in the circulation These data seem to be in line with the growing evidence that vitamin D supplementation could reduce the risk of COVID-19 infections and deaths The present trial aims to assess the efficacy and safety of immunotherapy with oral MAF plus standard-of-care therapy in hospitalized adult patients with COVID-19- induced pneumonia
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None