U.S. patent application number 17/700105 was filed with the patent office on 2022-07-07 for methods for treating diseases associated with respiratory viruses.
The applicant listed for this patent is Ampio Pharmaceuticals, Inc.. Invention is credited to David Bar-Or, Holli Cherevka.
Application Number | 20220211819 17/700105 |
Document ID | / |
Family ID | |
Filed Date | 2022-07-07 |
United States Patent
Application |
20220211819 |
Kind Code |
A1 |
Bar-Or; David ; et
al. |
July 7, 2022 |
METHODS FOR TREATING DISEASES ASSOCIATED WITH RESPIRATORY
VIRUSES
Abstract
The present disclosure provides a method of treating a disease
associated with a respiratory virus. The method comprises
administering an effective amount of a pharmaceutical composition
prepared by removing albumin from a solution of a human serum
albumin composition and/or comprising a diketopiperazine with amino
acid side chains of aspartic acid and alanine (DA-DKP), such as a
low molecular weight fraction of human serum albumin. The present
disclosure also provides a pharmaceutical product as well as a kit
comprising DA-DKP.
Inventors: |
Bar-Or; David; (Englewood,
CO) ; Cherevka; Holli; (Highlands Ranch, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ampio Pharmaceuticals, Inc. |
Englewood |
CO |
US |
|
|
Appl. No.: |
17/700105 |
Filed: |
March 21, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17482144 |
Sep 22, 2021 |
11278598 |
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17700105 |
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17211553 |
Mar 24, 2021 |
11129878 |
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17482144 |
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62994171 |
Mar 24, 2020 |
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International
Class: |
A61K 38/38 20060101
A61K038/38; A61K 9/00 20060101 A61K009/00; A61K 31/495 20060101
A61K031/495; A61P 31/14 20060101 A61P031/14; A61K 31/20 20060101
A61K031/20; A61P 11/00 20060101 A61P011/00; A61K 31/405 20060101
A61K031/405 |
Claims
1. A method of treating one or more symptoms of a
SARS-Coronavirus-2 (SARS-CoV-2) infection in a patient, comprising
administering to the patient a pharmaceutical composition prepared
by removing albumin from a solution of a human serum albumin
composition.
2. The method of claim 1, wherein the one or more symptoms are
selected from the group consisting of acute respiratory distress
syndrome (ARDS), acute lung injury (ALI), interstitial lung
disease, pulmonary fibrosis, pneumonia, reactive airway disease
syndrome, respiratory distress requiring supplemental oxygen, long
COVID and combinations thereof.
4. The method of claim 1, wherein the one or more symptoms are
selected from the group consisting of fatigue, shortness of breath
or difficulty breathing, low exercise tolerance, low blood oxygen
saturation, cough, sore throat, stuffy or runny nose, joint pain,
chest pain, tightness or discomfort, muscle pain, muscle weakness,
fever, heart palpitations, difficulty thinking and/or
concentrating, depression and combinations thereof.
5. The method of claim 4, wherein the patient has experienced the
one or more symptoms for at least four weeks, at least one month,
at least two months, or at least three months.
6. The method of claim 1, wherein the administration results in an
outcome selected from the group consisting of reduced ventilator
time, reduced mortality, improvement in oxygenation parameters,
reduced time to resolution of one or more respiratory symptoms,
improved pulmonary function, and combinations thereof.
7. The method of claim 1, wherein, after the administration, the
patient achieves improvement on the World Health Organization
COVID-19 ordinal scale of at least 4, at least 3, at least 2, or at
least 1.
8. The method of claim 1, wherein the composition is administered
in a form suitable for administration to the lungs.
9. The method of claim 8, wherein the composition is administered
in a nebulized form at a dose of 8 milliliters, quater in die, for
five days.
10. The method of claim 1, wherein the composition comprises
DA-DKP.
11. The method of claim 10, wherein the composition further
comprises N-acetyl-tryptophan (NAT), caprylic acid, caprylate or
combinations thereof.
12. A method of treating inflammation associated with a
SARS-Coronavirus-2 (SARS-CoV-2) infection in a patient, comprising
administering to the patient a pharmaceutical composition prepared
by removing albumin from a solution of a human serum albumin
composition.
13. The method of claim 12, wherein the inflammation is of a tissue
selected from the group consisting of lung, brain, heart, kidney,
blood vessel, skin, nerve, and combinations thereof.
14. The method of claim 12, wherein the inflammation causes a
symptom selected from the group consisting of fatigue, shortness of
breath or difficulty breathing, low exercise tolerance, low blood
oxygen saturation, cough, sore throat, stuffy or runny nose, joint
pain, chest pain tightness or discomfort, muscle pain, muscle
weakness, fever, heart palpitations, difficulty thinking and/or
concentrating, depression, and combinations thereof.
15. The method of claim 14, wherein the patient has experienced the
symptom for at least four weeks, at least one month, at least two
months, or at least three months.
16. The method of claim 12, wherein administration results in an
outcome selected from the group consisting of reduced ventilator
time, reduced mortality, improvement in oxygenation parameters,
reduced time to resolution of one or more respiratory symptoms,
improved pulmonary function, and combinations thereof.
17. The method of claim 12, wherein, after the administration, the
patient achieves improvement on the World Health Organization
COVID-19 ordinal scale of at least 4, at least 3, at least 2, or at
least 1.
18. The method of claim 12, wherein the patient has or had
respiratory distress requiring supplemental oxygen caused by
SARS-Coronavirus-2 (SARS-CoV-2) infection.
19. The method of claim 12, wherein the composition is administered
in a form suitable for administration to the lungs.
20. The method of claim 19, wherein the composition is administered
in a nebulized form at a dose of 8 milliliters quater in die for
five days.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 17/482,144, filed Sep. 22, 2021; which is a
continuation of U.S. patent application Ser. No. 17/211,553, filed
Mar. 24, 2021, and issued on Sep. 28, 2021 as U.S. Pat. No.
11,129,878; which claims the benefit of U.S. Provisional Patent
Application No. 62/994,171, filed Mar. 24, 2020; the disclosures of
each of which are incorporated herein by reference in their
entirety.
FIELD
[0002] The present disclosure relates to a method of treating
diseases associated with respiratory viruses, also referred to
herein as viral respiratory diseases. The method comprises
administering an effective amount of a pharmaceutical composition
prepared by removing albumin from a solution of a human serum
albumin composition and/or comprising a diketopiperazine with amino
acid side chains of aspartic acid and alanine (DA-DKP). The present
disclosure also provides a pharmaceutical product comprising
DA-DKP, in some embodiments in a nebulized form.
BACKGROUND
[0003] Common viral respiratory diseases are illnesses caused by a
variety of viruses that have similar traits and affect the upper
respiratory tract. The viruses involved may be the coronaviruses,
influenza viruses, respiratory syncytial virus (RSV), parainfluenza
viruses, or respiratory adenoviruses. Coronaviruses are a group of
related viruses that cause diseases in mammals and birds. In
humans, coronaviruses cause respiratory tract infections that can
be mild, such as some cases of the common cold (among other
possible causes, predominantly rhinoviruses), and others that can
be lethal, such as SARS, MERS, and COVID-19. Symptoms in other
species vary: in chickens, they cause an upper respiratory tract
disease, while in cows and pigs they cause diarrhea.
[0004] Diketopiperazines have been reported to exhibit a variety of
biological activities. See, e.g., U.S. Pat. No. 4,289,759
(immunoregulatory agents), 4,331,595 (immunoregulatory agents),
4,940,709 (PAF antagonists), 5,700,804 (inhibitors of plasminogen
activator inhibitor), 5,750,530 (inhibitors of plasminogen
activator inhibitor) and 5,990,112 (inhibitors of
metalloproteases); PCT publication nos. WO 97/36888 (inhibitors of
farnesyl-protein transferase) and WO 99/40931 (treatment of central
nervous system injury); EP Patent No. 0043219 (immunoregulatory
agents); Japanese patent application nos. 63 290868 (PAF
antagonists) and 31 76478 (immunosuppressive agents); and Shimazaki
et al., Chem. Pharm. Bull., 35(8), 3527-3530 (1987) (PAF
antagonists), Shimazaki et al., J. Med. Chem., 30, 1709-1711 (1987)
(PAF antagonists), Shimazaki et al., Lipids, 26(12), 1175-1178
(1991) (PAF antagonists), Yoshida et al., Prog. Biochem.
Pharmacol., 22, 68-80 (1988) (PAF antagonists), Alvarez et al., J.
Antibiotics, 47(11), 1195-1201 (1994) (inhibitors of calpain).
SUMMARY
[0005] In a first aspect, the present disclosure provides a method
of treating or preventing one or more symptoms of a viral
respiratory disease in a patient, comprising administering to the
patient a pharmaceutical composition prepared by removing albumin
from a solution of a human serum albumin composition.
[0006] In a second aspect, the present disclosure provides a method
of treating or preventing a viral respiratory disease in a patient,
comprising administering to the patient a pharmaceutical
composition comprising DA-DKP.
[0007] In a third aspect, the present disclosure provides a method
of treating or preventing inflammation associated with a viral
respiratory disease in a patient, comprising administering to the
patient a pharmaceutical composition prepared by removing albumin
from a solution of a human serum albumin composition.
[0008] In a fourth aspect, the present disclosure provides a method
of treating or preventing inflammation associated with a viral
respiratory disease in a patient, comprising administering to the
patient a pharmaceutical composition comprising DA-DKP.
[0009] In some embodiments the viral respiratory disease is
selected from the group consisting of Severe Acute Respiratory
Distress Syndrome (SARS), Middle East Respiratory Syndrome (MERS),
COVID-19, and a viral infection associated with asthma, pneumonia,
bronchitis and/or tuberculosis. In some embodiments, the viral
respiratory disease is COVID-19.
[0010] In some embodiments the viral respiratory disease is caused
by a virus selected from group consisting of a coronavirus, an
influenza virus, respiratory syncytial virus (RSV), a parainfluenza
virus, and a respiratory adenovirus. The virus is, in some
embodiments, selected from the group consisting of
SARS-Coronavirus-2 (SARS-CoV-2), SARS-associated coronavirus
(SARS-CoV), and Middle East Respiratory Syndrome Coronavirus
(MERS-CoV). In some aspects the method of Claim 8, wherein the
virus is SARS-Coronavirus-2 (SARS-CoV-2).
[0011] In some embodiments the patient has or is at risk of
developing inflammation of a tissue selected from the group
consisting of lung, brain, heart, kidney, blood vessel, skin, and
nerve. In some embodiments, the tissue is lung.
[0012] In some embodiments the patient has or is at risk of
developing a symptom selected from the group consisting of acute
respiratory distress syndrome (ARDS), acute lung injury (ALI),
interstitial lung disease, pulmonary fibrosis, pneumonia, and
reactive airway disease syndrome.
[0013] In some embodiments the patient has or is at risk of
developing a symptom selected from the group consisting of fatigue,
shortness of breath or difficulty breathing, low exercise
tolerance, low blood oxygen saturation, cough, sore throat, stuffy
or runny nose, joint pain, chest pain, tightness or discomfort,
muscle pain, muscle weakness, fever, heart palpitations, difficulty
thinking and/or concentrating, and depression.
[0014] In some embodiments the patient has experienced the symptom
at least four weeks, at least one month, at least two months, or at
least three months.
[0015] In some embodiments the administering results in an outcome
selected from the group consisting of reduced ventilator time,
reduced mortality, improvement in oxygenation parameters, reduced
time to resolution of one or more respiratory symptoms, improved
pulmonary function, and combinations thereof.
[0016] In certain embodiments, after the administration, the
patient achieves improvement on the World Health Organization
COVID-19 ordinal scale of at least 4, at least 3, at least 2, or at
least 1 (World Health Organization. (2020). WHO R&D Blueprint:
novel Coronavirus: COVID-19 Therapeutic Trial Synopsis, Feb. 18,
2020, Geneva, Switzerland).
[0017] In some embodiments the patient has respiratory distress,
and in certain embodiments the patient requires supplemental
oxygen.
[0018] In some embodiments the pharmaceutical composition reduces
vascular permeability in the patient, increases the production of
lung prostaglandins in the patient, and/or decreases the amount or
activity of one or more lung inflammatory signaling proteins in the
patient. In certain aspects the one or more lung inflammatory
signaling proteins is/are selected from the group consisting of
TNF-alpha, IL6 and CXCL10.
[0019] In some embodiments the composition is administered in a
form suitable for administration to the lung. In some embodiments
composition is administered in a nebulized form.
