Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04845971 |
| Other study ID # |
COral-MAF1 Trial - Version 1.0 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
November 5, 2020 |
| Est. completion date |
June 30, 2021 |
Study information
| Verified date |
April 2021 |
| Source |
Ospedale del Mare |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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 and/or 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
plasma/serum at concentrations of 300-600 mg/L. 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 GcMAF.On 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, GcMAF's
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 infection/inflammation and then to induce their
apoptosis by upregulating caspase activity via the p38 and JNK1/2 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 fibrinogen/fibrin 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 71.4% 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.
