FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
TITLE OF THE INVENTION
“Novel composition for the treatment of COVID-19”
APPLICANT
Meyer Organics Pvt. Ltd.
of A-303, Road No. 32, Wagle Estate, Thane, Mumbai 400604, India; Indian
The following specification particularly describes the invention and the manner in which it is to be performed

DESCRIPTION OF INVENTION
Title: Novel composition for the treatment of COVID-19
TECHNICAL FIELD
This invention concerns the development of a synergistic composition in a solid or liquid formulation for the treatment of the novel Coronavirus disease (COVID-19). The proposed formula includes both drug and nutrient ingredients to induce rapid treatment of typical COVID-19 symptoms, including fever, dry cough and respiratory distress, as well as naturally boosting the innate and adaptive immune system.
BACKGROUND ART
Coronavirus comprises of a large family of viruses that are common in humans as well animals, including camels, cattle, cats, and bats. There are several different strains of coronavirus, with SARS-CoV-2 being the novel coronavirus that causes coronavirus disease 2019 (COVID-19). Towards December 2019, this novel Coronavirus was identified as a cause of upper and lower respiratory tract infections in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in an epidemic throughout China, before spreading to other parts of the world before the WHO declared a global pandemic.
Transmission of COVID-19 is mainly reported via droplet transmission. The other possible modes of transmission involve touching surfaces contaminated by the virus and then touching the mouth, nose, or possibly the eyes.
Clinical features:
a. Incubation period: It is not exactly known but presumed to be between 2 to 14 days
after exposure to the virus.
b. Spectrum of illness severity:
Most infections are asymptomatic or self-limiting, though the disease can be serious, which is often fatal. COVID-19 tends to cause more severe illness in the elderly

population or in patients with comorbidities (such as heart disease, asthma or diabetes). Severe illness includes hypoxemia, respiratory failure, and multi-organ dysfunction syndrome. c. Age affected: mostly middle aged (>50 years) and elderly populations. Symptomatic infection in children and infants is uncommon.
Clinical Presentation: Common clinical features at the onset of illness are fever, fatigue, dry cough, myalgias and dyspnea. Pneumonia appears to be the most common symptom and severely affects the population. Acute respiratory distress syndrome is another common feature among the infected. Other symptoms include headache, sore throat, rhinorrhea and gastrointestinal symptoms.
About 80% of confirmed COVID-19 cases suffer from only mild to moderate disease and nearly 13% have severe disease (dyspnea, respiratory frequency ≥30/minute, blood oxygen saturation≤93%). Critical illness (respiratory failure, septic shock, and/or multiple organ dysfunction/failure) is noted in only less than 6% of cases.
COVID-19 affects different people in different ways. Most infected people will develop mild to moderate illness and recover without hospitalization.
Most common symptoms:
. fever
. cough
. tiredness
. loss of taste or smell.
Less common symptoms:
. sore throat
. headache
. aches and pains

. diarrhoea
. a rash on skin, or discolouration of fingers or toes
. red or irritated eyes.
Serious symptoms:
. difficulty breathing or shortness of breath . loss of speech or mobility, or confusion . chest pain.
Seek immediate medical attention if you have serious symptoms. Always call before visiting your doctor or health facility.
People with mild symptoms who are otherwise healthy should manage their symptoms at home.
On average it takes 5-6 days from when someone is infected with the virus for symptoms to show, however it can take up to 14 days.
Preventive measures:
Use of personal protective equipment including masks, hand hygiene practices, social distancing and isolation, case detection and contact tracing have been used as ways to reduce transmission. To date, no specific antiviral treatment or vaccine has proven effective; hence, infected patients primarily rely on the limited available symptomatic treatment and supportive care.
COVID-19 infected patients are categorized as follows:
1. Asymptomatic but positive

2. Symptomatic, URTI without co-morbidity
3. Symptomatic, URTI with co-morbidity
4. Pneumonia (LRTI) without respiratory failure
5. Pneumonia (LRTI) with respiratory failure
6. Pneumonia (LRTI) with respiratory failure multi organ dysfunction syndrome
The current therapies used in COVID-19
Current treatment includes a combination of drugs including antiviral, antimalarial (Hydroxychloroquine) and antibiotics (Azithromycin). The dose and combination of these medications depends on the severity and class of patient infected. An observational study found no clinical benefit associated with hydroxychloroquine leading the WHO to suspend all hydroxychloroquine studies.
a. Antiviral therapy- No anti-viral therapy has been proven to work for COVID-19 in
humans. Multiple RCTs are ongoing (Remdesivir, Lopinavir, Ritonavir, Ribavirin,
Oseltamivir).
b. ACE inhibitors- (ACEi) / angiotensin receptor blockers (ARBs) are under trial since
the SARS-CoV-2 virus binds to the ACE2 receptor for cellular entry.
c. Interferons- SARS CoV2 attenuates the interferon (IFN) response of the innate
immune system but has not yet shown in vitro beneficial effects.
d. Antimalarial (chloroquine/ hydroxychloroquine) - hampers the low pH dependant
steps of viral replication. Proposed to be used for prophylaxis, however, lacks
evidence.
e. Use of ILK-1 and IL-6 inhibitors to reduce cytokine storm in COVID-19.
f. Antibacterial agents initiated to treat secondary bacterial pneumonia.
g. Research focusing on therapies involving plasma collected from recovered patients.
There is therefore an acute need for effective symptomatic therapy combined with a natural
boost to the immune system.

Figure 2: Percent reduction in serum Ferritin levels within groups Figure 3: Percent reduction in serum CRP levels within groups
DISCLOSURE OF INVENTION
The object of the present invention is to develop a synergistic novel composition for the treatment of COVID-19 to induce rapid treatment across an array of typical COVID-19 symptoms and to naturally assist the body fight the specific SARS-CoV-2 infection.
The following form the key components of the invention, but are not to be construed as limiting the invention in scope or spirit, as possible modifications will be apparent from the disclosure to those skilled in this art.
Aspirin - This is not generally used or recommended for the treatment of COVID-19, despite its anti-viral, anticoagulant and anti-inflammatory effects. Aspirin has an inhibitory effect on platelet aggregation and has been shown to alter the profile of proteins in platelets involved in directing innate immune response to the site of injury and could thereby reduce lung injury.
Aspirin, has a well-known capacity to inhibit NF-kB. It efficiently blocks influenza virus replication in vitro and in vivo in a mechanism involving impaired expression of proapoptotic factors, subsequent inhibition of caspase activation, as well as blockage of caspase-mediated nuclear export of viral ribonucleoproteins. It showed no toxic side-effects or the tendency to induce resistant virus variants, hence may be suitable as an anti-influenza agent. (Cellular Microbiology (2007) 9(7), 1683–1694.)
Aspirin was found to be highly effective against influenza A H1N1 virus. The antiviral activity against further respiratory RNA viruses was less distinct. (Influenza Other Respir Viruses. 2017 Jan; 11(1): 85–92.)

Studies have shown that the nonspecific COX-2 inhibitor, aspirin, can reduce the yield of HCMV in cultures of smooth muscle cells by a factor of 2-3. Experimental studies have shown that the COX-2 inhibitors are acting by blocking the production of PGE2. (PNAS March 19, 2002 99 (6) 3932-3937.)
Acetylsalicylic acid and indomethacin dose-dependently exert stimulatory effects on the production of pro-inflammatory cytokines in whole blood. Aspirin shows dose-dependent immunomodulating effects on pro-inflammatory cytokine production. (Scandinavian Journal of Immunology, 60(4), 412-420.)
Aspirin has immunoregulatory potential in relevance to immune tolerance. It also displays some intriguing traits to modulate the innate and adaptive immune responses. (International immunopharmacology 12(1):10-20.)
Aspirin is well known to function as a blood thinning agent through inhibition of the enzyme Cox-1, which produces thromboxane A-2, necessary for platelet aggregation. Images of lung function in Covid-19 patients have found a lack of blood flow indicative of clotting within the small blood vessels in the lung. The Coronavirus spike protein binds to the ACE2 receptor and this binding complex may form a site for thrombosis. This specific intravascular clotting mechanism may account for the common clinical feature observed in Covid-19 patients of hypoxia, or very low oxygen, despite a lack of any vital warning signs of breathlessness.
Aspirin inhibits COX-2 mediated production of prostaglandins but switches on COX-2’s ability to produce novel protective lipid mediators. COX-2 inhibitors can abrogate the virus-mediated induction of prostaglandin E2 accumulation. (Proceedings of the National Academy of Sciences, 99(6), 3932-3937.)
Phenylephrine - This is a selective α 1-adrenergic receptor agonist. It is a nasal decongestant which has been found to reduce nasal airway resistance. (CMAJ. 2014 Feb 18; 186(3): 190-199.)