[0020] In some embodiments the composition is administered at a
dose of 8 milliliters, and in some embodiments the composition is
administered quater in die. In some embodiments the composition is
administered at a dose of 8 milliliters quater in die. In some
embodiments the composition is administered for five days.
[0021] In some embodiments the composition is administered in an
aerosolized form.
[0022] In some embodiments the composition is administered
intravenously. In some embodiments the composition is administered
at a dose of 250 cubic centimeters, and in some embodiments the
composition is administered bis in die. In certain embodiments the
composition is administered at a dose of 250 cubic centimeters bis
in die. In some embodiments the composition is administered for
five days.
[0023] In some embodiments the composition comprises DA-DKP, and in
some embodiments the composition further comprises
N-acetyl-tryptophan (NAT), caprylic acid, caprylate or combinations
thereof. In some embodiments the DA-DKP is in a composition
prepared by removing albumin from a solution of a human serum
albumin composition. In some embodiments removing the albumin
comprises treating the human serum albumin composition by a
separation method selected from the group consisting of
ultrafiltration, sucrose gradient centrifugation, chromatography,
salt precipitation, and sonication. In some embodiments the
removing comprises passing the human serum albumin composition over
an ultrafiltration membrane with a molecular weight cut off that
retains the albumin, and wherein the resulting filtrate comprises
DA-DKP. In certain aspects the ultrafiltration membrane has a
molecular weight cutoff of less than 50 kDa, less than 40 kDa, less
than 30 kDa, less than 20 kDa, less than 10 kDa, less than 5 kDa or
less than 3 kDa.
[0024] In a fifth aspect, the present disclosure provides a
pharmaceutical product comprising a DA-DKP-containing composition,
formulated for administration in some embodiments by nebulization
or aerosolization, and in some embodiments formulated for
intravenous administration. In some embodiments the DA-DKP is
prepared by removing albumin from a solution of a human serum
albumin composition. In certain embodiments removing the albumin
comprises treating the human serum albumin composition by a
separation method selected from the group consisting of
ultrafiltration, sucrose gradient centrifugation, chromatography,
salt precipitation, and sonication. In some embodiments the
removing comprises passing the human serum albumin composition over
an ultrafiltration membrane with a molecular weight cut off that
retains the albumin, and wherein the resulting filtrate comprises
DA-DKP. In some embodiments the ultrafiltration membrane has a
molecular weight cutoff of less than 50 kDa, less than 40 kDa, less
than 30 kDa, less than 20 kDa, less than 10 kDa, less than 5 kDa or
less than 3 kDa. In certain aspects the DA-DKP-containing
composition further comprises NAT, caprylic acid, caprylate and
combinations thereof.
[0025] Some embodiments include of the pharmaceutical composition
include a pharmaceutically-acceptable carrier.
[0026] In a sixth aspect, the present disclosure provides a kit
comprising a pharmaceutical product comprising a DA-DKP-containing
composition formulated for administration by nebulization or
aerosolization. In some embodiments the kit comprising a
pharmaceutical product comprising a DA-DKP-containing composition
formulated for intravenous administration. In certain embodiments
the DA-DKP is prepared by removing albumin from a solution of a
human serum albumin composition.
DETAILED DESCRIPTION
[0027] The present disclosure generally relates to a method of
treating a viral respiratory disease. The treatment comprises
administering an effective amount of a pharmaceutical composition
prepared by removing albumin from a solution of a human serum
albumin composition and/or comprising aspartyl-alanyl
diketopiperazine (DA-DKP) to an animal having a need thereof.
[0028] The present disclosure also relates to a method of reducing
lung inflammation associated with a viral infection in an animal in
need thereof. The method comprises administering an effective
amount of a pharmaceutical composition comprising DA-DKP to an
animal having a need thereof.
[0029] The present disclosure further relates to a method of
reducing vascular permeability in lungs of an animal in need
thereof. The method comprises administering an effective amount of
a pharmaceutical composition comprising DA-DKP to an animal having
a need thereof.
[0030] The present disclosure also relates to a method to up
regulate the production of lung prostaglandins in an animal in need
thereof. The method comprises administering an effective amount of
a pharmaceutical composition comprising DA-DKP to an animal having
a need thereof.
[0031] The present disclosure further relates to a method to down
regulate one or more lung inflammatory signaling proteins in a
subject in need thereof. The method comprises administering an
effective amount of a pharmaceutical composition comprising DA-DKP
to an animal having a need thereof. In one aspect, the lung
inflammatory signaling protein is TNF-alpha, interleukin-6 (IL6)
and C-X-C motif chemokine ligand 10 (CXCL10).
[0032] The present disclosure also provides for a pharmaceutical
product comprising a DA-DKP composition formulated for
administration to the lungs, including a nebulized form or
aerosolized form. The DA-DKP of the product may be prepared by
removing albumin from a solution of human serum albumin.
[0033] The present disclosure also provides for kit comprising a
DA-DKP composition formulated for administration to the lungs,
including a nebulized form or aerosolized form.
[0034] DA-DKP has multiple anti-inflammatory and immune modulating
effects including inhibition of multiple pro-inflammatory
cytokines, chemokines and signaling molecules at the transcription
level, inhibition of the migration and adhesion of T-cells and
monocytes, activity at the G-coupled protein receptor level,
activity on actin-dependent cytoskeletal events, and reduction in
vascular permeability and inhibition of inflammation induced by
platelet activating factor, among other effects. Because
inflammation is exacerbated by, or involves, activated T-cells, the
composition of the present disclosure comprising DA-DKP can be used
to treat lung inflammatory diseases and/or inflammation related to
viral respiratory diseases and/or to prevent lung inflammation and
lung inflammatory diseases related to viral respiratory diseases.
Thus, one embodiment of the present disclosure is a method of
reducing inflammation caused by a viral respiratory disease in an
individual.
[0035] The pharmaceutical composition comprising DA-DKP can be
prepared by removing albumin from a solution of human serum albumin
as disclosed herein.
[0036] A viral respiratory disease is an illness caused by a virus
and affects the respiratory tract. Such viral respiratory diseases
can include Severe Acute Respiratory Distress Syndrome (SARS),
Middle East Respiratory Syndrome (MERS), COVID-19, and viral
infection associated with asthma, pneumonia, bronchitis and/or
tuberculosis. Viruses that can cause one or more viral respiratory
diseases include coronaviruses, influenza viruses, respiratory
syncytial virus (RSV), parainfluenza viruses, and respiratory
adenoviruses. Coronaviruses include SARS-Coronavirus-2
(SARS-CoV-2), SARS-associated coronavirus (SARS-CoV), and Middle
East Respiratory Syndrome Coronavirus (MERS-CoV). Coronavirus
infections and other viral infections can cause acute respiratory
distress syndrome (ARDS), acute lung injury (ALI), interstitial
lung disease, pulmonary fibrosis, pneumonia, and reactive airway
disease syndrome. Coronavirus infections and other viral infections
can cause inflammation in tissues such as lung, brain, heart,
kidney, blood vessel, skin, and nerve. Coronavirus infections and
other viral infections can cause symptoms such as fatigue,
shortness of breath or difficulty breathing, low exercise
tolerance, low blood oxygen saturation, cough, sore throat, stuffy
or runny nose, joint pain, chest pain, tightness, or discomfort,
muscle pain, muscle weakness, fever, heart palpitations, difficulty
thinking and/or concentrating, and depression.
[0037] COVID-19 infection is a respiratory illness caused by the
novel coronavirus SARS-COV-2 and has been classified as a pandemic
with no known cure to date. COVID-19 is detected and diagnosed with
a laboratory test. The primary symptoms of COVID-19 infection
include mild symptoms such as fever, cough, chills, muscle pain,
headache, gastrointestinal symptoms, and the loss of taste or
smell. Once infected, the virus moves down a patient's respiratory
tract, where the lungs may become inflamed, making breathing
difficult and sometimes requiring supplemental oxygen in the more
severe cases of the disease.
[0038] Respiratory symptoms after a COVID-19 infection include
shortness of breath, cough, chest discomfort, low exercise
tolerance and low oxygen saturation, all of which point to
potential inflammation related complication sequalae. Infiltrating
or resident cells in the immune system (e.g., macrophages,
peripheral blood mononuclear cells, etc.) may be responsible for
the development of these respiratory long-term consequences.
Chronic or prolonged inflammation of the lungs maybe responsible
for a myriad of respiratory signs and symptoms experienced by
patients after a COVID-19 infection. Chest x-rays and CT scans
reveal disturbing patterns of perhaps extensive fibrosis and
potential loss of elasticity and oxygen diffusion capacity.
[0039] The SARS-Cov-2 virus transmits through the respiratory
system and can cause a severe dysregulation of the immune response
and damage in the lungs. Chronic, prolonged inflammation of the
lungs may be responsible for a myriad of continuing respiratory
signs and symptoms post-infection, including cough, shortness of
breath, chest discomfort, low exercise tolerance and low blood
oxygen saturation. The continued hyperinflammatory state is thought
to lead to prolonged clinical complications, and treatment with
immunomodulators at this later point in the disease is more
effective than anti-viral treatment.
[0040] Inflammation associated with COVID-19 may trigger even more
severe complications including pneumonia, acute lung injury (ALI)
and/or acute respiratory distress syndrome (ARDS), which is a
leading cause of mortality in COVID-19. ARDS is associated with
widespread inflammation in the lungs. The underlying mechanism of
ARDS involves diffuse injury to cells which form the barrier of the
microscopic air sacs (alveoli) of the lung, surfactant dysfunction,
and activation of the immune system. The fluid accumulation in the
lungs associated with ARDS is partially explained by vascular
leakage due to inflammation.
[0041] As disclosed herein, the composition of the present
disclosure, in an aqueous solution that can be delivered through
nebulization, can be used for suppressing inflammation in the
lungs, thus making it a therapy for ARDS. An important aspect of
ARDS, triggered by COVID-19, is an initial release of chemical
signals and other inflammatory mediators secreted by lung
epithelial and endothelial cells. Neutrophils and some
T-lymphocytes migrate into the inflamed lung tissue and contribute
to the amplification/deterioration of ARDS. A decrease in the
production of lipid mediators of inflammation (prostaglandins) may
impair the resolution of inflammation associated with ARDS
(Fukunaga, et. al., Cyclooxygenase 2 Plays a Pivotal Role in the
Resolution of Acute Lung Injury. Journal of Immunology 2005;
174:5033-5039; Gao et al J Immunol 2017; 199:2043-2054).
[0042] The World Health Organization (WHO)'s Clinical Care for
Severe Acute Respiratory Infection: COVID-19 Adaptation recommends
early intervention with supplemental oxygen for COVID-19 patients
with low blood oxygen saturation (SpO.sub.2) beginning with the
least invasive modality possible (e.g. hand-held oxygen source) and
moving to more invasive modalities (e.g. bilevel positive airway
pressure [BiPAP] and/or non-invasive ventilation (NIV)) as severity
increases. Treatment during early intervention for COVID-19
patients with respiratory distress requires monitoring of
respiratory function with treatment responsive to disease
progression. The CDC recommends following the guidelines for
treatment of COVID-19 patients with hypoxia in Surviving Sepsis
Campaign: Guidelines on the Management of Critically Ill Adults
with Coronavirus Disease 2019 (COVID-19).
[0043] Patients who fail to respond to less-invasive treatment are
at a high risk of developing ARDS, a rapidly progressive disease
characterized by widespread inflammation in the lungs that results
in flooding of the lungs' microscopic air sacs, which are
responsible for the exchange of gases such as oxygen and carbon
dioxide with capillaries in the lungs. Additional common findings
in ARDS include partial collapse of the lungs (atelectasis) and low
levels of oxygen in the blood (hypoxemia). The clinical syndrome is
associated with pathological findings including pneumonia and
diffuse alveolar damage, the latter of which is characterized by
diffuse inflammation of lung tissue. The triggering insult to the
tissue usually results in an initial release of chemical signals
and other inflammatory mediators secreted by local epithelial and
endothelial cells.
[0044] ARDS impairs the lungs' ability to exchange oxygen and
carbon dioxide. The underlying mechanism of ARDS involves diffuse
injury to cells that form the barrier of the microscopic air sacs
of the lungs, surfactant dysfunction, activation of the immune
system, and dysfunction of the body's regulation of blood
clotting.
[0045] Diagnosis of ARDS is based on the 2012 Berlin definition:
[0046] lung injury of acute onset, within 1 week of an apparent
clinical insult and with progression of respiratory symptoms [0047]
bilateral opacities on chest imaging (chest radiograph or CT) not
explained by other lung pathology (e.g. effusion, lobar/lung
collapse, or nodules) [0048] respiratory failure not explained by
heart failure or volume overload [0049] decreased ratio of partial
pressure arterial oxygen (PaO.sub.2) to fraction of inspired oxygen
(FiO.sub.2) of less than or equal to 300 mm Hg despite a positive
end-expiratory pressure (PEEP) of more than 5 cm H.sub.2O.
