DESC:
FIELD OF THE INVENTION

The present invention relates to a low strength Aviptadil composition comprising 5-45µg/ml of Aviptadil for the treatment of severe COVID-19 patients with respiratory failure, wherein the treatment comprises administering Aviptadil as 12 hours intravenous infusions on 3 successive days at ascending doses.

BACKGROUND OF THE INVENTION

Aviptadil, a Vasoactive Intestinal Polypeptide (VIP) is a linear, 28-AA peptide with an amidated C-terminus. All amino acids of Aviptadil are in L-configuration. The chemical name is H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2. Aviptadil has the following chemical structure

Commercially, Aviptadil is available as Invicorp®(25 micrograms / 2 mg Aviptadil and phentolaminemesylate) solution for injection and is used for the symptomatic treatment of erectile dysfunction in adult males due to neurogenic, vasculogenic, psychogenic, or mixed aetiology.

NeuroRx, Inc. in collaboration with Relief Therapeutics Holding AG is developing intravenously-administered ZYESAMI™ (aviptadil acetate) for the treatment of respiratory failure in critically-ill patients with COVID-19.

Acute Respiratory Distress Syndrome is a severe pulmonary parenchymal injury to most or all of both lungs. ARDS is the rapid onset of progressive malfunction of the lungs, especially with regard to the ability to take in oxygen, usually associated with the malfunction of other organs. The condition is associated with extensive lung inflammation and accumulation of fluid in the alveoli (air sacs) that leads to low oxygen levels in the lungs. ARDS is characterized by diffuse pulmonary microvascular injury resulting in increased permeability and, thus, non-cardiogenic pulmonary edema.

The rationale for Aviptadil’s use for the treatment of ARDS is based on the results from preclinical studies showing that Aviptadil is highly concentrated in the lung, where it prevents the activation of caspases NMDA-induced, inhibits IL-6 and TNF-a production and protects against HCl-induced pulmonary oedema.

Based on the published literature, the currently available strengths of Aviptadil compositions, which are under investigation for the treatment of severe COVID-19 patients with respiratory failure, range from 50 to 150 µg of Aviptadil per ml.

US8178489B2 relates to pharmaceutical formulations of Aviptadil and its derivatives. The stability of the Aviptadil formulation was shown to be improved by a formulation having a defined concentration of Aviptadil prepared in a buffer having a defined pH range.

In an attempt to develop better treatment and improving survival rate for severe COVID-19 patients with respiratory failure, the present inventors while working on Aviptadil compositions surprisingly found a lower strength of Aviptadil for the treatment of ARDS. The present inventors have developed new strength of Aviptadil composition, which is below 50 µg of Aviptadil per ml. The said composition of Aviptadil, was administered as 12 hours intravenous infusions on 3 successive days at ascending doses.

SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provideda low strength Aviptadil composition comprising of 5-45µg/ml of Aviptadil.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWING
Figure 1: Graphical representation of SOC distribution
Figure 2: Number of patients showing resolution of Respiratory failure On Day 3, 7, 14 and 28
Figure 3: Time to resolution from respiratory failure analyzed by life-table analysis
Figure 4: Clinical status on WHO 7-point ordinal scale
Figure 5: Number of patients showing =2-point improvement on WHO 7-point Ordinal Scale
Figure 6: Number of patients showing =4-point difference on WHO 7-point Ordinal Scale
Figure 7: Kaplan-Meier estimates for time to survival from the day of enrolment
Figure 8: Improvement in PaO2/FiO2 ratio

DETAILED DESCRIPTION OF THE INVENTION

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

The present invention relates to a low strength Aviptadil composition comprising 5-45µg/ml of Aviptadil for the treatment of severe COVID-19 patients with respiratory failure, wherein the treatment comprises administering Aviptadil as 12 hours intravenous infusions on 3 successive days at ascending doses.

The term “µg” and “mcg” has been interchangeably referred in the specification.

In one of the embodiment of the present invention, there is provided a low strength Aviptadil composition comprising 5-45µg/ml of Aviptadil for the treatment of severe COVID-19 patients with respiratory failure, wherein the treatment comprises administering Aviptadil as 12 hours intravenous infusions on 3 successive days at ascending doses of 0.166 mcg/kg/hr on Day 1, 0.332 mcg/kg/hr on Day 2 and 0.498 mcg/kg/hr on day 3.