It has pulmonary and systemic vasoconstrictor effects and is commonly used in intensive care. (Anesthesiology 7 1997, Vol.87, 18-25.)
Promethazine - is a derivative of phenothiazine and an antihistaminic used in treating symptoms of asthma, pneumonia, or other lower respiratory tract infections. (Biomed Res Int. 2013; 2013: 151509.) Anti-histamines block airway inflammation and bronchoconstriction caused by histamine release from mast cells. Mast cell activation and Histamine release may contribute to the inflammation associated with COVID-19 infection. Patients with COVID-19 have systemic elevation of pro-inflammatory cytokines IL-6 and TNF-α. The over activation of mast cells and release of cytokines might also have a role in the development of pulmonary fibrosis in COVID-19 patients. Promethazine may also act in COVID-19 patients as a cough suppressant, acting on part of the brain to reduce the need to cough.
Niacinamide - Vitamin B3 can be administered in two main supplemental forms; Nicotinamide (also known as Niacinamide) or niacin (or nicotinic acid). Both forms are required to maintain healthy cells but at high doses, nicotinamide and niacin can have different effects. An immunomodulatory role for nicotinamide in a wide variety of experimental systems has been reported, including modulation of cytokine action. As nicotinamide is recognised for its lung protective properties it has been recommended in COVID patients as soon as coughing begins (Shi, Y., Wang, Y., Shao, C. et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 27, 1451-1454 (2020)). Nicotinamide is emerging as a therapeutic agent with activity against both M. tuberculosis and HIV. (Clinical Infectious Diseases, Volume 36, Issue 4, 15 February 2003, Pages 453-460.) Niacin may play a role in T-cell immune activation as it may control the excess tryptophan oxidation, correcting tryptophan depletion, and improve CD4 recovery. The Pharmacokinetics of nicotinamide and its effect on blood pressure, pulse and body temperature in normal human volunteers has been studied. (Radiotherapy and Oncology, Volume 25, Issue 1, September 1992, Pages 37-42.)

Vitamin D - The role of vitamin D in immunomodulation has a significant impact on immune
function. A causal relationship exists between vitamin D function and innate and adaptive
immunity to infections. The mechanisms underlying vitamin D immune actions could be
attributed to a paracrine feedback loop that reduces inflammation as well as influencing the
differentiation fate of activated CD4 T cells, or the enhancement of suppressor T-cell
function; (Current Opinion in Otolaryngology & Head and Neck Surgery, 19(3), 224–228).
Vitamin D receptor (VDR) is expressed by the majority of the immune cells, including B and
T lymphocytes, monocytes, macrophages, and dendritic cells. Vitamin D and VDR signalling
together have a suppressive role on autoimmunity and an anti-inflammatory effect,
promoting dendritic c// /ell and regulatory T-cell differentiation and reducing T
helper Th 17 cell response and inflammatory cytokines secretion. (Nutrients. 2018 Nov; 10(11): 1656.) Vitamin D is a potent immune modifying micronutrient and if vitamin D status is sufficient, it could benefit vulnerable adults, in particular those 70+ years and older who are ‘cocooning’ during the COVID-19 outbreak. (TILDA study, April 2020.) Evidence suggests COVID-19 patients with high vitamin D levels are more likely to survive the disease. Correlation has been found between countries reporting low vitamin D levels with highest mortality and COVID-19 infection rates. Vitamin D may reduce COVID-19 severity by suppressing ‘cytokine storm’ in patients. This serious overreaction of the body’s immune system occurs when excessive or uncontrolled levels of cytokines are released, which then activate more immune cells, resulting in hyperinflammation, severe lung damage, acute respiratory distress syndrome (ARDS). Vitamin D therefore helps boost the innate immune response in COVID-19 but also suppress overreaction when necessary.
Vitamin C - Because Vitamin C contributes to immune defence by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C promotes the oxidant scavenging activity potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. Supplementation with vitamin C appears to be able to both prevent and treat respiratory and

systemic infections. (Nutrients. 2017 Nov 3;9(11). pii: E1211.) Vitamin C shows in vivo anti¬viral immune responses at the early time of infection, especially against influenza virus, through increased production of IFN-α/β. (Immune Netw. 2013 Apr; 13(2): 70-74.)
Zinc - a trace mineral that is found in cells throughout the body. Various immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired with zinc depletion, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation. (The Journal of Nutrition, Volume 133, Issue 5, May 2003, Pages 1452S-1456S.)
Zinc supplementation reduced the number of days of acute lower respiratory infection in Thai children. (Pediatr Rep. 2019 May 23; 11(2): 7954.)
Iodine - is an essential mineral required in trace amounts to make thyroid hormones which control metabolism. It is required for the function of all organ systems. Thyroid hormones directly affect multiple branches of the immune system. Studies have indicated complex networks operating between human immune cells and thyroid-related molecules, through which iodine may play a fundamental role in regulating the function of immune cells.
Selenium - an antioxidant and its status may affect the function of cells of both adaptive and innate immunity. Supranutritional selenium promotes proliferation and favours differentiation of naive CD4-positive T lymphocytes toward T helper 1 cells, thus supporting the acute cellular immune response. Its supplementation is beneficial in diseases; most notably with respect to HIV and influenza A virus (IAV) infections. (Adv Nutr. 2015 Jan; 6(1): 73-82.)
To summarize,

Aspirin may have lung-protective effects and reduce the need for mechanical ventilation, ICU
admission, and in-hospital mortality in hospitalized COVID-19 patients.( Anesthesia &
Analgesia: April 2021 - Volume 132 - Issue 4 - p 930-941)
There is growing evidence that thrombotic and inflammatory pathways contribute to the
severity of COVID-19. Common medications such as aspirin, that mitigate these pathways,
may decrease COVID-19 mortality. (PLoS ONE 16(2): e0246825)
Acetylsalicylic acid (ASA) has both anti-inflammatory and antithrombotic effects. In addition,
a significant ASA-mediated antiviral activity against DNA and RNA viruses, including
different human coronaviruses, has been documented. The use of ASA in patients with
different types of infections has been associated with reduced thrombo-inflammation and
lower rates of clinical complications and in-hospital mortality. (Drugs. 2020; 80(14): 1383-
1396.)
Promethazine have already shown to present antiviral activity, including against MERS-cov
and SARS-COV-1. (Bioorganic Chemistry Volume 106, January 2021, 104488)
PMZ presented a moderate MERS-cov S-protein mediated cell-cell fusion inhibiting activity,
with EC50 values of about 17 and 15 μm, respectively. (Bioorganic Chemistry Volume
106, January 2021, 104488)
Promethazine have shown in vitro activity against MERS-cov and SARS-cov and may have
value as candidates for repurposing for coronaviral infections.
Several other neurotransmitter inhibitors including promethazine were active against
MERS-cov and SARS-cov in cell culture. (Drugs. 2017; 77(18): 1935-1966.)
In addition to other classes of medications for example, antihistamines such as promethazine
have high efficacy in improving therapeutic outcomes in COVID-19 patients. (European
Journal of Inflammation 2021; Volume 19: 1-22)
Key dietary components such as vitamins C, D, zinc and selenium have well-established
immunomodulatory effects, with benefits in infectious disease. Some of these nutrients have
also been shown to have a potential role in the management of COVID-19. (Maturitas. 2021
Jan; 143: 1-9.)
Vitamins like C & D highlighted potentially beneficial roles in the fight against COVID-19 via
antioxidant effects, immunomodulation, enhancing natural barriers, and local paracrine

signaling. Level 1 and 2 evidence supports the use of vitamin C, and vitamin D in COVID-like respiratory diseases, ARDS, and sepsis. (Nutrients. 2020 Sep; 12(9): 2550.)
Abnormities in urinary levels of the trace metals were tightly associated with the severe illness and fatal outcome of COVID-19. (Environ Res. 2021 Mar; 194: 110670.)
The object of the present invention is to develop a composition for the management of Coronavirus disease (COVID-19) that overcomes the disadvantages of conventional treatment, especially in a non-hospital setting.
It has been widely recommended that paracetamol is routinely used in COVID-19, despite the side effects associated with paracetamol. However, in an unpublished clinical case study of COVID-19 (Data on file, London, April 2020) (severe symptoms but not hospitalised), including on average 9-12-days of persistent elevated temperature remaining consistently above 39 degrees centigrade, treatment with paracetamol alone was switched to the present inventive combination of Aspirin 300mg per day, Promethazine 15mg per day, Niacinamide 160mg (ten times the European NRV value), each in line with the invention. Clinical observations were made following this change in treatment administration.
A measured improvement in symptoms was observed within 12 hours of the intervention, including a case of reduction in body temperature to normal levels within 6 hours.
This rapid reduction in symptoms is not found and has never been reported with Aspirin alone, or with Niacinamide alone, or Promethazine alone, nor is this combination obvious.
It is believed that this is the first reported case study of such a finding using a combination of specific doses of Aspirin, Promethazine and Niacinamide.
The product which is the subject of the invention provides a better alternative to conventional treatment by specific focus on:
- Rapid immediate treatment of fever or hyperpyrexia without side effects.