[0050] The severity of ARDS is defined by the Berlin definition as:
[0051] mild ARDS: 201-300 mmHg (.ltoreq.39.9 kPa) [0052] moderate
ARDS: 101-200 mmHg (.ltoreq.26.6 kPa) [0053] severe ARDS:
.ltoreq.100 mmHg (.ltoreq.13.3 kPa)
[0054] There are no approved treatments for ARDS, and standard of
care (SOC) is supportive management.
[0055] Furthermore, COVID-19 can cause prolonged symptoms even
after the viral infection has seemingly been cleared. These
prolonged effects are referred to a post-COVID, post-acute COVID,
post-acute sequelae of SARS-CoV-2 infection (PASC), chronic COVID
syndrome (CCS), and long-haul COVID. The many symptoms can include
fatigue, shortness of breath or difficulty breathing, low exercise
tolerance, low blood oxygen saturation, cough, sore throat, stuffy
or runny nose, joint pain, chest pain, tightness or discomfort,
muscle pain, muscle weakness, fever, heart palpitations, difficulty
thinking and/or concentrating, and depression. Symptoms can also
include breathlessness, myalgia, anxiety, extreme fatigue, low
mood, sleep disturbances or difficulty sleeping, and memory
impairment. Other neurologic symptoms include brain fog
(non-specific cognitive problems), headache, numbness or tingling,
dysgeusia, dizziness, pain, blurred vision, tinnitus, and loss of
taste (ageusia) or smell (anosmia). Symptoms can last for a month
or more, including at least 1, at least 2, at least 3, at least 4,
at least 5, at least 6, at least 7, at least 8, at least 9, at
least 10, at least 11, at least 12 months, or longer. The continued
hyperinflammatory state is thought to lead to prolonged clinical
complications, and treatment with immunomodulators at this later
point in the disease is more effective than anti-viral
treatment.
[0056] In addition to lung symptoms and long COVID, SARS-CoV-2
infection can lead to damage to other organs, including the heart
and kidneys. SARS-CoV-2 infects endothelial cells and also leads to
systemic inflammation, causing vasculopathy that affects widespread
parts of the body. The vasculopathy or other phenomena can cause
damage to the heart (myocarditis or arrhythmia), kidneys (acute
kidney injury, chronic kidney disease, or renal failure), liver
(liver dysfunction), blood vessels (bleeding and blood clots), skin
(Kawasaki-like syndrome, rash, hair loss, and urticarial,
vesicular, purpuric, and papulosquamous lesions), digestive system
(anorexia, nausea, vomiting, diarrhea, and abdominal pain), brain
(described above), and nerves (symptoms described above and
cerebrovascular disease, ataxia, seizure, vision impairment, and
nerve pain). Other symptoms include lymphopenia, hypoxia, blood
hypercoagulability, multi-organ failure, sepsis, and septic
shock.
[0057] Conventional pharmaceutical therapies for viral respiratory
disease include anti-viral compositions such as amantadine and
ribavin.
[0058] In any of the methods and compositions disclosed herein,
forms for administration of the composition of the present
disclosure include nebulized form, aerosolized form, sprays, drops,
and powders. The active ingredient may be mixed under sterile
conditions with a pharmaceutically-acceptable carrier, and with any
buffers, or propellants which may be required. In some embodiments,
the form for administration is a sterile liquid that is
administered as a nebulized liquid form or intravenously.
[0059] Aerosol (inhalation) delivery can be performed using methods
standard in the art. Carriers suitable for aerosol delivery are
described herein. Devices for delivery of aerosolized formulations
include, but are not limited to, pressurized metered dose inhalers
(MDI), dry powder inhalers (DPI), and metered solution devices
(MSI), and include devices that are nebulizers and inhalers.
[0060] The composition of the present disclosure comprising DA-DKP
can be administered to an animal by any suitable route of
administration to the lungs, including nasal, intratracheal,
bronchial, direct instillation into the lung, inhaled and oral.
[0061] "Treat" is used herein to mean to reduce (wholly or
partially) the symptoms, duration or severity of a disease. In
accordance with the present state of the art, treat typically does
not mean to cure. As provided for herein, in any of the methods
disclosed herein treating includes that the animal experiences an
outcome including, but not limited to, reduced ventilator time,
reduced mortality, improvement in oxygenation parameters and
combinations thereof.
[0062] The pharmaceutical composition comprising DA-DKP of the
present disclosure is administered to an animal in need of
treatment. In some embodiments, the animal is a mammal, such as a
rabbit, goat, dog, cat, horse or human. In some embodiments, the
animal in need of treatment is a human. Effective dosage amounts
may vary with the severity of the disease or condition, the
route(s) of administration, the duration of the treatment, the
identity of any other drugs being administered to the animal, the
age, size and species of the animal, the discretion of the
prescribing health care provider, and like factors known in the
medical and veterinary arts.
[0063] The composition of the present disclosure may be a
pharmaceutical solution having a DA-DKP concentration range with a
lower endpoint of about 10 .mu.M, about 20 .mu.M, about 30 .mu.M,
about 40 .mu.M, about 50 .mu.M, about 60 .mu.M, about 70 .mu.M,
about 80 .mu.M, about 90 .mu.M, about 100 .mu.M, about 110 .mu.M,
about 120 .mu.M, about 130 .mu.M, about 140 .mu.M, about 150 .mu.M,
about 160 .mu.M, about 170 .mu.M, about 180 .mu.M, about 190 .mu.M,
about 200 .mu.M, about 210 .mu.M, about 220 .mu.M, about 230 .mu.M,
about 240 .mu.M, about 240, about 250 .mu.M, about 260 .mu.M, about
270 .mu.M, about 280 .mu.M, about 290 .mu.M, about 300 .mu.M, about
310, about 320 .mu.M, about 330 .mu.M, about 340 .mu.M, about 350
.mu.M, about 360 .mu.M, about 370 .mu.M, about 380 .mu.M, about 390
.mu.M, or about 400 .mu.M. The composition of the present
disclosure may be a pharmaceutical solution having a DA-DKP
concentration range with an upper endpoint of about 600 .mu.M,
about 580 .mu.M, about 570 .mu.M, about 560 .mu.M, about 550 .mu.M,
about 540 .mu.M, about 530 .mu.M, about 520 .mu.M, about 510 .mu.M,
about 500 .mu.M, about 490 .mu.M, about 480 .mu.M, about 470 .mu.M,
about 460 .mu.M, about 450 .mu.M, about 440 .mu.M, about 430 .mu.M,
about 420 .mu.M, about 410 .mu.M, about 400 .mu.M, about 390 .mu.M,
about 380 .mu.M, about 370 .mu.M, about 360 .mu.M, about 350, about
340 .mu.M, about 330 .mu.M, about 320 .mu.M, about 310 .mu.M, about
300 .mu.M, about 290 .mu.M, about 280, about 270 .mu.M, about 260
.mu.M, about 250 .mu.M, about 240 .mu.M, about 230 .mu.M, about 220
.mu.M, about 210 .mu.M, or about 200 .mu.M.
[0064] An effective amount of DA-DKP in the composition of the
present disclosure for treating a viral respiratory disease or
condition can be a range with a lower endpoint of about 10 .mu.g,
about 15 .mu.g, about 20 .mu.g, about 25 .mu.g, about 30 .mu.g,
about 35 .mu.g, about 40 .mu.g, about 45 .mu.g, about 50 .mu.g,
about 55 .mu.g, about 60 .mu.g, about 65 .mu.g, about 70 .mu.g,
about 75 .mu.g, about 80 .mu.g, about 85 .mu.g, about 90 .mu.g,
about 95 .mu.g, about 100 .mu.g, about 110 .mu.g, about 120 .mu.g,
about 130 .mu.g, about 140 .mu.g, about 150 .mu.g, about 160 .mu.g,
about 170 .mu.g, about 180 .mu.g, about 190 .mu.g, about 200 .mu.g,
about 210 .mu.g, about 220 .mu.g, about 230 .mu.g, about 240 .mu.g,
about 250 .mu.g, about 260 .mu.g, about 270 .mu.g, about 280 .mu.g,
about 290 .mu.g, about 300 .mu.g, about 310 .mu.g, about 320 .mu.g,
about 330 .mu.g, about 340 .mu.g, about 350 .mu.g, about 360 .mu.g,
about 370 .mu.g, about 380 .mu.g, about 390 .mu.g, about 400 .mu.g,
about 425 .mu.g, about 450 .mu.g, about 475 .mu.g or about 500
.mu.g. In addition, an effective amount of DA-DKP in the
composition of the present disclosure for treating a viral
respiratory disease or condition can be a range with upper endpoint
of about 500 .mu.g, about 490 .mu.g, about 480 .mu.g, about 470
.mu.g, about 460 .mu.g, about 450 .mu.g, about 440 .mu.g, about 430
.mu.g, about 420 .mu.g, about 410 .mu.g, about 400 .mu.g, about 390
.mu.g, about 380 .mu.g, about 370 .mu.g, about 360 .mu.g, about 350
.mu.g, about 340 .mu.g, about 330 .mu.g, about 320 .mu.g, about 310
.mu.g, about 300 .mu.g, about 290 .mu.g, about 280 .mu.g, about 270
.mu.g, about 260 .mu.g, about 250 .mu.g, about 240 .mu.g, about 230
.mu.g, about 220 .mu.g, about 210 .mu.g, about 200 .mu.g, about 190
.mu.g, about 180 .mu.g, about 170 .mu.g, about 160 .mu.g, about 150
.mu.g, about 140 .mu.g, about 130 .mu.g, about 120 .mu.g, about 110
.mu.g, about 100 .mu.g, about 90 .mu.g, about 80 .mu.g, about 70
.mu.g, about 60 .mu.g, about 50 .mu.g, about 40 .mu.g, about 30
.mu.g, or about 20 .mu.g.
[0065] Different doses of the disclosed compositions can be used
with different routes of administration. Administration to the
lung, for example by nebulizer, can involve doses of about 1, about
2, about 3, about 4, about 5, about 6, about 7, about 8, about 9,
about 10, about 11, about 12, about 13, about 14, about 15, about
16, about 17, about 18, about 19, or about 20 milliliters.
Intravenous administration can involve doses of about 50, about 55,
about 60, about 65, about 70, about 75, about 80, about 85, about
90, about 95, about 100, about 105, about 110, about 115, about
120, about 125, about 130, about 135, about 140, about 145, about
150, about 155, about 160, about 165, about 170, about 175, about
180, about 185, about 190, about 195, about 200, about 205, about
210, about 215, about 220, about 225, about 230, about 235, about
240, about 245, about 250, about 260, about 270, about 275, about
280, about 290, about 300, about 310, about 320, about 330, about
340, about 350, about 360, about 370, about 375, about 380, about
390, about 400, about 425, about 450, about 475, about 500, about
525, about 550, about 575, about 600, about 650, about 700, about
750, about 800, about 850, about 900, about 950, about 1000, about
1100, about 1200, about 1300, about 1400, or about 1500 milliliters
(or cubic centimeters). The disclosed compositions can be
administered 1, 2, 3, 4, 5, 6, 7, 8, or more times per day for 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. Disclosed
compositions can also be administered for 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 weeks, and/or for 4, 5, 6, 7, 8, 9, 10, 11, or 12 months
or more.
[0066] While it is possible for a compound of the present
disclosure, such as DA-DKP, to be administered alone, in many
embodiments the compound is administered as a pharmaceutical
formulation (composition). The pharmaceutical compositions of the
present disclosure comprise a compound or compounds of the present
disclosure as an active ingredient in admixture with one or more
pharmaceutically-acceptable carriers and, optionally, with one or
more other compounds, drugs or other materials. In some
embodiments, the compound is DA-DKP. Each carrier is advantageously
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the animal.
Pharmaceutically-acceptable carriers are well known in the art.
Regardless of the route of administration selected, the compounds
of the present disclosure are formulated into
pharmaceutically-acceptable dosage forms by conventional methods
known to those of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences (Easton, Pa.: Mack Pub. Co, 1965. Print;
23.sup.rd Ed. (2020) ISBN: 9780128200070).