In an embodiment of the present invention, the Aviptadil composition, the pharmaceutical compositions of the invention may also comprise pharmaceutically acceptable excipients selected from cosolvents/solubilizer, antioxidants, preservatives, buffers, alkali and stabilizers.

In an embodiment of the present invention, the Aviptadil composition, the pharmaceutical compositions of the invention may also comprise pharmaceutically acceptable excipients selected from sodium chloride, disodium edetate, sodium hydroxide/hydrochloric acid q.s. to adjust pH, or water of injection q.s .

In another the embodiment of the present invention, the Aviptadil composition is in the form of ready to use solution.

In another embodiment of the invention, the Aviptadil composition is in the form of ready to use solution, preferably at strength of 15µg/ml.

In yet another embodiment of the present invention, the Aviptadil composition is in the form of a lyophilized powder.

The compositions of the present invention contain 150µg of Aviptadil per vial and the final concentration of injection prior to the intravenous administration is 15µg/ml.

In a most preferred embodiment of the present invention, 12-hour intravenous infusions of Aviptadil over 3 successive days in ascending doses is given as 0.166 mcg/kg/hr on Day 1 (equivalent to one 10-mL vial of 150 mcg), 0.332 mcg/kg/hr on Day 2 (equivalent to two 10-mL vials of 150 mcg each) and 0.498 mcg/kg/hr on Day 3 (equivalent to three 10-mL vials of 150 mcg each).

Example 1: Ready to Use Aviptadil composition

Ingredients mg/ml
Aviptadil 0.015
Sodium chloride 40.0
Disodium edetate 2.30
Sodium hydroxide / Hydrochloric acid Q.S. to adjust the pH
Water for Injection Q.S. to 1 ml

In yet another aspect of the invention the Aviptadil composition is in the form of a lyophilized powder.

Example 2: Lyophilized Aviptadil composition
Ingredients mg / ml
Aviptadil 0.033
Di-Sodium hydrogen phosphate 0.23
Sodium dihydrogen phosphate monohydrate 2.54
Mannitol 42.0
Polysorbate 80 0.2
Sodium hydroxide / Hydrochloric acid / Orthophosphoric acid Q.S. to adjust the pH
Water for Injection Q.S. to 1 ml

In one of the aspects of the present invention, the clinical study evaluates efficacy and safety of lower strength of Aviptadil for the treatment of severe COVID-19 patients with respiratory failure.

Study design:
A Multi-centric, Comparative, Randomized, Double blind, Placebo controlled, Phase 3 clinical study was performed to evaluate the Efficacy and Safety of Intravenous Aviptadil, as an add-on to the “Standard of Care” in severe COVID-19 patients with respiratory failure.

A total of 105 adult patients with severe COVID-19 and with respiratory failure were enrolled in the study, out of which 3 patients discontinued during the study. Patients were treated with 12 hour infusions of the assigned drug (as per the randomization code) at ascending doses on 3 successive days. Patients were received 0.166 mcg/kg/hr of the assigned drug (as per the randomization code) on day 1, 0.332 mcg/kg/hr on Day 2 and 0.498 mcg/kg/hr on Day 3.

The “Standard of Care” treatment was continued to be administered as per Clinical Management Protocol: COVID-19 by Government of India in both the treated arms. (Details provided in Table 1 and Table 2).

Table 1: Standard of Care – Interventional group

Interventional Group
Interventional product Aviptadil 150 mcg injection
Standard of Care Antiviral Remdesivir, Favipiravir
Antibiotics Imipenem, Doxycycline, Meropenem, Ceftriaxone, Piperacilline+Tazobactum, Cefixime, Teicoplanin, Amoxicillin + Clavulanic Acid
Steroids Dexamethasone, Methylprednisolone
MVMM Vitamin C, Vitamin D3, Zinc
Mucolytic, Bronchodilator N-Acetyl Cysteine, Acebrophylline, Doxofylline, Acebrophylline
LMWH Enoxaparin
Antifungal Fluconazole, Amphotericin B, Caspofungin, Variconazole
Anti-allergic Montelukast + Levocetirizine, Levocetirizine
Anthelmintic Ivermectin
Anti-inflammatory Paracetamol
Other Pantoprazole, Pirfenidone, Ondansetron, Potassium Chloride, Antihypertensive agents, Antidiabetic agents, Nebulization