- Treatment of dry cough associated with COVID-19.
- Blockage of influenza virus replication through the mechanism of COX-2 inhibition.
- Naturally boosting both the innate and adaptive immune system.
- Targeting the novel respiratory aspects of the disease and endothelial vascular thrombosis, which differentiates COVID-19 from influenza conditions and pneumonia
- Preventing the hypoxia without breathlessness that is commonly associated with COVID-19 by reducing thrombosis within blood vessels in the lung.
- Modulation of cytokine action through multiple mechanisms.
- Reduce inflammatory cytokine storm and vascular thrombosis in sites across the body other than the lung, thereby reducing the risk of heart attack, stroke and other complications associated with COVID-19.
Disclosure of the ideal version of the invention is as follows:
Aspirin - 300mg
Phenylephrine - 20mg
Promethazine - 15mg
Vitamin D - 4,000 IU
Vitamin C - 1.5g
Niacinamide -160mg
Iodine – 200mcg
Zinc - 30mg (elemental)
Selenium - 165mcg (elemental)
In an acceptable size of solid dose form, this gives the following formulation for a three times daily capsule or tablet:
Aspirin- 100mg Phenylephrine- 6.67mg Promethazine- 5mg Vitamin D - 1,333.33 IU

Vitamin C- 0.5g
Niacinamide -53.33
Iodine- 66.67mcg
Zinc - 10mg (elemental)
Selenium- 55mcg (elemental)
A total of three tablets or capsules may be taken every day by the patient for 1-6 weeks until a beneficial improvement, partial or complete recovery is achieved.
The following examples are some of the possible alternative forms of the invention. These examples are not to be construed as limiting the invention in scope or spirit, as possible modifications to the invention will be apparent from the disclosure to those skilled in this art.
Example 1:
Aspirin- 500mg
Phenylephrine- 20mg
Promethazine- 25mg
Vitamin D- 10,000 IU
Vitamin C- 4g
Niacinamide- 500mg
Iodine – 250mcg
Zinc- 75mg (elemental)
Selenium- 200mcg (elemental)
Example 2: Aspirin- 500mg Phenylephrine- 10mg Promethazine- 25mg Vitamin D- 4000 IU Vitamin C- 2g

Niacinamide- 160mg
Iodine – 250mcg
Zinc- 40mg (elemental)
Selenium- 100mg (elemental)
Example 3:
Aspirin- 500mg
Phenylephrine- 20mg
Promethazine- 20mg
Vitamin D- 4000 IU
Vitamin C- 2g
Niacinamide- 160mg
Iodine – 200mcg
Zinc - 40mg (elemental)
Selenium - 100mg (elemental)
Example 4:
Aspirin- 500mg
Phenylephrine- 20mg
Promethazine- 20mg
Vitamin D- 4000 IU
Vitamin C- 2g
Niacinamide - 160mg
Iodine – 200mcg
Zinc- 40mg (elemental)
Selenium - 100mg (elemental)
Example 5: Aspirin- 325mg Phenylephrine- 20mg Promethazine- 15mg

Vitamin D- 10,000 IU
Vitamin C- 4g
Niacinamide-160mg
Iodine – 200mcg
Zinc- 75mg (elemental)
Selenium- 200mcg (elemental)
Example 6:
Aspirin- 300mg
Phenylephrine- 20mg
Promethazine- 15mg
Vitamin D- 3000 IU
Vitamin C- 2g
Niacinamide- 64mg
Iodine – 150mcg
Zinc- 37mg (elemental)
Selenium- 100mg (elemental)
Example 7:
Aspirin- 300mg
Phenylephrine- 10mg
Promethazine- 12mg
Vitamin D- 3000 IU
Vitamin C- 4g
Niacinamide-64mg
Iodine – 150mcg
Zinc- 75mg (elemental)
Selenium- 200mcg (elemental)
Example 8: Aspirin- 100mg

Phenylephrine- 10mg
Promethazine- 10mg
Vitamin D- 1000 IU
Vitamin C- 0.5g
Niacinamide-18mg
Iodine – 150mcg
Zinc- 10mg (elemental)
Selenium- 50mcg (elemental)
Example 9:
Aspirin- 150mg
Promethazine- 5mg
Vitamin D- 2000 IU
Vitamin C- 750mg
Niacinamide-80mg
Iodine – 100mcg
Zinc- 15mg (elemental)
Selenium- 82.5mcg (elemental)
Example 10:
Aspirin- 150mg
Promethazine- 12.5mg
Vitamin D- 500 IU
Vitamin C- 75mg
Niacinamide-50mg
Iodine – 75mcg
Zinc- 6.6mg (elemental)
Selenium- 20mcg (elemental)
Example 11: Aspirin- 150mg

Promethazine- 10mg
Vitamin D- 500 IU
Vitamin C- 75mg
Niacinamide-50mg
Iodine – 75mcg
Zinc- 6.6mg (elemental)
Selenium- 20mcg (elemental)
The natural glucoside of o-hydroxybenzylalcohol, Salicin, obtained from bark of the willow (Salix) may be used as a replacement for Aspirin in the product, as the mechanism of action is similar to aspirin through COX-2 inhibition. Studies have shown that drugs that block enzyme COX- 2, thereby reduce the manufacture of Prostaglandin E that helps viruses multiply and can have anti-viral effects.
MEANS OF ADMINISTRATION
The invention can be prepared most conveniently in solid tablet or capsule form, or can be prepared in liquid form depending on suitability, solubility and stability of ingredients present. Other factors like pharmacokinetics and bioavailability can affect the route of administration.
INDUSTRY APPLICABILITY
As measures to fight the novel COVID-19 are researched, emphasis is being placed on reducing the cytokine storm and immunity building benefits of COVID-19 treatment. The ingredients in the formulation represent a precise, tailored therapy for the symptoms of COVID, combined with natural constituents to help the body itself build immunity to fight this specific novel virus. The primary therapy currently being used in COVID-19 treatment is a mixture of antiviral drugs, antimalarials and antibiotics.
The invention is designed such that it constitutes components which have been shown by the inventors to synergistically support symptom recovery, provide antiviral effects and

provide a natural boost to the immunity. For this reason, it may also be administered prophylactically.
The investigational intervention APMV2020 has two tablets. First a combination of Aspirin and promethazine, the second component being multivitamins and trace elements. The ingredients in the formulation could prove a precise, tailored therapy for alleviating the symptoms of COVID, combined with nutraceutical constituents to help the host immunity. Through literature and available scientific references of the ingredients of APMV2020, it can synergistically support symptom recovery, provide antiviral effects and provide a natural boost to immunity.
Objective: The current research was conducted to clinically validate safety and efficacy of APMV2020 tablets, which consists of two tablets to be administered concomitantly first being combination of aspirin and promethazine and the second being a tablet of multivitamins and multiminerals formulated for the purpose of Covid 19 management. Study design: The study was a randomized controlled trial comprised of Covid 19 positive subjects.
Groups: We screened 65 participants of which 59 participants completed the study. They were randomized using a computer-generated randomization sheet, either in the control group where the patients were provided clinical management protocol for COVID 19 advocated by Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India or to the treatment group with treatment of APMV2020 tablets along with the standard protocol (Treatment Group).
Outcome measures: The primary outcome of the study was to evaluate improvement of clinical symptoms including fever, headache, diarrhea, breathlessness, cough, anosmia, fatigue and myalgia, reduction in elevated levels of inflammatory markers, such as CRP, LDH Ferritin and D-Dimer from baseline to day10 of intervention and assessment of changes in SpO2 level.
The secondary outcomes of trial were to assess requirement of hospitalization and admission to ICU. Adverse events were analyzed from baseline to end of the study. Results: This randomized, controlled trial evaluated the effect of APMV2020 tablets in COVID-19 revealed that when used along with standard of care treatment, APMV2020