[0067] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the present
disclosure include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable
mixtures thereof, vegetable oils, such as olive oil, and injectable
organic esters, such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of coating materials, such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0068] These compositions may also contain adjuvants such as
wetting agents, emulsifying agents and dispersing agents. It may
also be desirable to include isotonic agents, such as sugars,
sodium chloride, and the like in the compositions. In addition,
prolonged absorption of the injectable pharmaceutical form may be
brought about by the inclusion of agents which delay absorption
such as aluminum monostearate and gelatin.
[0069] The formulations may be presented in unit-dose or multi-dose
sealed containers, for example, ampoules and vials, and may be
stored in a lyophilized condition requiring only the addition of
the sterile liquid carrier, for example water for nebulization,
immediately prior to use.
[0070] Kits comprising the pharmaceutical products of the present
disclosure are also provided. The kits can comprise a DA-DKP
composition formulated for administration to the lung including a
nebulized form and/or an aerosolized form. The DA-DKP can be
prepared as described herein, such as by removing albumin from a
solution of a human albumin composition. The kits may contain
unit-dose or multi-dose sealed containers, for example, ampoules
and vials, and may be stored in a lyophilized condition requiring
only the addition of the sterile liquid carrier, for example water,
immediately prior to use. The kits may also be stored in a
condition, wherein the contents are ready for direct use or
injection.
[0071] The composition of the present disclosure may further
comprise N-acetyl-tryptophan (NAT), caprylic acid, caprylate or
combinations thereof. In some embodiments, the composition
comprises NAT. Compositions of the present disclosure having NAT,
caprylic acid, caprylate or combinations thereof have a
concentration range with a lower endpoint of about 1 mM, about 2
mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM,
about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM,
about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM,
about 18 mM, about 19 mM, or about 20 mM. In addition, compositions
of the present disclosure having NAT, caprylic acid, caprylate or
combinations thereof have a concentration range with an upper
endpoint of about 40 mM, about 39 mM, about 38 mM, about 37 mM,
about 36 mM, about 35 mM, about 34 mM, about 33 mM, about 32 mM,
about 31 mM, about 30 mM, about 29 mM, about 28 mM, about 27 mM,
about 26 mM, about 25 mM, about 24 mM, about 23 mM, about 22, or
about 21 mM. In some embodiments, the concentration range is about
4 mM to about 20 mM.
[0072] In addition, the composition of the present disclosure can
also comprise a second drug such as an anti-viral, an antibiotic,
chloroquine, hydroxychloroquine, known drugs for treating
pneumonia, an analgesic (such as lidocaine or paracetamol), an
anti-inflammatory (such as corticosteroids, such as dexamethasone
and betamethasone, non-steroid anti-inflammatory drugs (NSAIDs),
ibuprofen, naproxen), and/or other suitable drugs.
[0073] Methods of making diketopiperazines, such as DA-DKP, are
well known in the art, and these methods may be employed to
synthesize the diketopiperazines of the present disclosure. See,
e.g., U.S. Pat. Nos. 4,694,081, 5,817,751, 5,990,112, 5,932,579 and
6,555,543, US Patent Application Publication Number 2004/0024180,
PCT applications WO 96/00391 and WO 97/48685, and Smith et al.,
Bioorg. Med. Chem. Letters, 8, 2369-2374 (1998).
[0074] For instance, diketopiperazines, such as DA-DKP, can be
prepared by first synthesizing dipeptides. The dipeptides can be
synthesized by methods well known in the art using L-amino acids,
D-amino acids or a combination of D- and L-amino acids. In some
embodiments solid-phase peptide synthetic methods are employed. Of
course, dipeptides are also available commercially from numerous
sources, including DMI Synthesis Ltd., Cardiff, UK (custom
synthesis), Sigma-Aldrich, St. Louis, Mo. (primarily custom
synthesis), Phoenix Pharmaceuticals, Inc., Belmont, Calif. (custom
synthesis), Fisher Scientific (custom synthesis) and Advanced
ChemTech, Louisville, Ky.
[0075] Once the dipeptide is synthesized or purchased, it is
cyclized to form a diketopiperazine. This can be accomplished by a
variety of techniques. For example, U.S. Patent Application
Publication Number 2004/0024180 describes a method of cyclizing
dipeptides. Briefly, the dipeptide is heated in an organic solvent
while removing water by distillation. In some embodiments, the
organic solvent is a low-boiling azeotrope with water, such as
acetonitrile, allyl alcohol, benzene, benzyl alcohol, n-butanol,
2-butanol, t-butanol, acetic acid butylester, carbon tetrachloride,
chlorobenzene chloroform, cyclohexane, 1,2-dichlorethane,
diethylacetal, dimethylacetal, acetic acid ethylester, heptane,
methylisobutylketone, 3-pentanol, toluene and xylene. The
temperature depends on the reaction speed at which the cyclization
takes place and on the type of azeotroping agent used. In some
embodiments, the reaction is carried out at 50-200.degree. C., in
some embodiments at 80-150.degree. C. The pH range in which
cyclization takes place can be easily determine by the person
skilled in the art. In some embodiments the pH range will
advantageously be 2-9, in some embodiments 3-7.
[0076] When one or both of the amino acids of the dipeptide has, or
is derivatized to have, a carboxyl group on its side chain (e.g.,
aspartic acid or glutamic acid), the dipeptide is cyclized as
described in U.S. Pat. No. 6,555,543. Briefly, the dipeptide, with
the side-chain carboxyl still protected, is heated under neutral
conditions. Typically, the dipeptide will be heated at from about
80.degree. C. to about 180.degree. C., in some embodiments at about
120.degree. C. The solvent will be a neutral solvent. For instance,
the solvent may comprise an alcohol (such as butanol, methanol,
ethanol, and higher alcohols, but not phenol) and an azeotropic
co-solvent (such as toluene, benzene, or xylene). In some
embodiments, the alcohol is butan-2-ol, and the azeotropic
co-solvent is toluene. The heating is continued until the reaction
is complete, and such times can be determined empirically.
Typically, the dipeptide will be cyclized by refluxing it for about
8-24 hours, in some embodiments about 18 hours. Finally, the
protecting group is removed from the diketopiperazine. In doing so,
the use of strong acids (mineral acids, such as sulfuric or
hydrochloric acids), strong bases (alkaline bases, such as
potassium hydroxide or sodium hydroxide), and strong reducing
agents (e.g., lithium aluminum hydride) should be avoided, in order
to maintain the chirality of the final compound.
[0077] Dipeptides made on solid phase resins can be cyclized and
released from the resin in one step. See, e.g., U.S. Pat. No.
5,817,751. For instance, the resin having an N-alkylated dipeptide
attached is suspended in toluene or toluene/ethanol in the presence
of acetic acid (e.g., 1%) or triethylamine (e.g., 4%). Typically,
basic cyclization conditions are utilized for their faster
cyclization times.
[0078] Other methods of cyclizing dipeptides and of making
diketopiperazines are known in the art and can be used in the
preparation of diketopiperazines useful in the practice of the
present disclosure. See, e.g., those references listed above. In
addition, many diketopiperazines suitable for use in the present
disclosure can be made as described below from proteins and
peptides. Further, diketopiperazines for use in the practice of the
present disclosure can be obtained commercially from, e.g., DMI
Synthesis Ltd., Cardiff, UK (custom synthesis).
[0079] The DA-DKP composition and/or products of the present
disclosure can be prepared from solutions containing DA-DKP,
including from the commercially-available pharmaceutical
compositions comprising albumin, such as human serum albumin, by
well known methods, such as ultrafiltration, chromatography,
size-exclusion chromatography (e.g., Centricon filtration),
affinity chromatography (e.g., using a column of beads having
attached thereto an antibody or antibodies directed to the desired
diketopiperazine(s) or an antibody or antibodies directed to the
truncated protein or peptide), anion exchange or cation exchange,
sucrose gradient centrifugation, salt precipitation, or sonication,
that will remove some or all of the albumin in the solution. The
resultant DA-DKP-containing composition and/or product can be used
and incorporated into pharmaceutical compositions as described
above.
[0080] Using an ultrafiltration separation method, a human serum
albumin composition can be passed over an ultrafiltration membrane
having a molecular weight cut-off that retains the albumin while
the DA-DKP passes into the resulting filtrate or fraction. This
filtrate may comprise components having molecular weights less than
about 50 kDa, less than about 40 kDa, less than 30 kDa, less than
about 20 kDa, less than about 10 kDa, less than about 5 kDa, less
than about 3 kDa. In some embodiments, the filtrate comprises
components having molecular weights less than about 5 kDa (also
referred to as "<5000 MW" and/or low molecular weight fraction
"LMWF"). This <5000 MW fraction or filtrate contains DA-DKP
which is formed after the dipeptide aspartate-alanine is cleaved
from albumin and subsequently cyclized into the
diketopiperazine.
[0081] The term "LMWF" refers to a low molecular weight fraction of
HSA that is a composition prepared by separation of high molecular
weight components from human serum albumin (HSA). For example, LMWF
can be prepared by filtration of a commercially available HSA
solution wherein molecular weight components of more than 3 kilo
daltons (kDa), 5 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, are
separated from the HSA solution. Alternatively, the term LMWF can
refer to a composition prepared by separation of the high molecular
weight components by other techniques, including but not limited to
ultrafiltration, column chromatography including size exclusion
chromatography, affinity chromatography, anion exchange, cation
exchange, sucrose gradient centrifugation, salt precipitation, or
sonication. LMWF also refers to a composition that includes
components of HSA having a molecular weight less than 50,000
daltons (Da) (or 50 kDa), 40 kDa, 30 kDa, 20 kDa, 10 kDa, 5000 Da,
4000 Da, or 3000 Da (corresponding to 50,000 g/mol, 40,000 g/ml,
30,000 g/mol, 20.00 g/mol, 10,000 g/mol, 5,000 g/mol, 4,000 g/mol
or 3,000 g/mol respectively). AMPION.RTM. (Ampio Pharmaceuticals,
Inc., Englewood, Colo. USA) is a <5 kDa fraction of human serum
albumin (HSA). AMPION.RTM. can be produced, for example, by
filtering commercially available HSA as described herein.
Commercially available HSA is produced by fractionation of blood,
for example by the Cohn process or its variations. AMPION.RTM. can
be produced by filtering such commercially available HSA, for
example a 5% HSA solution, to remove components above 5 kDA.
[0082] AMPION.RTM. is currently approved for clinical use by the
United States Food and Drug Administration, as an
anti-inflammatory, immunomodulating drug. The novel mode of action
of AMPION.RTM. involves multiple biochemical pathways associated
with resolving inflammation. AMPION.RTM. is a suitable drug for the
treatment of viral diseases for several reasons, including but not
limited to those below.
[0083] First, an important aspect of ARDS, triggered by COVID-19,
is an initial release of chemical signals and other inflammatory
mediators secreted by lung epithelial and endothelial cells.
Neutrophils and some T-lymphocytes migrate into the inflamed lung
tissue and contribute to the amplification/deterioration of ARDS. A
decrease in the production of lipid mediators of inflammation
(prostaglandins) may impair the resolution of inflammation
associated with ARDS.
[0084] Second, AMPION.RTM. was reported to up regulate the
production of these healing lipid mediators' prostaglandins
in-vitro. Gao et al., J. Immunol. (2017); 199:2043-2054. In
addition, multiple inflammatory signals (i.e., TNF.alpha., IL6,
CXCL10) have been reported to be attenuated by AMPION.RTM.,
including a decrease in vascular permeability. Bar-Or et al., On
the Mechanisms of Action of the Low Molecular Weight Fraction of
Commercial Human Serum Albumin in Osteoarthritis. Current
Rheumatology Reviews (2019), 15, 189-200.
[0085] Third, more than 1,000 patients with another inflammatory
disease, osteoarthritis, have received AMPION.RTM. without any
serious drug related adverse events. A subset of these patients
were given AMPION.RTM. multiple times over the course of a year,
and no serious drug related adverse events were observed.
[0086] Fourth, AMPION.RTM. is formulated as a sterile liquid and is
easily administered as a nebulized liquid form or intravenously.
AMPION.RTM., particularly in aerosolized and/or nebulized form, can
be used in the treatment of viral diseases and related conditions.
For example, easing use for treatment of Acute Respiratory Distress
Syndrome ("ARDS"), AMPION.RTM. is an aqueous solution that may be
delivered through nebulization and would be suitable for
suppressing inflammation in the lungs.
[0087] Physiologically-acceptable salts of the DA-DKP of the
present disclosure may also be used in the practice of the present
disclosure. Physiologically-acceptable salts include conventional
non-toxic salts, such as salts derived from inorganic acids (such
as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, and the
like), organic acids (such as acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, glutamic,
aspartic, benzoic, salicylic, oxalic, ascorbic acid, and the like)
or bases (such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation or organic cations derived
from N,N-dibenzylethylenediamine, D-glucosamine, or
ethylenediamine). The salts are prepared in a conventional manner,
e.g., by neutralizing the free base form of the compound with an
acid.