Table 2: Standard of Care – Control group
Control Group
Control Placebo identical with Interventional product
Standard of Care Antiviral Remdesivir, Favipiravir
Antibiotics Imipenem, Doxycycline, Meropenem, Ceftriaxone, Piperacilline+Tazobactum, Cefixime, Feropenem, Levofloxacin, Amoxicillin + Clavulanic Acid
Steroids Dexamethasone, Methylprednisolone, Prednisolone
MVMM Vitamin C, Vitamin D3, Zinc
Mucolytic, Bronchodilator N-Acetyl Cysteine, Acebrophylline, Doxofylline, Acebrophylline
LMWH Enoxaparin, Heparin
Antifungal Fluconazole, Amphotericin B, Caspofungin, Variconazole
Anti-allergic Montelukast + Levocetirizine, Desloratidine+Montelukast, Levocetirizine
Anthelmintic Ivermectin
Anti-inflammatory Paracetamol
Other Pantoprazole, Pirfenidone, ondansetron, Potassium Chloride, Antihypertensive agents, Antidiabetic agents, Nebulization

Patients were evaluated for two major outcomes:
Primary outcome, which is Resolution of Respiratory Failure [Time frame: Day 0 through Day 28] and Secondary outcomes and involve improvement on WHO ordinal scale (key secondary measure), Survival, hospital discharge, discharge alive and improvement in PaO2/FiO2 ratio [Time frame: Day 0 through day 28].

The interim results are compiled below:
Resolution of Respiratory Failure: Resolution of respiratory failure is defined as clinical status in states <4 of the WHO 7-point ordinal scale.

Table 3: Number of patients resolved the respiratory failure
Aviptadil
n (%) Placebo
n (%) p value*
N 51 51 -
Day 3 14 (27.45) 5 (9.80) p = 0.007
Day 7 32 (62.75) 15 (29.41) p = 0.003
Day 14 38 (74.50) 24 (47.06) p = 0.044
Day 28 39 (76.47) 31 (60.78) p = 0.046

Clinical Status on WHO 7-point Score
Clinical status of the patients was assessed by WHO 7-point ordinal scale recommendation which consists of the following numeric scale and scale descriptors.

At day 3, the mean difference value for clinical status on the seven-category ordinal scale was 0.78 (95% CI: 0.16 to 1.40) between-group difference respectively.

At day 7, the mean difference value for clinical status on the seven-category ordinal scale was 1.33 (95% CI: 0.50 to 2.16) between-group difference respectively.

At day 14, the mean difference value for clinical status on the seven-category ordinal scale was 1.53 (95% CI: 0.52 to 2.54) between-group difference respectively.

At day 28, the mean difference value for clinical status on the seven-category ordinal scale was 1.50 (95% CI: 0.32 to 2.69) between-group difference respectively.

Table 4: Clinical Status on WHO 7-point Score - Aviptadil Group (Test)
Aviptadil Group (Test)
Score Description Number of patients reported the respective score
Day 1 Day 2 Day 3 Day 7 Day 14 Day 28
0 No clinical or virological evidence of infection 0 0 0 1 2 10
1 No limitation of activities 0 0 3 7 17 21
2 Limitation of activities 0 0 2 8 10 7
3 Hospitalized, no oxygen therapy 0 5 9 16 9 1
4 Oxygen by mask or nasal prongs 3 9 11 1 2 0
5 Non-invasive ventilation or high flow oxygen 31 25 17 9 1 0
6 Intubation and mechanical ventilation 15 10 6 3 1 0
7 Ventilation + additional organ support- pressors, RRT, ECMO 2 2 2 0 0 0
8 Death 0 0 1 6 9 12