significantly improved symptoms of COVID 19 like cough, breathlessness and fatigue,
myalgia, headache, diarrhea, anosmia. APMV2020 treatment reduced inflammatory
markers like LDH, ferritin and CRP. There was an observed faster clinical recovery with improved prognosis upon incorporating APMV2020 in treatment protocol of COVID. Conclusion: It can be concluded from the present research that APMV2020 treatment to COVID 19 patients provides several advantages as compared to treatment with only standard of care. There was early clinical recovery of subjects from COVID 19 symptoms. APMV2020 led to reduced inflammatory markers like LDH Ferritin, CRP and also mitigated symptoms significantly. The reduced oxygen supplementation and hospital admission confirm a reduced burden on healthcare infrastructure with APMV2020. Treatment with APMV2020 has a clinical potential of avoiding progression of COVID 19. However, large scale multi-centric cohort study is warranted.
The disease COVID-19 has led to unprecedented changes in the lives of all people of the world. The corona virus (COVID-19) has affected 220 countries and territories [1].
Coronavirus Disease 2019 (COVID-19) is putting administrations and healthcare systems under extraordinary stress. The extreme facility of transmission of the disease with the incredibly wide range of clinical scenarios (ranging from asymptomatic carriers to critically ill patients) warrants extraordinary research efforts directed towards prevention, cure and management of complications associated with Covid 19.
The clinical spectrum of COVID-19 infection ranges from asymptomatic to life-threatening conditions. Patients with mild disease can present with symptoms of fever, cough, and fatigue [2] and some patient’s condition deteriorate quickly after a short period of mild symptoms. Sepsis, respiratory failure, acute respiratory distress syndrome (ARDS), heart failure, and septic shock are commonly observed with progression of the disease. [3]. Medical imaging of lung tissue together with some inflammatory markers like serum levels of CRP, LDH and ferritin can be interpreted for assessment of the severity of disease. Symptom alleviation, reduction of elevated inflammatory markers, minimal or no need for hospital admission together with no need of supplemental oxygen could be the working definition of clinical recovery from Covid 19 [4].

Since the emergence of SARS-CoV-2 pandemic, the virus has undergone numerous mutations and has presented several phases/ waves of disease. Difference in disease severity could be due to factors independent of the virus or to the evolution of the virus. Evolutionarily important mutations and deletions have emerged in the SARS-CoV-2 genes encoding proteins that interact with the host immune system. The rate of mutations in proteins involved in the relationship to the immune system continues to increase after the first outbreak. The cross-reactivity on the one hand and the viral mutations observed on the other hand could explain the evolution of the pandemic until the summer of 2020. Mutations appeared during the summer in the spike protein, in particular, N439K in RBD: according to Chen et al. [5], the most frequent mutations in the spike (including D614G, N439K, and S477N) increase its transmissibility. A strain with D614G associated with mutations at RBD is more infective and resistant to some neutralizing antibodies with obvious bad implication on the recovery of COVID-19 [6].
Considering the nature of the virus, clinical scenario, viral mutations and waves of the infections coming in, there is need of a validated intervention that can be used along with conventional medication safely and can help in managing any long term complications, improve prognosis and supporting host immunity.
The intervention APMV2020 has two tablets. First Aspirin and promethazine combination, second multivitamin and multiminerals tablet. The ingredients in the formulation could prove a precise, tailored therapy for the symptoms of COVID, combined with nutraceutical constituents to help the host immunity. Through the literature and available scientific references of ingredients of APMV2020, it can synergistically support symptom recovery, provide antiviral effects and provide a natural boost to the immunity.
The current research was conducted to clinically validate safety and efficacy of APMV2020 tablets, which has two tablet to be administered concomitantly first being combination of aspirin and promethazine in tablet and a multivitamin and multiminerals tablet composition in the management of Covid 19. The outcomes are depicted and interpreted in the draft.
1. INDUSTRIAL APPLICABILITY
As measures to fight the novel COVID-19 are researched, emphasis is being placed on reducing the cytokine storm and immunity building benefits of COVID-19 treatment. The

ingredients in the formulation represent a precise, tailored therapy for the symptoms of COVID, combined with natural constituents to help the body itself build immunity to fight this specific novel virus. The primary therapy currently being used in COVID-19 treatment is a mixture of antiviral drugs, antimalarials and antibiotics.
The invention is designed such that it constitutes components which have been shown by the inventors to synergistically support symptom recovery, provide antiviral effects and provide a natural boost to the immunity. For this reason, it may also be administered prophylactically.
The investigational intervention APMV2020 has two tablets. First a combination of Aspirin and promethazine, the second component being multivitamins and trace elements. The ingredients in the formulation could prove a precise, tailored therapy for alleviating the symptoms of COVID, combined with nutraceutical constituents to help the host immunity. Through literature and available scientific references of the ingredients of APMV2020, it can synergistically support symptom recovery, provide antiviral effects and provide a natural boost to immunity.
Objective: The current research was conducted to clinically validate safety and efficacy of APMV2020 tablets, which consists of two tablets to be administered concomitantly first being combination of aspirin and promethazine and the second being a tablet of multivitamins and multiminerals formulated for the purpose of Covid 19 management. Study design: The study was a randomized controlled trial comprised of Covid 19 positive subjects.
Groups: We screened 65 participants of which 59 participants completed the study. They were randomized using a computer-generated randomization sheet, either in the control group where the patients were provided clinical management protocol for COVID 19 advocated by Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India or to the treatment group with treatment of APMV2020 tablets along with the standard protocol (Treatment Group).
Outcome measures: The primary outcome of the study was to evaluate improvement of clinical symptoms including fever, headache, diarrhea, breathlessness, cough, anosmia,

fatigue and myalgia, reduction in elevated levels of inflammatory markers, such as CRP, LDH Ferritin and D-Dimer from baseline to day10 of intervention and assessment of changes in SpO2 level.
The secondary outcomes of trial were to assess requirement of hospitalization and
admission to ICU. Adverse events were analyzed from baseline to end of the study.
Results: This randomized, controlled trial evaluated the effect of APMV2020 tablets in
COVID-19 revealed that when used along with standard of care treatment, APMV2020
significantly improved symptoms of COVID 19 like cough, breathlessness and fatigue,
myalgia, headache, diarrhea, anosmia. APMV2020 treatment reduced inflammatory
markers like LDH, ferritin and CRP. There was an observed faster clinical recovery with improved prognosis upon incorporating APMV2020 in treatment protocol of COVID. Conclusion: It can be concluded from the present research that APMV2020 treatment to COVID 19 patients provides several advantages as compared to treatment with only standard of care. There was early clinical recovery of subjects from COVID 19 symptoms. APMV2020 led to reduced inflammatory markers like LDH Ferritin, CRP and also mitigated symptoms significantly. The reduced oxygen supplementation and hospital admission confirm a reduced burden on healthcare infrastructure with APMV2020. Treatment with APMV2020 has a clinical potential of avoiding progression of COVID 19. However, large scale multi-centric cohort study is warranted.
The disease COVID-19 has led to unprecedented changes in the lives of all people of the world. The corona virus (COVID-19) has affected 220 countries and territories [1].
Coronavirus Disease 2019 (COVID-19) is putting administrations and healthcare systems under extraordinary stress. The extreme facility of transmission of the disease with the incredibly wide range of clinical scenarios (ranging from asymptomatic carriers to critically ill patients) warrants extraordinary research efforts directed towards prevention, cure and management of complications associated with Covid 19.
The clinical spectrum of COVID-19 infection ranges from asymptomatic to life-threatening conditions. Patients with mild disease can present with symptoms of fever, cough, and fatigue [2] and some patient’s condition deteriorate quickly after a short period of mild symptoms. Sepsis, respiratory failure, acute respiratory distress syndrome (ARDS), heart