[0088] Additional objects, advantages and novel features of the
present disclosure will become apparent to those skilled in the art
by consideration of the following non-limiting examples. The
following experimental results are provided for purposes of
illustration and are not intended to limit the scope of the
claims.
EXAMPLES
Example 1. A Randomized, Controlled Study to Evaluate the Safety
and Efficacy of AMPION.RTM. in Patients with Prolonged Respiratory
Complications after COVID-19 Infection
[0089] This study focuses on patients who have long-term symptoms
and clinical signs related to continued respiratory illness after
the viral infection is cleared.
[0090] AMPION.RTM. is delivered by inhalation using a nebulizer as
a 32 cubic centimeters (cc) daily dose administered four times a
day (8 cc per treatment) for five days, for a total dose of a total
combined dose of 160 cc. This treatment regimen provides a positive
clinical outcome while minimizing safety risks.
[0091] AMPION.RTM. is aerosolized for inhalation using the
AEROGEN.RTM. Ultra handheld nebulizer (Aerogen Limited, Galway,
Ireland, FDA 510K K133360), which consists of the AEROGEN.RTM.
Pro-X Controller and the AEROGEN.RTM. Ultra handheld unit. The
system is a portable medical device for single patient use
indicated for aerosolization of physician-prescribed solutions for
inhalation. AMPION.RTM. is nebulized using the continuous setting
on the AEROGEN.RTM. controller, and the study drug is nebulized
until it is fully aerosolized.
[0092] This is a randomized, controlled Phase 1 trial to evaluate
the safety and efficacy of a 5-day AMPION.RTM. inhalation treatment
in participants with prolonged respiratory complications after a
COVID-19 infection. Participants (n=40) are randomized in active
(n=20) or control (n=20) groups. Both groups receive the standard
of care (SOC) for individuals with prolonged COVID-19 symptoms. The
treatment arm receives AMPION.RTM. inhalation treatment in addition
to the SOC, and the control arms will receive the SOC alone.
[0093] The trial objectives are to evaluate the safety and
tolerability of inhaled AMPION.RTM. in adult participants with
prolonged respiratory complications after COVID-19 infection and to
assess the effect of inhaled AMPION.RTM. compared to SOC on the
clinical outcomes for participants with prolonged respiratory
complications after a COVID-19 infection. The effect of AMPION.RTM.
compared to SOC on safety is determined by assessing incidence of
adverse events (AEs) and serious adverse events (SAEs) from
baseline through Day 28. The effect of AMPION.RTM. compared to SOC
on respiratory symptom improvement is assessed by time to
respiratory symptom improvement as measured using the symptom
questionnaire from baseline through Day 7 and the percentage of
participants demonstrating improvement on the respiratory symptom
questionnaire on Days 1 through 7. The effect of AMPION.RTM.
compared to SOC on respiratory symptom resolution is assessed by
time to respiratory symptom resolution as described using the
symptom questionnaire from baseline through Day 7 and change in the
respiratory symptom questionnaire from baseline through Day 7. The
effect of AMPION.RTM. compared to SOC on pulmonary function is
assessed by change in blood oxygen saturation from baseline through
Day 7, change in six-minute walk test score from baseline through
Day 7, change in pulmonary function tests (spirometry, lung volume,
diffusion capacity) from baseline through Day 7, and change in
chest x-ray imaging from baseline to Day 28.
Diagnosis and Main Criteria for Inclusion:
[0094] 1. Male or female adults: .gtoreq.18 years 2. Prior
diagnosis with COVID-19, as evaluated by PCR test confirming
infection, or suspected COVID-19 diagnosis based on radiological
clinical findings. 3. Two negative COVID-19 tests to indicate
infection has cleared. 4. Experiencing two or more COVID-19
respiratory symptoms for at least 4 weeks (28 days) after initial
positive COVID-19 diagnosis, including cough, sore throat, stuffy
or runny nose, shortness of breath (difficulty breathing),
tightness of chest, chest discomfort, and low exercise tolerance 5.
No clinical signs indicative of severe or critical COVID-19,
including respiratory failure, shock, multi-organ failure. 6. No
clinically significant findings via electrocardiogram (ECG),
including acute myocardial infarction, acute ischemic changes,
atrial fibrillation, atrial flutter, paced rhythms in individuals
who have undergone permanent pacemaker placement, evidence of prior
infarction, unchanged stable conduction abnormalities e.g., right
bundle branch block, or any other finding which does not
significantly impact mortality. 7. Women of childbearing potential
and their partner must agree to use at least one highly effective
method of contraception (e.g., hormonal contraceptives [implants,
injectables, combination oral contraceptives, transdermal patches,
or contraceptive rings], intrauterine devices, bilateral tubal
occlusion, or sexual abstinence) for the duration of the study. 8.
Informed consent obtained from the patient or the patient's legal
representative.
Main Criteria for Exclusion:
[0095] 1. Severe or critical COVID-19 with clinical diagnosis of
respiratory failure, pneumonia, or acute respiratory distress
syndrome (ARDS). 2. Patient has severe chronic obstructive or
restrictive pulmonary disease (COPD) as defined by prior pulmonary
function tests, chronic renal failure, or significant liver
abnormality (e.g., cirrhosis, transplant, etc.). 3. Patient is on
chronic immunosuppressive medication. 4. Patient requires surgery
that could be life-threatening within the study window. 5. A
history of allergic reactions to human albumin (reaction to
non-human albumin such as egg albumin is not an exclusion
criterion) or excipients in 5% human albumin (N-acetyltryptophan,
sodium caprylate). 6. Patient has known pregnancy or is currently
breastfeeding. 7. Participation in another clinical trial for an
investigational treatment for COVID-19. 8. No clinically
significant findings via electrocardiogram (ECG), including acute
myocardial infarction, acute ischemic changes, atrial fibrillation,
atrial flutter, paced rhythms in individuals who have undergone
permanent pacemaker placement, evidence of prior infarction,
unchanged stable conduction abnormalities e.g., right bundle branch
block, or any other finding which does not significantly impact
mortality. 9. As a result of the medical review and screening
investigation, the Principal Investigator considers the patient
unfit for the study.
[0096] Safety is assessed by recording adverse events, vital signs,
blood oxygen saturation, and laboratory findings (biochemistry,
hematology) for the duration of treatment and for the length of the
study (28 days).
[0097] Efficacy is assessed by recording the effects of IV
AMPION.RTM. compared to SOC on the clinical outcomes for
participants with prolonged respiratory complications after a
COVID-19 infection using the following clinical outcomes: blood
oxygen saturation, COVID-19 respiratory symptom assessment, a walk
test, pulmonary function tests (e.g., spirometry, lung volume, and
diffusion capacity), and chest x-ray. Assessments for clinical
outcomes are performed from baseline through Day 7.
Description of Study Visits
Screening (-3 Days to Day 0)
[0098] Evaluate all inclusion and exclusion criteria to ensure that
patients meet all inclusion criteria and none of the exclusion
criteria.
[0099] Confirm date of initial positive COVID-19 test. Confirm
date(s) of two negative follow up COVID-19 tests.
[0100] Medical history, pre-existing conditions, and comorbidities.
Include the symptom onset date for COVID-19 symptoms.
[0101] Obtain informed consent before the starting any study
specific procedures, including COVID testing.
Baseline (Day 0)
[0102] Confirm eligibility (review inclusion/exclusion
criteria).
[0103] Demographics (age, sex, race, height and weight).
[0104] Randomize patient to study arm. If randomized to the active
treatment arm, start treatment within 24 hours.
[0105] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate.
[0106] SpO.sub.2 and supplementation oxygen mode/flow rate, as
applicable.
[0107] Respiratory symptom assessment and walk test.
[0108] Pulmonary function tests (PFTs): spirometry, lung volume,
diffusion capacity.
[0109] Chest x-ray imaging.
[0110] Hematology, biochemistry tests.
[0111] Concomitant medications/therapies.
[0112] AEs.
Treatment Period (Day 1 to Day 5)
[0113] Subjects enrolled in the active treatment arm will
administer inhaled AMPION.RTM. through nebulization daily. These
subjects will have a general health check conducted via telephone
or text message on Days 1, 3, 5.
[0114] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate.
[0115] SpO.sub.2 and supplementation oxygen mode/flow rate, as
applicable.
[0116] Respiratory symptom assessment and walk test.
[0117] PFTs: spirometry, lung volume, diffusion capacity.
[0118] Concomitant medications/therapies.
[0119] AEs.
Post Treatment Follow Up (Day 7)
[0120] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate.
[0121] SpO.sub.2 and supplementation oxygen mode/flow rate, as
applicable.
[0122] Respiratory symptom assessment and walk test.
[0123] Pulmonary function tests (PFTs): spirometry, lung volume,
diffusion capacity.
[0124] Hematology, biochemistry tests.
[0125] Concomitant medications/therapies.
[0126] AEs.
Post-Treatment Follow-Up (Day 28)
[0127] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate.
[0128] SpO.sub.2 and supplementation oxygen mode/flow rate, as
applicable.
[0129] Respiratory symptom assessment and walk test.
[0130] Pulmonary function tests (PFTs): spirometry, lung volume,
diffusion capacity.
[0131] Chest x-ray imaging.
[0132] Concomitant medications/therapies.
[0133] AEs.
Assessment Methods
[0134] Demographic Data: Demographic data are collected: age,
gender, race, height and weight, comorbidities. Health Check: A
general health check is be conducted every other day during the
treatment period for the AMPION.RTM. treatment group. Vital Signs:
Vital signs are collected daily during the treatment period and at
follow-up visits as follows: heart rate (or pulse rate), systolic
BP, diastolic BP, body temperature, respiratory rate. Blood Oxygen
Saturation (SpO.sub.2): SpO.sub.2 is collected daily during the
treatment period and at follow-up visits using a pulse-oxygen
measuring device. Respiratory Symptom Assessment: The symptoms and
the date experiencing symptoms are recorded at every visit from
baseline to Day 7. The following symptoms are evaluated: cough,
sore throat, stuffy or runny nose, shortness of breath (difficulty
breathing), tightness of chest, chest discomfort, low exercise
tolerance. Each symptom is rated as follows: 0 None, 1 Mild, 2
Moderate, or 3 Severe. Walk Test: A six-minute walk test is
recorded at every visit from baseline to Day 28. [0135] 1. Flat,
straight corridor 30 m (100 feet) in length [0136] 2. Turnaround
points marked with a cone [0137] 3. Patient should wear comfortable
clothes and shoes [0138] 4. Patient rests in chair for at least 10
minutes prior to test (i.e., no warm-up period) [0139] 5. Heart
rate and pulse oxygen saturation (SpO.sub.2) should be monitored
throughout the test [0140] 6. If the patient is using supplemental
oxygen, record the flow rate and type of device [0141] 7. Have
patient stand and rate baseline dyspnea and overall fatigue using
Borg scale (Borg G A. Psychophysical bases of perceived exertion.
Med Sci Sports Exerc 1982; 14:377). [0142] 8. Set lap counter to
zero and timer to six minutes [0143] 9. Instruct the patient:
Remember that the object is to walk AS FAR AS POSSIBLE for 6
minutes, but don't run or jog. Pivot briskly around the cone.
[0144] 10. Standardized encouragement statements should be provided
at one minute intervals, such as "You are doing well. You
have_minutes to go" and "Keep up the good work. You have_minutes to
go." [0145] 11. At the end of the test, mark the spot where the
patient stopped on the floor [0146] 12. If using a pulse oximeter,
measure the pulse rate and SpO.sub.2 and record [0147] 13. After
the test record the Borg dyspnea and fatigue levels [0148] 14. Ask,
"What, if anything, kept you from walking farther?" [0149] 15.
Calculate the distance walked and record [0150] American Thoracic
Society. ATS statement: Guidelines for the six-minute walk test. Am
J Respir Crit Care Med 2002; 166:111. [0151] Holland A E, Spruit M
A, Troosters T, et al. An official European Respiratory
Society/American Thoracic Society technical standard: field walking
tests in chronic respiratory disease. Eur Respir J 2014; 44:1428.