Table 5: Clinical Status on WHO 7-point Score - Placebo Group (Test)
Placebo Group (Control)
Score Description Number of patients reported the respective score
Day 1 Day 2 Day 3 Day 7 Day 14 Day 28
0 No clinical or virological evidence of infection 0 0 0 0 1 2
1 No limitation of activities 0 0 0 1 3 7
2 Limitation of activities 0 0 2 2 8 13
3 Hospitalized, no oxygen therapy 0 1 3 12 12 9
4 Oxygen by mask or nasal prongs 1 12 15 9 7 1
5 Non-invasive ventilation or high flow oxygen 35 21 15 11 2 1
6 Intubation and mechanical ventilation 11 9 6 2 1 0
7 Ventilation + additional organ support- pressors, RRT, ECMO 4 2 1 0 0 0
8 Death 0 6 9 14 17 18

Table 6: Mean difference of WHO 7-point ordinal score
Aviptadil
Mean (±SD) Placebo
Mean (±SD) Mean Difference From Day 1 (95% CI) p value*
N 51 51 - -
Day 1 5.31 (±0.6477) 5.36 (±0.6579) - -
Day 2 4.90 (±0.9644) 5.33 (±1.2754) 0.39 (-0.04 to 0.82) p = 0.0752
Day 3 4.33 (±1.5055) 5.16 (±1.6416) 0.78 (0.16 to 1.40) p = 0.013
Day 7 3.64 (±2.4801) 5.01 (±2.0927) 1.33 (0.50 to 2.16) p = 0.002
Day 14 3.03 (±2.5919) 4.60 (±0.6311) 1.53 (0.52 to 2.54) p = 0.003
Day 28 2.62 (±3.0787) 4.17 (±2.9779) 1.50 (0.32 to 2.69) p = 0.013

Table 7: Number of patients reported the clinical severity on WHO 7-point ordinal scale
Study Day Aviptadil Group (Test)
n (%) Placebo Group (Control)
n (%)
Score <4 Score
4 to 7 Score 8 Score <4 Score 4 to 7 Score 8
Day 1 0 51 (100) 0 0 51 (100) 0
Day 2 5 (9.80) 46 (90.20) 0 1 (1.96) 44 (86.27) 6 (11.76)
Day 3 14 (27.50) 36 (70.59) 1 (1.96) 5 (09.80) 37 (72.54) 9 (17.65)
Day 7 32 (62.75) 13 (25.49) 6 (11.76) 15 (29.41) 22 (43.14) 14 (27.45)
Day 14 38 (74.50) 4 (7.84) 9 (17.65) 24 (47.06) 10 (19.61) 17 (33.33)
Day 28 39 (76.47) 0 12 (23.53) 31 (60.78) 2 (3.92) 18 (35.30)

4-point improvement on WHO 7-point Ordinal Scale
There were significant differences between the Aviptadil and Placebo groups for 4-point or greater improvement in clinical status on Day 3, 7, 14 and 28 (p<0.05 by Pearson chi2 test).

Table 8: Number of patients who have shown 4-point improvement on WHO 7-point Ordinal Scale
Study Day Aviptadil Group (Test)
n (%) Placebo Group (Control)
n (%) p value*
N 51 51 -
Day 3 4 (7.84) 0 p = 0.041
Day 7 10 (19.61) 1 (1.96) p = 0.004
Day 14 23 (45.09) 5 (9.80) p = 0.001
Day 28 32 (62.75) 13 (25.49) p = 0.001
*Pearson chi2 test

2-point improvement on WHO 7-point Ordinal Scale
There were significant differences between the Aviptadil and Placebo groups for 2-point or greater improvement in clinical status on Day 7, 14 and 28 (p<0.05 by Pearson chi2 test).

Table 9: Number of patients who have shown 2-point improvement on WHO 7-point Ordinal Scale
Study Day Aviptadil Group (Test)
n (%) Placebo Group (Control)
n (%) p value*
Day 1 0 0 -
Day 2 7 (13.73) 4 (7.84) -
Day 3 14 (57.45) 7 (13.73) p = 0.049
Day 7 33 (64.71) 14 (27.45) p = 0.001
Day 14 39 (76.47) 24 (47.06) p = 0.033
Day 28 39 (76.47) 31 (60.78) p = 0.046

Survival at Day 28
By day 28, a total of 39/51 (76.5%) patients survived in the Aviptadil group, and 33/51 (64.7%) in the placebo group.