failure, and septic shock are commonly observed with progression of the disease. [3]. Medical imaging of lung tissue together with some inflammatory markers like serum levels of CRP, LDH and ferritin can be interpreted for assessment of the severity of disease. Symptom alleviation, reduction of elevated inflammatory markers, minimal or no need for hospital admission together with no need of supplemental oxygen could be the working definition of clinical recovery from Covid 19 [4].
Since the emergence of SARS-CoV-2 pandemic, the virus has undergone numerous mutations and has presented several phases/ waves of disease. Difference in disease severity could be due to factors independent of the virus or to the evolution of the virus. Evolutionarily important mutations and deletions have emerged in the SARS-CoV-2 genes encoding proteins that interact with the host immune system. The rate of mutations in proteins involved in the relationship to the immune system continues to increase after the first outbreak. The cross-reactivity on the one hand and the viral mutations observed on the other hand could explain the evolution of the pandemic until the summer of 2020. Mutations appeared during the summer in the spike protein, in particular, N439K in RBD: according to Chen et al. [5], the most frequent mutations in the spike (including D614G, N439K, and S477N) increase its transmissibility. A strain with D614G associated with mutations at RBD is more infective and resistant to some neutralizing antibodies with obvious bad implication on the recovery of COVID-19 [6].
Considering the nature of the virus, clinical scenario, viral mutations and waves of the infections coming in, there is need of a validated intervention that can be used along with conventional medication safely and can help in managing any long term complications, improve prognosis and supporting host immunity.
The intervention APMV2020 has two tablets. First Aspirin and promethazine combination, second multivitamin and multiminerals tablet. The ingredients in the formulation could prove a precise, tailored therapy for the symptoms of COVID, combined with nutraceutical constituents to help the host immunity. Through the literature and available scientific references of ingredients of APMV2020, it can synergistically support symptom recovery, provide antiviral effects and provide a natural boost to the immunity.

The current research was conducted to clinically validate safety and efficacy of APMV2020 tablets, which has two tablet to be administered concomitantly first being combination of aspirin and promethazine in tablet and a multivitamin and multiminerals tablet composition in the management of Covid 19. The outcomes are depicted and interpreted in the draft.
2. Materials and methods
2.1 Study design
The study was a randomized controlled trial comprised of Covid 19 patients from outpatient department of Lokmanya Medical Research Centre, Lokmanya Hospital, Chinchwad, Pune, India. The study was approved by the Institutional Ethics Committee Lokmanya medical Research Centre and was registered with Clinical Trial Registry of India (CTRI/2021/06/034254). The CONSORT flow of the entire study is depicted in Fig. 1
2.2 Inclusion criteria
Fig.1: CONSORT flow diagram


Subjects in age range from 18 to 60 years old (both males and females), which had a confirmed Covid 19 positive RT-PCR report with mild symptomatic presentation with no symptoms of severity were recruited in the study. Home isolated subjects with no necessity of dedicated hospital admission at the time of screening were considered for the trial. Those subjects who were willing to provide consent and follow up for the duration of the study were included in the study.
2.3 Exclusion criteria
Patients with autoimmune disease or self-reports HIV or syphilis infection were deemed ineligible for the trial. Subject suffering from disorders where aspirin is contraindicated and/or as per the discretion of investigator not fit for trial were not allowed to participate. Pregnant or lactating women were excluded for the study. Requiring hospital admission at screening were not considered in the trial. Any other comorbidity which is critical stage at screening which in investigator discretion finds subject not suitable for the trial participation were excluded from study.
2.4 Groups
We screened 65 participants of which 59 participants completed the study. They were randomized using a computer-generated randomization sheet, either in the standard treatment arm (Control Group) where the patients were provided with conventional care as recommended in clinical management protocol for COVID 19 advocated by Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India or to the treatment arm where the patients were treated with APMV2020 tablets along with the standard protocol (Treatment Group). See Fig. 1 for the flow of events of this trial.
2.5 Sample size
Sample size calculation is derived taking considerations of primary and secondary outcomes by a qualified statistician. The software used for calculation of sample size is SPSS version 10.0.
2.6 Intervention and dosage

AMPV2020 tablets possess two tablets i.e. component A and B, the details of composition is as follows-
Table 1: Composition of component A

Aspirin 150 mg and Promethazine Hydrochloride 5 mg Tablet
Each Film coated Tablet contains:
Aspirin IP 150 mg
Promethazine Hydrochloride IP 5 mg
Excipients q.s.
Colours : Iron Oxide Yellow, Titanium Dioxide IP
Table 2: Composition of component B

Multivitamins and Multiminerals Tablets
Vitamin D3 (as Stabilised) 2000 IU
Vitamin C (as coated) 750 mg
Niacinamide IP/BP 80 mg
Zinc Sulphate Monohydrate IP/USP eqvt. to Elemental Zinc 15 mg
Potassium Iodide IP/BP eqvt to. Elemental Iodine 100 mcg
Sodium Selenate Eqvt. to Elemental Selenium 82.5 mcg
Excipients q.s.
Colours : Iron Oxide Yellow, Iron Oxide Black , Iron Oxide Red , Titanium Dioxide IP/BP
The dosage of the intervention was 1 tablet of component A and B each twice a day with water for 10 days.
Standard of care treatment:

Following medication was used as a standard care treatment- Favipiravir oral, paracetamol, azithromycin to all subjects from both groups and additionally cetirizine, montelukast and multivitamin tablet to control group.
2.7 Outcome measures
The primary outcome of the study was to evaluate improvement of clinical symptoms including fever, headache, diarrhea, breathlessness, cough, anosmia, fatigue and myalgia, reduction in elevated levels of inflammatory markers, such as CRP, LDH Ferritin and D-Dimer from baseline to day10 of intervention and assessment of changes in SpO2 level. The secondary outcomes of trial were to assess requirement of hospitalization and admission to ICU. Adverse events were analyzed from baseline to end of the study.
2.8 Methodology
After approval from institutional EC clinical study was registered on CTRI website and study was conducted at Lokmanya Medical Research Centre, Lokmanya Hospital, Chinchwad, Pune. On screening visit, a written informed consent was obtained from subjects for their participation in the study. Subject’s demographic details were recorded. Clinical examination of each subject was performed. Subject’s medical, surgical and treatment history was recorded. Subject’s current medication if any was noted in the case record from (CRF) along with the vitals like pulse, blood pressure, body temperature were recorded. The subjects were considered for further evaluation as per the inclusion and exclusion criteria. On screening visit all hematological and inflammatory marker tests were performed and reviewed on baseline day (Day 0). Subject fitting in all inclusion criteria and showing absence of all exclusion criteria were randomized to either of the two-treatment arm with computer generated randomization sheet. Subjects were on standard of care for Covid 19 as per ICMR protocol for both the treatment arms. A screening window of 1-2 days was considered, in case if there is delay in availability of tests reports or in case few tests need to be repeated. The record of concomitant medication was properly maintained. Treatment compliance was assessed daily. Assessment of SpO2 and symptom grading recorded on daily basis in patient diary. All subjects were advised to follow their diet routine. The presence of any adverse events was strictly monitored and reported. On day 10 all the blood parameters were

repeated. The treatment was followed till day 10. Symptomatic was assessed telephonically as well every alternate day and on day10 if subject not willing to visit hospital again and there is absence of any adverse events, blood collection from home was arranged for the patients not visiting hospital physically. The patient diaries were collected from patients.
2.9 Data analysis
Patients without any major protocol violation were included in the per protocol population (pp), including those patients who had good treatment compliance, who did not take any prohibited medications during the study period with completed CRF were used for analysis. Both descriptive and inferential analyses were used in inferring the data.
2.10 Demographic and baseline information
Continuous variables that are age and other demographical characteristics were summarized by using summary statistics i.e. the number of observations, mean and standard deviation. Categorical values like gender and clinical Examination were summarized using frequencies and percentages.
2.11 Analysis of primary efficacy parameters
In this study percentage population relieved of symptoms on Day 5 and 10 were analyzed and compared between groups by using Chi square test. Other Primary efficacy variables like inflammatory markers and symptom scoring was analyzed by Wilcoxon signed rank test for within group analysis and independent student t test for between group analyses and SpO2 levels were evaluate by student t test paired and unpaired test wherever applicable.
2.12 Secondary efficacy parameters
Secondary variables like requirement of hospitalization and ICU and days of oxygen supplementation were represented as percentage.
2.13 Safety analysis
Hematological parameters, body temperature were evaluated by student t test. Adverse events (AEs) and serious adverse events (SEs) were summarized, counting both the number

of separate events and the number of subjects experiencing events occurring during the study period. All p-values were reported based on two-sided significance test and all the statistical tests were interpreted at 5% level of the significance level.
3. Results and observations:
3.1 Demographic characteristics:
In the present study the mean age of male and female subjects in test and control group were comparable and ranged from 33.52 to 39.53 years. The ratio of male to female in test and control group was around 63.33:35 male: female which is in line with the more prevalence in male candidates as per the literature available. There were no subjects with presenting comorbidity. The details are presented in table 3.
Table 3: Demographic details of study subjects