Pulmonary Function Tests (PFTs): PFTs are recorded at every visit
from baseline to Day 7 or 28 using spirometry, lung volume, and
diffusion capacity tests. Chest X-Ray Imaging: Chest x-ray images
are taken at baseline and Day 28. The standard chest examination
consists of a PA (posterioranterior) and lateral chest x-ray. The
films are read together. The PA exam is viewed as if the patient is
standing in front of you with their right side on your left. The
patient is facing towards the left on the lateral view. Hematology:
Hematology lab tests are collected at baseline and on Day 7. In the
case of an abnormal lab result, continue to collect and test those
samples to follow subject through resolution. The following
hematology labs are tested: white cell count, red blood cell count,
hemoglobin, hematocrit, mean cell volume (MCV), mean cell
hemoglobin (MCH), mean cell hemoglobin concentration (MCHC),
platelets, neutrophils, lymphocytes, monocytes, eosinophils, and
basophils. Serum Biochemistry: Biochemistry lab tests are collected
at baseline and on Day 7. In the case of an abnormal lab result,
continue to collect and test those samples to follow subject
through resolution. The following biochemistry lab tests are
tested: sodium, potassium, chloride, bicarbonate, urea, creatinine,
glucose, total calcium, phosphate, ferritin, high-sensitivity
C-reactive protein (hs-CRP), protein, albumin, globulins, total
bilirubin, alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST) and lactate dehydrogenase
(LDH). Concomitant Medications: Concomitant medications are
collected: prior (pre-hospitalization) concomitant medications,
in-patient concomitant medications. Adverse Events: Any documented
adverse event, which is any undesired medical occurrence in a
patient or clinical investigation patient receiving a
pharmaceutical product which does not necessarily have a causal
relationship with this treatment. These include but are not limited
to the following: cardiac injury, arrhythmia, septic shock, liver
dysfunction, acute kidney injury, and multi-organ failure.
Example 2. A Randomized, Double-Blinded, Placebo-Controlled Phase
II Study to Evaluate the Safety and Efficacy of Inhaled AMPION.RTM.
in Adults with Respiratory Distress Secondary Due to COVID-19
[0152] This is a phase II randomized controlled trial (RCT) to
evaluate inhaled AMPION.RTM. for adults with respiratory distress
due to COVID-19. AMPION.RTM. is an immunomodulatory therapy with
anti-inflammatory effects potentially treating COVID-19 patients
with respiratory complications who have a need for supplemental
oxygen and breathing assistance. AMPION.RTM. targets and reduces
the production of inflammatory cytokines induced by viruses,
including SARS-CoV-2, and mitigates the severity of the disease in
patients, such as those for whom ongoing inflammation is
responsible for COVID-19 disease severity and the progression to
respiratory distress.
[0153] The primary trial objective is to evaluate the effect of
AMPION.RTM. on all-cause mortality in adult participants with
respiratory distress due to COVID-19. The secondary trial
objectives are to evaluate the safety and efficacy of inhaled
AMPION.RTM. versus control in improving the clinical course and
outcomes of participants with respiratory distress due to
COVID-19.
[0154] The primary endpoint assesses the effect of AMPION.RTM.
compared to placebo on all-cause mortality. All-cause mortality is
measured as the percentage of participants with a successful
outcome (life) or unsuccessful outcome (death) by Day 28.
[0155] Secondary endpoints assess the effect of inhaled AMPION.RTM.
treatment compared to placebo on the clinical outcomes for
participants with respiratory distress COVID-19. The effect of
AMPION.RTM. compared to placebo on safety is assessed as incidence
of adverse events (AEs) and serious adverse events (SAEs) from
baseline at Day 5. The effect of AMPION.RTM. compared to placebo on
hospital stay is assessed as hospital length of stay (LOS) from
admission to discharge. The effect of AMPION.RTM. compared to
placebo on oxygen use is assessed as duration of oxygen use, blood
oxygen saturation, and oxygen flow rate from baseline through Day
5. The effect of AMPION.RTM. compared to placebo on progression to
respiratory failure is assessed as proportion of participants who
progress to respiratory failure (i.e., need for mechanical
ventilation, ECMO, non-invasive ventilation) by Day 28. The effect
of AMPION.RTM. compared to placebo on intensive care is assessed as
percentage of participants who require Intensive Care Unit (ICU)
admission by Day 28 and as ICU LOS from ICU admission to discharge.
The effect of AMPION.RTM. compared to placebo on clinical
improvement is assessed as change in ordinal scale from baseline
through Day 5 and as change in ordinal scale from baseline to
hospital discharge.
[0156] Exploratory endpoints assess the effect of inhaled
AMPION.RTM. treatment compared to placebo on the clinical outcomes
for participants with respiratory distress due to COVID-19. The
effect of AMPION.RTM. compared to placebo on clinical health is
assessed as change in NEWS2 score from baseline through Day 5 and
as change in NEWS2 score from baseline to hospital discharge. The
effect of AMPION.RTM. compared to placebo cytokine profile is
assessed as modulation of cytokine levels from baseline to Day
5.
Inclusion Criteria--Patients should Fulfill all the Following
Inclusion Criteria: 1. Male or female, .gtoreq.18 years old 2.
Diagnosed with COVID-19, as evaluated by laboratory diagnostic test
or diagnosis based on radiological clinical findings. 3.
Respiratory distress as evidenced by at least two of the
following:
[0157] Radiographic infiltrates by imaging (chest x-ray, CT scan,
etc.)
[0158] Recording of SpO.sub.2.ltoreq.90% or the patient is
requiring oxygen to maintain an SpO.sub.2.gtoreq.90%.
[0159] Requiring supplemental oxygen.
[0160] Diagnosis of mild, moderate, or severe ARDS by Berlin
definition.
4. Informed consent obtained from the patient or the patient's
legal representative.
Exclusion Criteria--Patients Fulfilling One or More of the
Following Criteria May not be Enrolled in the Study:
[0161] 1. As a result of the medical review and screening
investigation, the Principal Investigator considers the patient
unfit for the study and/or progression to death is imminent and
inevitable irrespective of the provision of treatments. 2. Patient
has severe chronic obstructive or restrictive pulmonary disease
(COPD) (as defined by prior pulmonary function tests), chronic
renal failure, or significant liver abnormality (e.g., cirrhosis,
transplant, etc.). 3. Patient has chronic conditions requiring
chemotherapy or immunosuppressive medication. 4. A history of
allergic reactions to human albumin (reaction to non-human albumin
such as egg albumin is not an exclusion criterion) or ingredients
in 5% human albumin (N-acetyltryptophan, sodium caprylate). 5.
Prolonged QT interval. 6. Patient has known pregnancy or is
currently breastfeeding. 7. Patient planning to become pregnant, or
father a child, during the treatment and follow-up period and/or is
not willing to remain abstinent or use contraception. 8.
Participation in another clinical trial (not including treatments
for COVID-19 as approved by the FDA through expanded access,
emergency, or compassionate use), or participation in a trial in
the last 30 days.
[0162] Participants are randomized 1:1 to one of two groups, active
(AMPION.RTM.) or control (placebo). Participants randomized to the
active arm (n=100) will receive a daily dose (32 mL/day) of
AMPION.RTM. inhaled via nebulizer delivered in four equally divided
doses of 8 mL, every 6 hours. Participants randomized to the
control arm (n=100) will receive a daily dose (32 mL/day) of
placebo inhaled via nebulizer delivered in four equally divided
doses of 8 mL, every 6 hours. Treatment is repeated for 5 days.
[0163] Nebulized study intervention (active or placebo) is
delivered using the AEROGEN.RTM. Solo Nebulizer System with the
AEROGEN.RTM. Solo Adaptor (FDA 510K K133360) manufactured by
AEROGEN.RTM. Limited, Galway, Ireland. The AEROGEN.RTM. Solo
Adaptor is a vibrating mesh nebulizer with a drug reservoir used in
a hospital setting for delivery of respiratory therapy, including
the hand-held AEROGEN.RTM. Ultra, NIV, and/or a mechanically
ventilated circuit.
[0164] All participants receive the SOC for COVID-19 in a hospital
setting as required based on disease severity, or as required for
the course of hospital stay as follows:
[0165] Oxygen administration to maintain oxygen saturation of 90%
or greater, including the use of supplemental oxygen, NIV, and
mechanical ventilation circuits.
[0166] Nursing physical that may include review of neurological;
pulmonary; cardiac; gastrointestinal; and urinary assessment at
least daily during treatment.
[0167] Vital monitoring (heart rate, blood pressure, temperature,
respiratory rate, SpO.sub.2) at least daily during treatment.
[0168] Telemetry monitoring to evaluate heart rhythm and rate.
[0169] Diet as tolerated to satisfy nutritional needs.
[0170] Treatments for COVID-19 symptoms including antibiotics,
cough suppressants/expectorants, anti-coagulants, fever
reducers/pain killers, anti-nausea drugs, and/or
bronchodilators.
[0171] Treatments for COVID-19 as approved by the FDA including
expanded access, emergency, or compassionate use (i.e., remdesivir,
dexamethasone, convalescent plasma).
[0172] Medications are recorded as concomitant medication,
tabulated, and compared among groups.
[0173] Primary efficacy is assessed by recording the effects of
AMPION.RTM. compared to placebo on mortality. Secondary endpoints
will evaluate safety and other clinical outcomes of AMPION.RTM.
compared to placebo on length of stay (LOS) in the hospital, oxygen
use (including SpO.sub.2 and flow rate), progression to respiratory
failure (i.e., need for mechanical ventilation, ECMO, non-invasive
ventilation), need for intensive care, ICU LOS, and ordinal scale
for clinical improvement (8-point scale). Exploratory endpoints
will evaluate safety and other clinical outcomes of AMPION.RTM.
compared to placebo National Early Warning Score (NEWS) 2 score for
the degree of illness of a patient) and modulation of cytokine
levels.
[0174] Safety is assessed by recording adverse events, vital signs,
blood oxygen saturation, and laboratory findings (biochemistry,
hematology) for the duration of treatment and for the length of
stay in the hospital (as applicable). Laboratory tests
(biochemistry, hematology) are performed at baseline and every
other day through treatment and through hospital stay unless an
abnormal value is observed. In the case of an abnormal lab result,
continue to collect and test those samples to follow subject
through resolution.
Description of Study Visits
Screening (-3 Days to Day 0)
[0175] Evaluate all inclusion and exclusion criteria to ensure that
patients meet all inclusion criteria and none of the exclusion
criteria.
[0176] Medical history, pre-existing conditions, and comorbidities.
Include the symptom onset date for COVID-19 symptoms and date of
COVID-19 test.
[0177] Diphenhydramine, hydroxychloroquine, and azithromycin all
prolong the cardiac QT interval, increasing risk of fatal cardiac
arrhythmia. Therefore, severely-ill subjects receiving multiple
drugs that prolong QT intervals are reviewed carefully by the P.I.
on a case-by-case adjudication for benefit-risk ratio and close
cardiovascular monitoring. Note, subjects who have baseline QT
prolongation are excluded from this study.
[0178] Obtain informed consent before the starting any study
specific procedures, including COVID testing.
Baseline (Day 0)
[0179] Confirm eligibility (review inclusion/exclusion
criteria).
[0180] Randomize patient to study arm.
[0181] Demographics (age, sex, race, height and weight)
[0182] Concomitant medications/therapies
[0183] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate.
[0184] SpO.sub.2 and supplementation oxygen mode/flow rate
[0185] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals
[0186] Hematology, biochemistry tests
[0187] Cytokine and chemokine assays
[0188] Ordinal scale and NEWS2 assessments
[0189] AEs
Treatment Period (Day 1 to Day 5)
[0190] Begin inhalation treatment of study intervention (active or
placebo) within 6 hours of randomization.
[0191] Concomitant medications/therapies
[0192] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate
[0193] SpO.sub.2 and supplementation oxygen mode/flow rate
[0194] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals--monitored as needed for patients who
have abnormal readings or events requiring measurements.
[0195] Hematology, biochemistry tests--these tests are performed at
baseline and every other day through treatment and through hospital
stay unless an abnormal value is observed. In the case of an
abnormal lab result, continue to collect and test those samples to
follow subject through resolution.
[0196] Cytokine and chemokine assays--these tests are performed at
baseline and at Day 5.
[0197] Ordinal scale and NEWS2 assessments
[0198] AEs
Hospitalization Period, as Applicable (Day 6 Through Hospital
Discharge)
[0199] Concomitant medications/therapies
[0200] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate
[0201] SpO.sub.2 and supplementation oxygen mode/flow rate
[0202] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals--monitored as needed for patients who
have abnormal readings or events requiring measurements.
[0203] Hematology, biochemistry tests--these tests are performed at
baseline and every other day through treatment and through hospital
stay unless an abnormal value is observed. In the case of an
abnormal lab result, continue to collect and test those samples to
follow subject through resolution.