Table 10: Number of patients survived at Day 28 in accordance with the study treatment group
Treatment Group Survival Status at Day 28 p value
Survived,
n (%) Death,
n (%)
Aviptadil Group (Test) N=51 39 (76.5) 12 (23.5) p = 0.0307*
Placebo Group (Control) N=51 33 (64.7) 18 (35.3)
N: Number of patients allotted to treatment group
n: Number of patients who reported the event
*Pearson chi2 test

Hospital Discharge: All patients receiving Aviptadil were discharged from hospital, whereas 2 patients in the placebo arm hospitalized at Day 28
Table 11: Number of patients discharged from the hospital
Treatment Group Hospital Discharge at Day 28
At Day 14, n (%) At Day 28, n (%)
Aviptadil Group (Test) N=51 33 (64.70) 39 (76.47)
Placebo Group (Control) N=51 26 (50.98) 31 (60.78)

Conclusions from the clinical study:
The interim results from the current study reinforced the point that Aviptadil is an effective drug in treating ARDS due to COVID-19. The primary end point of resolution of respiratory failure was assessed using “WHO 7-point ordinal scale”.

Aviptadil group showed considerable improvement of clinical symptoms on the “WHO 7-point ordinal scale” as compared to the placebo group.

In the patients with Severe COVID-19, Aviptadil treatment group had a significantly better survival rate as compared to the placebo group.

Patients in the Aviptadil group had a marked improvement in PaO2/FiO2 ratio, as compared to placebo group.

Thus, based on interim analysis of the study, a clear cut improvement was observed in terms of the higher rate of disease resolution and patient survival, improvement in WHO 7-point Ordinal Scale. Safety of Aviptadil was found to be comparable to Placebo.

Study Design II: (2-arm trial): Number of patients: 150
A Multi-centric, Comparative, Randomized, Double blind, Placebo controlled Phase 3 trial to evaluate the Efficacy and Safety of Intravenous Aviptadil, as an add-on to the ‘Standard of care in severe COVID-19 patients with respiratory failure.

The primary objective is to evaluate the efficacy of aviptadil in severe COVID-19 patients with respiratory failure.

The secondary objective is to evaluate the safety of aviptadil in severe COVID-19 patients with respiratory failure.

A total of 150 adult volunteers who or his/her LAR had given written informed consent for the study participation, and who complied with inclusion and exclusion criteria were enrolled in the study.

The study was designed to evaluate the efficacy and safety of aviptadil 150 mcg injection in severe COVID-19 patients with respiratory failure.

The patients assigned to the Test group received the Aviptadil 150 mcg injection with Standard of Care as per Government of India guidelines and the Control group received Placebo with Standard of Care as per Government of India guidelines. Treatment day 1 was considered once the subject was enrolled in the study (Day 1). On Day 1,the enrolled patients were treated with the study medication, as per the randomization schedule. The treatment phase was continued for consecutive 3 days. The observations were conducted at the timeline specified in the study protocol. All the patients were followed-up post-discharge upto Day 28 and on Day 60 from the day of enrolment. Safety was assessed during the entire study duration based on an adverse event(s).

Dose and Mode of Administration:
The assigned drug was administered intravenously.

Patients were treated with 12-hour infusions of the assigned drug at ascending doses on 3 successive days.

Patients received the assigned drug at a dose of 0.166 mcg/kg/hr on Day-1 (1 vial), 0.332 mcg/kg/hr on Day-2 (2 vials) and 0.498mcg/kg/hr on day-3 (3 vials).

Duration of treatment: The study treatment was provided for 3 consecutive days.

Summary:
A total of 150 patients (mean age, 49.9 years) were randomized and received Aviptadil or placebo for 3 days as per the dosage schedule (as per randomization) as an add-on to the ongoing standard of care treatment as per the Clinical Management Protocol for COVID-19 as per the guidelines laid by the Government of India, in both the treatment groups.

The standard of care for symptomatic treatment or treatment for COVID-19 or SARS-CoV-2infection as per the Clinical Management Protocol for COVID-19 as per the guidelines laid by the Government of India was permitted during the study. During the treatment phase, the details of concomitant medication (Standard of Care) and is presented in Table 12 and figure 1.