Parameter Treatment Control
Group Male (n=20) Female(n=9) Male(n=18) Female(n=12)
Age (years) 34.4+8.99 31.56+5.51 39.56+10.36 39.5+11.01
Total Age (years) 33.52+8.13 39.53+10.53
3.2 Primary outcomes of the study 3.2.1 Changes in symptoms of COVID 19
Clinical symptoms such as cough, breathlessness, fatigue, myalgia, headache, diarrhea and anosmia were assessed from baseline to day 10. There is significant reduction in symptoms in both groups from baseline to day 10 when compared within group. It was evidently observed from the data obtained that there was faster relief of symptoms in treatment group compared to control. There were more subjects getting relieved of cough, breathlessness, fatigue and myalgia from treatment group as compared to control on day 5 and day 10. The table 4 depicts percent reduction in symptoms score on day 5 and 10. There faster reduction in symptom score denoted by higher reduction at day 5 in treatment group than control. On day 10 the treatment group showed significantly reduced symptom scores than control (cough, breathlessness, fatigue and myalgia). The data of subjects getting relieved of symptoms are greater in treatment group than control (table 5). Table 6 depicts data of mean

changes in symptom score between groups. The symptom scoring was on 0-10 VAS score. 0-1 being no symptoms, 2-5 mild symptoms i.e. symptoms interfering with the daily activities, 6-8 moderate symptoms i.e. symptoms interfering too much in daily activities, 9-10 severe symptoms requiring medical assistance. It illustrated the significant reduction in breathlessness and myalgia in treatment group than control.
Table 4: Percent reduction in symptoms between groups

Symptoms Treatment Control

Day 5 Day 10 Day 5 Day 10
Cough 53.86% 80.60% 44.15% 60.38%
Breathlessness 52.39% 77.54% 47.08% 55.73%
Fatigue 54.92% 67.99% 45.99% 57.16%
Myalgia 47.05% 63.02% 16.93% 23.06%
Headache 60.50% 71.78% 45% 61.67%
Diarrhea 63.01% 76.48% 52% 60.46%
Anosmia 59.43% 80.32% 59.31% 56.53%

Table 5: Subjects population with symptom score between groups

Duration/ score Treatment Control

0-1 No. 2-5 No. 6-10 No. 0-1 No. 2-5 No. 6-10 No.
Cough
Baseline 0 13 16 0 13 17
5 12* 16 1 6 18 6
10 24* 4 1 15 11 4
Breathlessness
Baseline 0 15 14 0 18 12
5 11 17 1 14 12 4
10 22* 6 1 12 15 3
Fatigue
Baseline 0 14 15 0 15 15
5 19 3 7 10 15 5
10 20* 5 4 12 16 2
Myalgia
Baseline 0 18 11 0 20 10
5 17* 4 8 9 7 14
10 18* 7 4 9 8 13
Headache
Baseline 0 14 15 0 15 15
5 18 8 3 11 15 4
10 19 8 2 18 10 2
Diarrhea
Baseline 0 20 9 0 20 10
5 18 11 0 14 16 0
10 20 9 0 14 16 0
Anosmia
Baseline 0 18 11 0 20 10

5 15 14 0 16 14 0
10 21 8 0 12 18 0
Data analyzed by chi square test. *Significant at p<0.05
Table 6: Changes in symptom score between groups

(Mean ± SD) Cough Score
Duration Test Control P value
Baseline 5.31±2.14 5.73±2.24 0.4651
5 2.45±1.75 3.20±2.07
10 1.03±1.20 2.27±2.21
Mean diff (Baseline – Day 5) 2.86±1.52 2.53±1.62 0.4286
(p value) <0.05 <0.05

Mean diff (Baseline – Day 10) 4.28±2.35 3.47±2.05 0.1672
(p value) <0.05 <0.05

(Mean ± SD) Breathlessness Score
Duration Test Control P value
Baseline 5.21±2.14 4.97±2.31 0.6829
5 2.48±1.69 2.63±2.19
10 1.17±1.24 2.20±1.75
Mean diff (Baseline – Day 5) 2.72±2.40 2.33±1.20 0.4336
(p value) <0.05 <0.05

Mean diff (Baseline – Day 10) 4.03±2.06 2.77±1.03 0.0042
(p value) <0.05 <0.05

(Mean ± SD) Fatigue Score

Duration Test Control P value
Baseline 5.28±2.07 5.37±2.25 0.8734
5 2.38±2.64 2.90±2.10
10 1.69±2.02 2.30±1.92
Mean diff (Baseline - Day 5) 2.90±1.44 2.47±1.03 0.1945
(p value) <0.05 <0.05

Mean diff (Baseline - Day 10) 3.59±1.51 3.07±1.45 0.1865
(p value) <0.05 <0.05

(Mean ± SD) Myalgia Score
Duration Test Control P value
Baseline 4.76±2.08 4.90±2.02 0.7939
5 2.52±2.71 4.07±3.01
10 1.76±2.15 3.77±2.69
Mean diff (Baseline - Day 5) 2.24±1.11 0.83±1.30 <0.001
(p value) <0.05 <0.05

Mean diff (Baseline - Day 10) 3.00±1.43 1.13±1.19 <0.001
(p value) <0.05 <0.05

(Mean ± SD) Headache Score
Duration Test Control P value
Baseline 5.14±2.06 5.40±2.19 0.6409
5 2.03±2.21 2.97±2.11
10 1.45±1.69 2.07±2.02

Mean diff (Baseline – Day 5) 3.10±1.41 2.43±1.18 0.0546
(p value) <0.05 <0.05

Mean diff (Baseline – Day 10) 3.69±1.66 3.33±1.85 0.443
(p value) <0.05 <0.05

(Mean ± SD) Anosmia Score
Duration Test Control P value
Baseline 4.93±2.31 4.67±2.27 0.6621
5 2.00±1.96 1.90±1.61
10 0.97±1.14 2.03±1.57
Mean diff (Baseline – Day 5) 2.93±1.30 2.77±0.96 0.5848
(p value) <0.05 <0.05

Mean diff (Baseline – Day 10) 3.97±1.71 2.63±1.12 0.0008
(p value) <0.05 <0.05

(Mean ± SD) Diarrhea Score
Duration Test Control P value
Baseline 4.38±2.21 4.73±2.31 0.5536
5 1.62±1.73 2.27±1.80
10 1.03±1.08 1.87±1.47
Mean diff (Baseline – Day 5) 2.76±1.11 2.47±1.21 0.3442
(p value) <0.05 <0.05

Mean diff (Baseline – Day 10) 3.34±1.50 2.87±1.58 0.2429
(p value) <0.05 <0.05

Analyzed by Wilcoxon signed rank test for within group analysis and independent student t test for between group analyses. Significant at p<0.05
3.2.2 Changes in SpO2 levels
The average SpO2 levels in treatment group was 96.6 ± 1.19 and was improved to 96.8 ± 1.80 and 98.1± 1.03 on day 5 and 10 respectively. In control group, the mean SpO2 levels were 95.8 ± 1.90, 96.1 ± 1.23 and 97.8 ± 1.75 on baseline, day 5 and day 10 respectively. The difference was not statistically significant between groups.
3.2.3 Changes in inflammatory markers
Inflammatory markers like CRP, LDH, D-dimer and ferritin were elevated in both groups at baseline. There was statistically significant reduction in elevated levels of serum LDH and ferritin between treatment and control groups. There was 63.33 % reduction of elevated serum CRP levels in treatment group compared to 55.34 % in control group. Results are displayed in table 7.
Table 7: Changes in mean inflammatory markers between groups

Changes in D-Dimer (µg/ml) between groups
Duration in days Treatment Control P Value between
Baseline 0.32±0.36 0.36±0.35 0.758
Day 10 0.33±0.36 0.32±0.31
Mean Difference -0.01±0.55 0.05±0.27 0.590
P value within 0.9069 0.3898