[0204] Cytokine and chemokine assays--these tests are performed at
hospital discharge.
[0205] Ordinal scale and NEWS2 assessments
[0206] AEs
Post-Treatment Follow-Up (Days 28, 60)
[0207] Mortality
[0208] Concomitant medications/therapies
[0209] Hospital LOS
[0210] ICU LOS
[0211] Ordinal scale and NEWS2 assessments
[0212] AEs
Assessment Methods
[0213] Demographic Data: Demographic data are collected from
medical records: age, gender, race, height and weight,
comorbidities. Medical History: Medical history and pre-existing
conditions are collected from medical records. Concomitant
Medications: Concomitant medications are collected from the medical
records: prior (pre-hospitalization) concomitant medications,
in-patient concomitant medications. Mortality: All-cause mortality
is recorded at hospital discharge, Days 28 and 60, as applicable.
Cause of mortality is assessed and documented. All-cause mortality
is calculated for the primary endpoint as the percentage of
participants with a successful outcome (life) or unsuccessful
outcome (death). Length of Stay (LOS): Dates of hospitalization and
ICU admission as well as discharge dates are recorded at hospital
discharge, Days 28 and 60, as applicable. The hospital LOS and ICU
LOS are calculated as follows:
[0214] ICU admission: defined (in days) as the first study day when
ICU status is changed to "yes" minus baseline date+1
[0215] Hospital LOS: is defined (in days) as the date of hospital
discharge minus date of hospital admission+1
[0216] ICU LOS: defined (in days) as the date moved out of ICU
minus first study date when ICU admission changed to "yes"+1
Oxygen Use: Oxygen use measured as blood oxygen saturation
(SpO.sub.2) and oxygen flow rate (liters per minute, 1 pm) are
recorded at every visit from baseline to Day 5.
Intubation/Extubation: Date and time of intubation/extubation and
days on ventilator are recorded at hospital discharge, Days 28 and
60, as applicable. Proportion of participants who progress to
respiratory failure (i.e., need for mechanical ventilation, ECMO,
non-invasive ventilation, or high-flow nasal cannula oxygen) are
evaluated. Vital Signs: Vital signs are collected daily during the
treatment period and at follow-up visits from medical records as
follows: heart rate (or pulse rate), systolic BP, diastolic BP,
body temperature (.degree. F. in the US, .degree. C. out of the
US), respiratory rate. Hematology: Hematology lab tests are
collected from the medical records at baseline and every other day
through treatment and hospital stay (as applicable) unless an
abnormal value is observed. In the case of an abnormal lab result,
continue to collect and test those samples to follow subject
through resolution. The following hematology labs are tested: white
cell count, red blood cell count, hemoglobin, hematocrit, mean cell
volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin
concentration (MCHC), platelets, neutrophils, lymphocytes,
monocytes, eosinophils, and basophils. Serum Biochemistry:
Biochemistry lab tests are collected from the medical records at
baseline and every other day through treatment and hospital stay
(as applicable) unless an abnormal value is observed. In the case
of an abnormal lab result, continue to collect and test those
samples to follow subject through resolution. The following
biochemistry lab tests are tested: sodium, potassium, chloride,
bicarbonate, urea, creatinine, glucose, total calcium, phosphate,
ferritin, high-sensitivity C-reactive protein (hs-CRP), protein,
albumin, globulins, total bilirubin, alkaline phosphatase (ALP),
alanine aminotransferase (ALT), aspartate aminotransferase (AST)
and lactate dehydrogenase (LDH). Cytokine and Chemokine Assays:
Cytokine and chemokine assay lab test results are collected and
recorded before and after treatment (at baseline and again at Day 5
and at hospital discharge). A cytokine panel is tested to include,
but not limited to: Tumor Necrosis Factor alpha (TNF.alpha.),
interferon gamma (IFN.gamma.), Interleukin 1 beta (IL-1.beta.),
interleukins (IL-6, IL-8, IL-10, IL-12). Data is reported for
research purposes, and the sample is destroyed after data is
collected. Ordinal Scale for Clinical Improvement: The clinical
status is recorded at every visit from baseline to Day 60 using the
World Health Organization (WHO) "Ordinal Scale for Clinical
Improvement". This 8-point ordinal scale was created to be
responsive to the eligible patient population, intervention, and
course of illness of COVID-19. The following scores are
collected:
TABLE-US-00001 Score Descriptor 0 No clinical or virological
evidence of infection 1 No limitation of activities 2 Limitation of
activities 3 Hospitalized, no oxygen 4 Hospitalized, oxygen by mask
or nasal prongs 5 Hospitalized, non-invasive ventilation or
high-flow oxygen 6 Hospitalized, mechanical ventilation 7
Hospitalized, ventilation + additional organ support -- pressors,
RRT, ECMO 8 Death
NEWS2 Score for Determining the Degree of Illness: The National
Early Warning Score 2 (NEWS2) score, a well-known clinical risk
score, is recorded at every visit from baseline to Day 60 using the
vitals collected during the visit. The NEWS2 score is recommended
by the National Institute for Health and Care Excellence ("NICE")
for managing COVID-19 patients. Adverse Events: Any documented
adverse event, which is any undesired medical occurrence in a
patient or clinical investigation patient receiving a
pharmaceutical product which does not necessarily have a causal
relationship with this treatment. These include but are not limited
to the following: cardiac injury, arrhythmia, septic shock, liver
dysfunction, acute kidney injury, and multi-organ failure.
Results
[0217] 27 patients have been enrolled in the study. The mean age of
patients is 67 years, with 63% male and 93% white patients.
Dexamethasone was administered for nearly all subjects (n=23), and
REMDESIVIR.RTM. was used in 10 subjects. All patients have
completed their 5-day treatment window, with no serious safety
observations to date.
[0218] The study indicates positive clinical outcomes due to
AMPION.RTM. use in COVID-19 patients with respiratory distress. The
all-cause mortality in COVID-19 patients was lower in the
AMPION.RTM. treatment arm compared to control (7.7% AMPION.RTM.;
21.4% SOC; n=27). Following 5-day treatment, it was observed that
subjects who received AMPION.RTM. may require less oxygen than SOC
patients (average oxygen use at 5 liters per minute, LPM, for
AMPION.RTM.; 9 LPM for SOC) with a greater proportion of
AMPION.RTM.-treated subjects remaining stable, or decreasing the
amount of required oxygen, compared to SOC (86% of AMPION.RTM.; 75%
of SOC). Improvement on the WHO ordinal scale were observed in
AMPION.RTM. patients as early as Day 2 and continued to Day 5 with
86% vs 75% of patients remaining stable or demonstrating
improvement with AMPION.RTM. treatment compared to SOC,
respectively, by Day 5. In subjects who have been discharged from
the hospital (n=17), patients who received AMPION.RTM. required
less hospitalization time overall compared to SOC alone (6 days
with AMPION.RTM. treatment; 9 days with SOC).
Example 3. A Randomized, Double-Blinded, Placebo-Controlled Phase
I/II Study to Evaluate the Safety and Efficacy of Intravenous
AMPION.RTM. in Adult COVID-19 Patients Requiring Oxygen
Supplementation
[0219] There are primary endpoints for safety and efficacy. The
primary endpoint for safety is incidence and severity of AEs at Day
5. The primary efficacy endpoint is the effect of AMPION.RTM. on
all-cause mortality by Day 28.
[0220] Secondary efficacy endpoints assess the effect of IV
AMPION.RTM. compared to SOC on the clinical outcomes for
participants with COVID-19 who require supplemental oxygen. The
effect of AMPION.RTM. compared to placebo on hospital stay is
assessed as hospital length of stay (LOS) from admission to
discharge. The effect of AMPION.RTM. compared to placebo on oxygen
use is assessed as duration of oxygen use, blood oxygen saturation,
and oxygen flow rate from baseline through Day 5. The effect of
AMPION.RTM. compared to placebo on progression to respiratory
failure is assessed as proportion of participants who progress to
respiratory failure (i.e., need for mechanical ventilation, ECMO,
non-invasive ventilation) by Day 28. The effect of AMPION.RTM.
compared to placebo on intensive care is assessed as percentage of
participants who require Intensive Care Unit (ICU) admission by Day
28 and as ICU LOS from ICU admission to discharge. The effect of
AMPION.RTM. compared to placebo on clinical improvement is assessed
as change in ordinal scale from baseline through Day 5 and as
change in ordinal scale from baseline to hospital discharge. The
effect of AMPION.RTM. compared to placebo on clinical health is
assessed as change in NEWS2 score from baseline through Day 5 and
as change in NEWS2 score from baseline to hospital discharge. The
effect of AMPION.RTM. compared to placebo on oxygen use is assessed
as duration of oxygen use, blood oxygen saturation, and oxygen flow
rate from baseline through Day 5.
[0221] The participant population are those infected with
SARS-CoV-2 that have developed severe symptoms consistent with
COVID-19 and require supplemental oxygen to maintain blood oxygen
saturation levels. Treatment of COVID-19 depends on the stage and
severity of disease with a hyperinflammatory state observed in the
moderate to severe stages that are thought to lead to clinical
complications, so treatment with immunomodulators at this point in
the disease is more effective than anti-viral treatments.
Inclusion Criteria
[0222] Patients should fulfill all the following inclusion
criteria: 1. Male or female, .gtoreq.18 years old. 2. Diagnosed
with COVID-19, as evaluated by laboratory diagnostic test or
diagnosis based on radiological clinical findings. 3. Clinical
signs indicative of severe systemic illness with COVID-19, such as
respiratory rate 22 30 per minute, heart rate .gtoreq.125 per
minute, SpO.sub.2.ltoreq.93% on room air at sea level
(SpO.sub.2.ltoreq.90% at altitude) or PaO.sub.2/FiO.sub.2<300 4.
Patient is receiving supplemental oxygen to maintain a
SpO.sub.2.gtoreq.90%. 5. Informed consent obtained from the patient
or the patient's legal representative.
Exclusion Criteria
[0223] Patients fulfilling one or more of the following criteria
may not be enrolled in the study: 1. As a result of the medical
review and screening investigation, the Principal Investigator
considers the patient unfit for the study and/or progression to
death is imminent and inevitable irrespective of the provision of
treatments. 2. Patient has severe chronic obstructive or
restrictive pulmonary disease (COPD) (as defined by prior pulmonary
function tests), chronic renal failure, or significant liver
abnormality (e.g., cirrhosis, transplant, etc.). 3. Patient has
chronic conditions requiring chemotherapy or immunosuppressive
medication. 4. A history of allergic reactions to human albumin
(reaction to non-human albumin such as egg albumin is not an
exclusion criterion) or ingredients in 5% human albumin
(N-acetyltryptophan, sodium caprylate). 5. Prolonged QT interval.
6. Patient has known pregnancy or is currently breastfeeding. 7.
Patient planning to become pregnant, or father a child, during the
treatment and follow-up period and/or is not willing to remain
abstinent or use contraception. 8. Participation in another
clinical trial (not including treatments for COVID-19 as approved
by the FDA through expanded access, emergency, or compassionate
use), or participation in a trial in the last 30 days.
Study Plan
[0224] Participants randomized to the active arm (n=30) receive a
daily dose (250 mL/day) of IV AMPION.RTM. delivered in two equally
divided doses of 125 mL, every 12 hours. Participants randomized to
the control arm (n=30) receive a daily dose (250 mL/day) of IV
placebo delivered in two equally divided doses of 125 mL, every 12
hours. Treatment is repeated for 5 days.
[0225] Intravenous study intervention (active or placebo)
AMPION.RTM. are administered using an infusion pump through an
existing intravenous access (central line, PICC, peripheral, or
saline lock). AMPION.RTM. is administered as an intravenous
piggyback/secondary if the patient at the time of the
administration of AMPION.RTM. has an existing primary infusion. If
there are no intravenous fluids being administered at the time of
the AMPION.RTM. infusion, AMPION.RTM. treatment is infused as an
intermittent intravenous infusion. AMPION.RTM. is administered
undiluted at a flow rate of 100 cc/hour.
[0226] All participants receive the SOC for COVID-19 in a hospital
setting as required based on disease severity, or as required for
the course of hospital stay as follows:
[0227] Oxygen administration to maintain oxygen saturation of 90%
or greater.
[0228] Nursing physical that may include review of neurological;
pulmonary; cardiac; gastrointestinal; and urinary assessment at
least daily during treatment.
[0229] Vital monitoring (heart rate, blood pressure, temperature,
respiratory rate, SpO.sub.2) at least daily during treatment.
[0230] Telemetry monitoring to evaluate heart rhythm and rate.