Details of the Standard of Care used in clinical trial.

Table 12 Details of standard of care in clinical trial:

Figure 1 represents graphical representation of SOC distribution

EFFICACY EVALUATION:

Resolution of Respiratory Failure (Primary End point)
On the WHO, 7-point ordinal scale the resolution of respiratory failure is defined as when the clinical status is at <4 points, since this clinical point represents no oxygen support requirement.

In this study the number of patients showing resolution of the respiratory failure is given in Table 13 and figure 2.

Table 13: Number of patients resolved the respiratory failure

*Unpaired t-test; NS: Non significant; S: Significant

Figure 2 shows the number of patients showing resolution of Respiratory failure On Day 3, 7, 14 and 28

a. Resolution of Respiratory Failure (Primary End point)
On the WHO, 7-point ordinal scale the resolution of respiratory failure is defined as when the clinical status is at <4 points, since this clinical point represents no oxygen support requirement. In the current study the number of patients showing resolution of the respiratory failure is presented in Table 13.

b. Time to resolution from respiratory failure: (measured using Kaplan Meier Table)
An earlier resolution from respiratory failure with a median decrease of 7-days was observed in Aviptadil-treated patients as compared to 14 days with the placebo-treated patients. (Figure 3)

c. Improvement on WHO 7-point Ordinal Scale (Secondary End Point):
For the analysis of the key secondary outcome measure, the distribution of the WHO 7-point ordinal clinical status scale with 7 categories was evaluated. The clinical Status on WHO 7-point Ordinal

Scale is defined in Table 5. The number of subjects by the distribution of WHO 7-point ordinal scale is presented by the treatment arm at study Day 1, 2, 3, 7, 14, and 28 in Table 14 and Table 15.

Table 14: Clinical Status on WHO 7-point ordinal scale Aviptadil Group

2 patients of Aviptadil group were discontinued on Day 2 from the trial hence their data are not available

Table 15: Clinical Status on WHO 7-point ordinal scale Placebo Group

1 patient of Placebo group was dropped-out on Day 2 from the trial hence her data is not available.

Clinical status on WHO 7-point ordinal scale is presented in stacked bar charts by day in Figure 4.

i. Mean score of WHO 7-point ordinal scale on Day1, 2, 3, 7, 14 and 28
The mean difference of WHO 7-point ordinal score was assessed on Day 1, 2, 3, 7, 14 and 28. The results are summarized in Table 16

Table 16: Mean on difference of WHO 7-point ordinal score

*Unpaired t-test; NS: Non significant; S: Sign

The improvement in clinical symptoms on Day 7, 14 and 28 was significantly (p<0.05) better in the Aviptadil group than the placebo group.

ii. =2-point improvement on WHO 7-point Ordinal Scale

Improvement on a WHO 7-point Ordinal Scale was also observed in terms of patients’ clinical status improvement which has defined as reduction by 2 or more points representing a clinically meaningful improvement. Details of number of patients showing =2 point improvement on WHO 7-point Ordinal Scale are given in Table 17 and figure 5.

Table 17: Number of patients showing =2-point improvement on WHO 7-point Ordinal Scale

*Pearson chi2 test

Aviptadil treated group showed a greater improvement in 2 or more points on the WHO 7-pointOrdinal Scale on Day 7 and 14 (p<0.05).

Number of patients showing =2-point improvement on WHO 7-point Ordinal Scale is shown in figure 5.
iii. =4-point improvement on WHO 7-point Ordinal Scale

Patients having a score of <4 on WHO 7-point Ordinal Scale, show the meaningful improvement since it represents normal blood oxygen saturation without oxygen requirement. Patents showing =4-point improvement on WHO 7-point Ordinal Scale are given in Table 18 and figure 6.

Table 18: Number of patients showing =4-point improvement on WHO 7-point Ordinal Scale

*Pearson chi2 test

A substantially higher proportion of patients from Aviptadil group achieved clinically meaningful 4or more points improvement on the WHO 7-point Ordinal Scale. Aviptadil treated group showed a greater improvement in the clinical status on Day 7, 14 and 28 (p<0.05) with a statistically significant difference of =4 point the WHO 7-point Ordinal Scale.