Changes in LDH (U/L) between groups

Baseline 301.45±117.73 317.52±107.70 0.6
Day 10 261.79±70.06 367.17±190.36
Mean Difference 48.69±145.38 -81.40±245.78 0.017
% change 13.16 -15.63
P value within 0.1642 0.2751
Changes in Ferritin (ng/ml) between groups
Baseline 144.08±280.54 130.88±95.16 0.818
Day 10 73.13±66.17 158.93±132.91
Mean Difference 73.47±270.68 -41.14±127.11 0.042
% change 49.24 -21.43
P value within 0.2455 0.2215
Changes in CRP (mg/l) between groups
Baseline 9.98±17.21 10.01±13.75 0.878
Day 10 3.66±4.84 4.47±5.92
Mean Difference 5.84±17.17 5.53±15.07 0.942
% change 63.33 55.34
P value within 0.0809 0.055
Data analyzed by student t test. Significant at p<0.05
3.3 Secondary outcomes of the study 3.3.1 Requirements of hospitalization

From the control group, 20% subjects i.e. 6 subjects developed need for hospitalization in Lokmanya Hospital a dedicated Covid set up. No subject from treatment arm developed need of hospitalization i.e. 100% subjects got clinically recovered in home isolation.
3.3.2 Requirements of supplemental oxygen
From the control group, 20% subjects i.e. 6 subjects who were admitted at Lokmanya Hospital (a dedicated Covid set up) required supplemental oxygen. 50% subjects i.e. three subjects required oxygen supplementation on and off till 5-6 days. Rest 50% subjects i.e. three subjects required oxygen high flow supplementation till 8-9 days. No subject from treatment arm developed need of supplemental oxygen thus 100% subjects maintained the oxygen saturation on room air.
3.3.3 Requirements of ICU admission
There was requirement of ICU admission to 10% (3 subjects) of subjects from control group on the contrary there was no requirement of ICU admission in treatment group. There was no mortality in both groups.

3.3.4 Changes in body temperature between groups

Duration in Days Mean Body temperature °F (Mean + SD) P value

N
22
22 02 02 02 Treatment N Control

Baseline
99.89 ±0.12 26 100.88 ± 0.24 0.95 (NS)
2
98.44 + 0.44 26 99.54 + 0.87

4
98.49 + 0.31 03 98.47 + 0.39

7
98.14 + 0.32 03 98.40 + 0.57

10
97.90 + 0.19 03 98.11 + 0.76

By Student t Test NS =Not Significant
There was no significant difference in the changes in body temperature between groups. The subjects had antipyretic medication like paracetamol in their standard of care treatment.
3.4 Safety outcomes
Hematological parameters like complete blood count were assessed on baseline and day 10. There were significant changes in the parameters between groups. The data depicted in table 8.
Table 8: Changes in hematological parameters

Parameters Treatment Control

Baseline Day 10 Baseline Day 10
Total Leukocyte (/cumm) 8.36±2.39 7.82±2.19 6.88±2.32 9.84±3.93
Neutrophils (%) 66.49±12.77 61.82±8.36 72.58±13.89 68.48±9.97
Lymphocytes (%) 26.72±11.24 30.23±6.80 21.14±11.85 26.40±9.74
Monocytes (%) 3.02±0.97 3.34±1.11 4.73±3.46 3.17±1.95
Eosinophil (%) 3.31±3.28 4.13±3.64 1.17±0.97 1.43±0.78
Basophils (%) 0.18±0.04 0.18±0.04 0.17±0.19 0.24±0.19

Total RBC Count (million/cumm) 4.94±0.74 4.93±0.77 4.62±0.68 4.88±0.59
Hemoglobin (G/dl) 13.80±2.50 13.88±1.97 13.29±1.93 13.88±1.56
Hematocrit (%) 42.97±5.47 42.72±4.34 41.04±4.93 44.07±4.02
Platelets (/cumm) 287.14±71.05 269.97±74.49 215.05±65.81 334.93±98.41
Platelet Distribution (fL) 11.81±1.35 11.88±2.36 11.98±2.28 12.53±3.29
Mean Platelet Volume (fL) 10.36±0.64 10.35±0.85 9.82±1.47 10.50±1.16
Data analyzed by Student t-Test. Non-significant p>0.05
3.5 Adverse events
There were no adverse events related to study medication throughout the study period. There were no adverse events related to possible engagement of test intervention.

4. Discussion:
This randomized, controlled trial evaluated the effect of APMV2020 tablets in COVID-19 has revealed that when used along with standard of care treatment, APMV2020 significantly improved symptoms of COVID 19 like cough, breathlessness and fatigue, myalgia, headache, diarrhea, anosmia. APMV2020 treatment reduced inflammatory markers like LDH, ferritin and CRP.
Overall incorporating APMV2020 in treatment protocol of COVID 19 there was faster clinical recovery with improved prognosis. The working definition of the clinical recovery in this study context is getting relieved of symptoms.
Covid 19 patients who develop acute respiratory distress syndrome have a high mortality rate in general. It is thought that a hyper inflammatory state is induced by the infection which leads to multi-organ dysfunction syndrome [7]. APMV2020 administration can play an important role in supporting the immune system and also help patients, getting faster symptomatic recovery and halt the progress of disease [8].
In the present research, participants from APMV2020 treated group, did not show need of admission to hospital. This fact is supported by the no requirement of the supplemental oxygen to the patients in APMV2020 treated group. There were 20% subjects from control group required hospitalization with 50% of which (3 subjects) shown requirement of admission to intensive care unit. The hospitalized subjects from control group required supplemental oxygen from 5 days to 9 days. On the yardstick of advantages of novel intervention treatment regime in Covid management protocol; APMV2020 has proved itself worth scheduling. These are the valid implications of incorporating APMV2020 in standard of treatment which can put off encumbrance on healthcare systems and ease out economic proposition for patients.
Another important concern around integrating the APMV2020 regime could be around safety and patient compliance. In the present study, we have assessed hematological parameters which suggested no significant change post treatment and no adverse events recorded indicating safety of the intervention. All patients were compliant to APMV2020 consumption for 10 days. There was no abnormality in pulse rate; blood pressure was

observed after treatment of APMV2020. There was no significant difference in the changes in body temperature between groups.
In COVID-19 dyspnea being predominant symptom, it becomes very crucial to manage and maintain SpO2 levels more than 96% for better clinical outcomes [9]. Though statistically not-significant treatment with APMV2020 demonstrated increased SpO2 levels during the study period compared to baseline, reflected in significantly reduced breathlessness further lowering risk profile of disease.
Patients in APMV2020 treated group showed faster recovery in symptoms like cough, breathlessness and fatigue, myalgia, headache, diarrhea, anosmia; which can be very well connected to improved prognosis of disease. There is strong relationship between symptom regressions and recovery in COVID 19. Our results depict that subjects treated with APMV2020 were relieved of cough, breathlessness and fatigue and myalgia more effectively than control within five days of treatment, which further mitigates the risk of severity of COVID-19.
In this study, both groups were comparable in terms of clinical characteristics, disease severity and comorbidity status which removed the prejudice at baseline. The presenting symptoms were cough, breathlessness and fatigue, myalgia, headache, diarrhea, anosmia. Many researches support the fact that immuno-inflammatory responses play a critical role in the progression of COVID-19 [10, 11]. Triggered inflammatory responses is the result of rapid viral replication of SARS-CoV-2. Viral replication and cellular destruction can stimulate release of cytokines and chemokine through macrophages and monocytes [12] activating acquired immune responses. This cascade leads to cytokine storms in Covid 19. [13] Inflammatory markers such as serum lactate dehydrogenase, serum ferritin, C-reactive protein (CRP) and interleukin-6 (IL-6) have been reported to be positively correlated to the high risks of severity and fatality in COVID-19 [13]. Elevated inflammatory markers bear the risk of lung involvement (higher HRCT score) possibly forecasting fatality in COVID-19. [14] One of the main objective of all clinicians treating Covid 19 is always to lower the aggravated response of the cytokines and to lower down their levels to mitigate the risk.
In the present study, treatment with APMV2020 has demonstrated excellent anti-inflammatory activity by reducing serum levels of LDH, Ferritin, and CRP significantly than