[0231] Diet as tolerated to satisfy nutritional needs.
[0232] Treatments for COVID-19 symptoms including antibiotics,
cough suppressants/expectorants, anti-coagulants, fever
reducers/pain killers, anti-nausea drugs, and/or
bronchodilators.
[0233] Treatments for COVID-19 as approved by the FDA including
expanded access, emergency, or compassionate use (i.e., remdesivir,
dexamethasone, convalescent plasma).
[0234] Medications are recorded as concomitant medication,
tabulated, and compared among groups.
Safety is assessed by recording adverse events, vital signs, blood
oxygen saturation, and laboratory findings (biochemistry,
hematology) for the duration of treatment and for the length of
stay in the hospital (as applicable). Laboratory tests
(biochemistry, hematology) are performed at baseline and every
other day through treatment and through hospital stay unless an
abnormal value is observed. In the case of an abnormal lab result,
continue to collect and test those samples to follow subject
through resolution.
[0235] Efficacy is assessed by recording the effects of IV
AMPION.RTM. compared to placebo on the clinical outcomes for
participants with COVID-19 using the following: mortality, oxygen
use (including SpO.sub.2 and flow rate), need for intensive care,
length of stay (LOS) in the hospital, LOS in the ICU, ordinal scale
for clinical improvement (8-point scale), National Early Warning
Score (NEWS) 2 score for the degree of illness of a patient, and
modulation of cytokine levels.
Description of Study Visits
Screening (-3 Days to Day 0)
[0236] Evaluate all inclusion and exclusion criteria to ensure that
patients meet all inclusion criteria and none of the exclusion
criteria.
[0237] Medical history, pre-existing conditions, and comorbidities.
Include the symptom onset date for COVID-19 symptoms and date of
COVID-19 test.
[0238] Diphenhydramine, hydroxychloroquine, and azithromycin all
prolong the cardiac QT interval, increasing risk of fatal cardiac
arrhythmia. Therefore, severely-ill subjects receiving multiple
drugs that prolong QT intervals are reviewed carefully by the P.I.
on a case-by-case adjudication for benefit-risk ratio and close
cardiovascular monitoring. Note, subjects who have baseline QT
prolongation are excluded from this study.
[0239] Obtain informed consent before the starting any study
specific procedures, including COVID testing.
Baseline (Day 0)
[0240] Confirm eligibility (review inclusion/exclusion
criteria).
[0241] Randomize patient to study arm.
[0242] Demographics (age, sex, race, height and weight)
[0243] Concomitant medications/therapies
[0244] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate
[0245] SpO.sub.2 and supplementation oxygen mode/flow rate
[0246] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals
[0247] Hematology, biochemistry tests
[0248] Cytokine and chemokine assays
[0249] Ordinal scale and NEWS2 assessments
[0250] AEs
Treatment Period (Day 1 to Day 5)
[0251] Administer AMPION.RTM. or placebo control as a daily IV
infusion. Begin treatment within 6 hours of randomization.
[0252] Concomitant medications/therapies
[0253] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate--vital signs are collected shortly
after (within 30 minutes) treatment.
[0254] SpO.sub.2 and supplementation oxygen mode/flow rate
[0255] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals--monitored as needed for patients who
have abnormal readings or events requiring measurements.
[0256] Hematology, biochemistry tests--these tests are performed at
baseline and every other day through treatment and through hospital
stay unless an abnormal value is observed. In the case of an
abnormal lab result, continue to collect and test those samples to
follow subject through resolution.
[0257] Cytokine and chemokine assays--these tests are performed at
baseline and at Day 5.
[0258] Ordinal and NEWS2 assessments
[0259] AEs
Hospitalization Period, as Applicable (Day 6 Through Hospital
Discharge)
[0260] Concomitant medications/therapies
[0261] Vital signs: heart rate, systolic and diastolic BP, body
temperature, respiratory rate
[0262] SpO.sub.2 and supplementation oxygen mode/flow rate
[0263] ECG monitoring (telemetry) or 12-lead ECG: record aberrant
changes in waves/intervals--monitored as needed for patients who
have abnormal readings or events requiring measurements.
[0264] Hematology, biochemistry tests--these tests are performed at
baseline and every other day through treatment and through hospital
stay unless an abnormal value is observed. In the case of an
abnormal lab result, continue to collect and test those samples to
follow subject through resolution.
[0265] Cytokine and chemokine assays--these tests are performed at
hospital discharge.
[0266] Ordinal scale and NEWS2 assessments
[0267] AEs
Post-Treatment Follow-Up (Days 28, 60)
[0268] Mortality
[0269] Concomitant medications/therapies
[0270] Hospital LOS
[0271] ICU LOS
[0272] Ordinal scale and NEWS2 assessments
[0273] AEs
Assessment Methods
[0274] Demographic Data: Demographic data is collected from medical
records: age, gender, race, height and weight, comorbidities.
Medical History: Medical history and pre-existing conditions are
collected from medical records. Concomitant Medications:
Concomitant medications are collected from the medical records:
prior (pre-hospitalization) concomitant medications, in-patient
concomitant medications. Mortality: All-cause mortality is recorded
at hospital discharge, Days 28 and 60, as applicable. Cause of
mortality is assessed and documented. All-cause mortality is
calculated for the primary endpoint as the percentage of
participants with a successful outcome (life) or unsuccessful
outcome (death). Length of Stay (LOS): Dates of hospitalization and
ICU admission as well as discharge dates are recorded at hospital
discharge, Days 28 and 60, as applicable. The hospital LOS and ICU
LOS are calculated as follows:
[0275] ICU admission: defined (in days) as the first study day when
ICU status is changed to "yes" minus baseline date+1
[0276] Hospital LOS: is defined (in days) as the date of hospital
discharge minus date of hospital admission+1
[0277] ICU LOS: defined (in days) as the date moved out of ICU
minus first study date when ICU admission changed to "yes"+1
Oxygen Use: Oxygen use measured as blood oxygen saturation
(SpO.sub.2) and oxygen flow rate (liters per minute, 1 pm) are
recorded at every visit from baseline to Day 5.
Intubation/Extubation: Date and time of intubation/extubation and
days on ventilator are recorded at hospital discharge, Days 28 and
60, as applicable. Proportion of participants who progress to
respiratory failure (i.e., need for mechanical ventilation, ECMO,
non-invasive ventilation, or high-flow nasal cannula oxygen) is
evaluated. Vital Signs: Vital signs are collected daily during the
treatment period and at follow-up visits from medical records as
follows: heart rate (or pulse rate), systolic BP, diastolic BP,
body temperature (.degree. F. in the US, .degree. C. out of the
US), respiratory rate. Vital signs are collected shortly after
(within 30 minutes) treatment. Hematology: Hematology lab tests are
collected from the medical records at baseline and every other day
through treatment and hospital stay (as applicable) unless an
abnormal value is observed. In the case of an abnormal lab result,
continue to collect and test those samples to follow subject
through resolution. The following hematology labs are tested: white
cell count, red blood cell count, hemoglobin, hematocrit, mean cell
volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin
concentration (MCHC), platelets, neutrophils, lymphocytes,
monocytes, eosinophils, and basophils. Serum Biochemistry:
Biochemistry lab tests are collected from the medical records at
baseline and every other day through treatment and hospital stay
(as applicable) unless an abnormal value is observed. In the case
of an abnormal lab result, continue to collect and test those
samples to follow subject through resolution. The following
biochemistry lab tests are tested: sodium, potassium, chloride,
bicarbonate, urea, creatinine, glucose, total calcium, phosphate,
ferritin, high-sensitivity C-reactive protein (hs-CRP), protein,
albumin, globulins, total bilirubin, alkaline phosphatase (ALP),
alanine aminotransferase (ALT), aspartate aminotransferase (AST)
and lactate dehydrogenase (LDH). Cytokine and Chemokine Assays:
Cytokine and chemokine assay lab test results are collected and
recorded before and after treatment (at baseline and again at Day 5
and at hospital discharge). A cytokine panel is tested to include,
but not limited to: Tumor Necrosis Factor alpha (TNF.alpha.),
interferon gamma (IFN.gamma.), Interleukin 1 beta (IL-1.beta.),
interleukins (IL-6, IL-8, IL-10, IL-12). Data is reported for
research purposes, and the sample is destroyed after data is
collected. Ordinal Scale for Clinical Improvement: The clinical
status is recorded at every visit from baseline to Day 60 using the
World Health Organization (WHO) "Ordinal Scale for Clinical
Improvement". See Example 2 at Ordinal Scale for Clinical
Improvement for further information on the ordinal scale. NEWS2
Score for Determining the Degree of Illness: The National Early
Warning Score 2 (NEWS2) score, a well-known clinical risk score, is
recorded at every visit from baseline to Day 60 using the vitals
collected during the visit. The NEWS2 score is recommended by the
National Institute for Health and Care Excellence ("NICE") for
managing COVID-19 patients. Adverse Events: Any documented adverse
event, which includes any undesired medical occurrence in a patient
or clinical investigation patient receiving a pharmaceutical
product which does not necessarily have a causal relationship with
this treatment. These include but are not limited to the following:
cardiac injury, arrhythmia, septic shock, liver dysfunction, acute
kidney injury, and multi-organ failure.
Results
[0278] The incidence of adverse events (AEs) at day 90 was
determined, which was successfully achieved with no
treatment-related serious adverse events reported, and no
difference in the incidence or severity of AEs between the
AMPION.RTM. treatment and standard of care (SOC) at Day 5 and at
the 90-day follow-up.
[0279] Ten hospitalized patients with lab-confirmed COVID-19
infection who were receiving supplemental oxygen were randomized
1:1 to AMPION.RTM. plus SOC (active) or SOC alone (control). The
standard of care (SOC) included respiratory support,
corticosteroids, and anti-viral therapies such as Remdesivir. The
majority of patients were male (70%), white (90%), and had a median
age of 74 years.
[0280] Nearly all (90%) patients received dexamethasone: 80%
AMPION.RTM. and 100% SOC. Remdesivir was not required for
AMPION.RTM. treated patients (0% AMPION.RTM. vs. 80% SOC). A
greater proportion of patients treated with AMPION.RTM. had
clinical improvement from baseline on the WHO ordinal scale on each
day on treatment; Day 5 improvement was 75% AMPION.RTM. vs. 50%
SOC. Likewise, a greater proportion of patients treated with
AMPION.RTM. had improvements in oxygen requirements from baseline
each day on treatment compared to SOC (Day 5 improvement: 75%
AMPION.RTM. vs. 50% SOC).
Example 4. Calculation of AMPION.RTM. Dose
[0281] This example describes a method to calculate the dose of
AMPION.RTM. for intravenous administration. This method can be
applied to other administration routes.
[0282] Human serum albumin, including 5% human serum albumin (HSA),
has been administered safely via IV for many years at volumes
exceeding 500 cc in a day (5% HSA prescribing information). A
comparison of the active components in AMPION.RTM. against those in
the starting material HSA demonstrates that the proposed daily dose
(250 cc) of AMPION.RTM. can be safely administered via IV.
[0283] A daily dose of 250 cc is based on AMPION.RTM.'s in vitro
biological activity and the amount of AMPION.RTM. required to
achieve its in vitro anti-inflammatory effect (FIG. 1). The
biological activity of AMPION.RTM. was measured using a bioassay
which tests the release of pro-inflammatory cytokine (TNF.alpha.)
in activated immune cells. In the bioassay, human peripheral blood
mononuclear cells (PBMC) are stimulated to release TNF.alpha.. The
cells are treated with either AMPION.RTM. or saline, and
AMPION.RTM. activity is reported as inhibition (%) of TNF.alpha. in
cells treated with AMPION.RTM. compared to the cells treated with
saline. In the bioassay, the treatment effect is achieved by adding
50 .mu.L of AMPION.RTM. to 100,000 cells. A dose-dependent effect
is observed.
[0284] To model efficacy of an in vivo clinical dose of
AMPION.RTM., the number blood monocytes in the bloodstream provides
a means of estimating the concentration of immune cells in
circulation. Based on the average monocyte density in an adult
human bloodstream, and the ratio of cells used in the AMPION.RTM.
TNF.alpha. bioassay, a therapeutic dose range of AMPION.RTM.
(250-1187 cc) would be required to achieve the anti-inflammatory
effect.
[0285] While various embodiments of the present disclosure have
been described in detail, it is apparent that modifications and
adaptations of those embodiments will occur to those skilled in the
art. It is to be expressly understood, however, that such
modifications and adaptations are within the scope of the present
disclosure, as set forth in the following exemplary claims.
* * * * *