control. APMV2020 can be thought of an intervention with balanced immunomodulatory and anti-inflammatory activity.
Aspirin from APMV2020 inhibits platelet aggregation triggered by the release of arachidonic acid (AA) from platelet cells. Aspirin acetylates a serine residue irreversibly at 529 position, located inside the hydrophobic channel. It is present in close proximity to the catalytic site where AA gets metabolized. It results in interference of cyclooxygenase activity causing inhibition of Thromboxane A2 which is responsible for thrombo-inflammation and thrombosis. This blockage is created for the life of the platelets which is usually 7-12 days. Thus, it can be considered as one of the reasons which confers aspirin pulmonary and cardioprotective benefits. It also helps in counteracting harm done by coagulation and thrombosis in patients. Hence, the function performed by aspirin can help in prevention of thrombo-inflammation, pulmonary embolism and thrombosis found commonly in COVID-19 patients. [15]
Aspirin is researched molecule with antiviral activity against influenza A H1N1 virus. [16] Aspirin is a NSAID that inhibits the systemic inflammatory response syndrome via the cyclooxygenase pathway by initially blocking prostaglandins and thromboxane synthesis. It prevents neutrophil activation and aggregation, decreases the production of superoxide radicals from activated neutrophils, and stabilizes lysosomal membranes and enzymes. It limits the release of inflammatory mediators, and provide hemodynamic protection and inhibit oxidant injury, especially if given early at the onset of inflammation. There are studies indicating potent anti-inflammatory activity of aspirin which can mitigate the elevated inflammatory state and prevent cytokine storm in Covid 19. There is increasing interest of many researchers worldwide to use aspirin in early stages of Covid 19 to inhibits acute inflammation and alter platelet-biology to prevent thromo- inflammatory lung changes. [17] Promethazine from APMV2020 is an antihistaminic used in treating symptoms of asthma, pneumonia, or other lower respiratory tract infections. It can block airway inflammation and bronchoconstriction caused by histamine release from mast cells. Mast cell activation and Histamine release may contribute to the inflammation associated with COVID-19 infection. Patients with COVID-19 have systemic elevation of pro-inflammatory cytokines IL-6 and TNF-α. The over activation of mast cells and release of cytokines might also have a role in the

development of pulmonary fibrosis in COVID-19 patients. Promethazine may also act in COVID-19 patients as a cough suppressant. [18]
Recent studies have shown that low vitamin D levels in COVID-19 patients are associated with the severity of diseases and mortality in Covid 19. Optimal serum levels of 25-hydroxyvitamin D have been suggested to have immunomodulatory and anti-inflammatory properties and could benefit COVID-19 patients. [19]
Administration of vitamin C to patients with pneumonia can decrease the severity and duration of the disease. The vitamin C has pleiotropic physiological functions, many of which are relevant to COVID-19. These include its antioxidant, anti-inflammatory, antithrombotic and immuno-modulatory functions. There are plenty of evidences suggesting immunomodulatory and antioxidant potential of Vitamin C for improving prognosis of patient. [20]
The primary receptor for SARS Cov2 is the ACE2 receptor; upon binding, the virus enters the host cell via endocytosis, leading to viral multiplication. Selenium and selenoproteins affect viral activities by contributing to several defensive mechanisms. Selenium supports structural integrity and intactness of respiratory epithelial barrier, which will lower viral entry to respiratory cells. Selenium is required for the activities of phagocytic cells. Phagocytic cells are a major component of the innate immunity system.[21]
Zn own antiviral effects through generating innate and acquired (humoral) immune responses, stabilization of cell membrane inhibiting the entry of the virus, and inhibition of viral replication through interference with the viral genome transcription, protein translation, polyprotein processing, viral attachment, and uncoating. Multiple antiviral effects of Zn have been demonstrated in a variety of viral species, including SARS-CoV-2. There are strong evidences of usefulness of zinc supplementation in reducing the risk and severity of Covid 19. [22]
Undeniably, nutrition is a key denominator of maintaining good health. Dietary components such as vitamins C, D, selenium and zinc from APMV2020 have well-established antiviral, antioxidant and immunomodulatory potential in Covid 19. [23]
There are three approaches in which APMV2020 can prove as good candidate for integrating in Covid 19 standard care protocol. First- offering speedy clinical recovery getting burden off on healthcare infrastructure and easing economic drain of patients and second- showing

anti- inflammatory potential to improve prognosis, third-promising immunity modulator to offer long term protection through multivitamin and trace element combination. The present research confirms safety and efficacy of the treatment of APMV2020 in COVID 19 patients. However, large scale multi-centric cohort study is warranted.
5. Conclusion
It can be concluded from the present research that APMV2020 treatment to COVID 19 patients provide several advantages over only standard of care. There was early clinical recovery of subjects from COVID 19 symptoms of subjects. APMV2020 led to reduced inflammatory markers like LDH Ferritin, CRP and also mitigated symptoms significantly. The reduced oxygen supplementation and hospital admission confirm reducing burden on healthcare infrastructure. Treatment with APMV2020 has potential of avoiding progression of COVID 19. There are three approaches in which APMV2020 can prove as good candidate for integrating in Covid 19 standard care protocol. First- offering speedy clinical recovery getting burden off on healthcare infrastructure and easing economic drain of patients and second- showing anti- inflammatory potential to improve prognosis, third-promising immunity modulator to offer long term protection through multivitamin and trace element combination. This study will definitely pave the path for further researches using aspirin, promethazine, vitamin D, C and micronutrient therapy as an interventions in management of Covid 19. However, large scale multi-centric cohort study is warranted.
6. References
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WE CLAIM:
1. A pharmaceutical composition for the specific treatment or prophylactic use against COVID-19, for combined, sequential or simultaneous administration, in any form, via any biological route, consisting essentially of Aspirin, Promethazine, and Niacinamide.
2. A pharmaceutical composition for the specific treatment or prophylactic use against COVID-19, for combined, sequential or simultaneous administration, in any form, via any biological route, consisting essentially of Aspirin at a daily dose not lower than 20mg and not exceeding 2,000mg, Promethazine at a daily dose not lower than 3mg and not exceeding 75mg, and Niacinamide at a daily dose not lower than 2mg and not exceeding 700mg.

3. A pharmaceutical composition according to claim 2 that also includes Phenylephrine.
4. A pharmaceutical composition according to claim 3 that also includes average dietary level intakes of Vitamin D and Iodine.
5. A pharmaceutical composition according to claim 3 that also includes Vitamin D at a daily dose not lower than 200IU and not exceeding 30,000IU and Iodine at a daily dose not lower than 10mcg and not exceeding 500mcg.
6. A pharmaceutical composition according to claim 5 that also includes average dietary level intakes of vitamin C, Zinc and Selenium.
7. A pharmaceutical composition according to claim 5 that also includes vitamin C at a daily dose not lower than 10mg and not exceeding 7g, Zinc at a daily dose not lower than 3mg and not exceeding 250mg and Selenium at a daily dose not lower than 5mcg and not exceeding 500mcg.
8. A pharmaceutical composition beneficial as complementary therapy to be indicated in
COVID-19, for combined, sequential or simultaneous administration, in any form, via any

biological route, comprising Aspirin, Phenylephrine, and Promethazine, combined with vitamins or minerals.
9. A composition according to any one of the claims in which Aspirin is replaced with Salcin
or any natural salicinoid or extract obtained from the tree bark of the Salix (willow) or
Populus (poplar).
10. A composition according to any one of the claims in which Niacinamide is replaced with niacin (or nicotinic acid) or any other form of Vitamin B3.
11. A composition according to any one of the claims in which the composition includes one or more carriers or excipients.
12. A composition according to any one of the claims in which the composition is
administered as a single or multiple dose either in solid (tablet or capsule) or liquid dosage
form.
13. A composition according to any one of the claims wherein the composition is administered prophylactically to high risk patient groups or those workers at high risk of COVID-19 transmission or infection.
14. A composition according to any one of the claims wherein the composition is administered to reduce thrombosis and improve blood flow within the small blood vessels in the lungs of COVID-19 patients.
15. A composition according to any one of the claims wherein the composition consists essentially of the components defined in that claim.
16. A composition consisting of few or all of the ingredients viz., Aspirin, Phenylephrine, Promethazine, Vitamin D, Vitamin C, Niacinamide, Iodine, Zinc & Selenium composed in any

strengths adjusted as per available literature or doses found suitable for enhancing therapeutic efficacy in targeted indications.