Number of patients showing =2-point improvement on WHO 7-point Ordinal Scale is shown in figure 6.

d. Survival of the Patients at Day 28 and Day 60

A total 77.63% patients of the Aviptadil group and 74.32% patients of the placebo group survived at Day 28, out of which all the surviving patients in Aviptadil group and 53 (71.62%) patients in placebo group were discharged. Two of the patients in placebo group were discharged on day 38 and day 46.

At Day 60 follow-up, 77.63% of patients in the Aviptadil group and 74.32% of patients in the placebo group survived.

The secondary endpoint of “survival of the patients” was evaluated using the Kaplan Meier life table.

Aviptadil-treated patients survived 1.1-fold more at day 60 as compared to placebo. The relative risk of failure to survive was reduced by 13% in the Aviptadil group as compared to the placebo.

The number of patients were survived at Day 28 and Day 60 in the study treatment group are given in Table 19

Table 19: Survival Status of the patients at Day 28 and Day 60

The Kaplan Meier curves for the time to death are shown in Figure 7.

e. Improvement in PaO2/FiO2 ratio:
Patients in the Aviptadil group had a clinically meaningful and statistically significant improvement in PaO2/FiO2 ratio starting from day 3 onwards, as compared to the placebo group. The improvement in PaO2/FiO2 ratio is shows in figure 8.

Efficacy Conclusions
In this clinical trial, faster resolution from respiratory failure was observed in Aviptadil-treated patients as compared to placebo-treated patients. A substantially higher proportion of patients from Aviptadil group achieved clinically meaningful improvement on the WHO 7-point Ordinal Scale.

The results of the clinical study show a clear improvement in terms of the higher rate of disease resolution, patient survival and improvement in the WHO 7-point Ordinal Scale.

SAFETY ANALYSIS
Safety was evaluated based on the incidences of adverse events and Serious Adverse Events reported in the Test and control groups.

Adverse Events: In the test group, 8 adverse events (AEs) (severe bronchospasm, tachypnea, tachycardia, swelling and redness, dizziness, irregular heart rate, chills and headache) were reported in 6 patients, whereas 4 AEs were reported in 4 patients in the placebo group (nausea, headache, rashes and excessive sweating). The causality assessment revealed that the AEs may or may not be associated with the investigational drugs as all the patients were receiving Standard of treatment along with. All adverse events were of mild to moderate severity and resolved without any sequelae. Two of the six patients in the Aviptadil group who experienced adverse events were discontinued from the study and one patient in Placebo group withdrew from the study after first dose and left the hospital against the Medical advice.

Serious Adverse Events: A total of 33 Serious Adverse Events (SAEs) were reported in the study including 15 (deaths) in the Aviptadil group and 18 (deaths) in the Placebo group. Respiratory failure was the primary cause of death in COVID-19. The reported SAEs (death due to COVID pneumonitis, acute respiratory distress syndrome with the presence of comorbidities) were not related to the study drug.

Conclusion: The primary endpoint of resolution of respiratory failure was assessed using the “WHO-7- point faster resolution (median 7-days) from respiratory failure was observed in Aviptadil-treated patients as compared to placebo-treated patients. A substantially higher proportion (~78%) of patients from Aviptadil group achieved clinically meaningful improvement on the WHO 7-point Ordinal Scale. Additionally, the relative risk of failure to survive was reduced by 13% in the Aviptadil group as compared to the placebo.

The results from the Aviptadil group show clinically meaningful and statistically significant improvement in PaO2/FiO2 ratio starting from day 3 onwards, as compared to the placebo group.

Aviptadil treatment was well tolerated and the safety was found to be comparable to the Placebo.

In conclusion, the current study reinforced the point that Aviptadil is an effective drug in treating acute respiratory distress syndrome.

It is to be understood that the present invention is susceptible to modifications, changes and adaptations by those skilled in the art. Such modifications, changes, adaptations are intended to be within the scope of the present invention.
,CLAIMS:
1. An Aviptadil composition comprising of 5-45µg/ml of Aviptadil

2. The Aviptadil composition as claimed in claim 1 is in the form of ready to use solution.

3. The Aviptadil composition as claimed in claim 2 wherein the ready to use solution comprises pharmaceutically acceptable excipients selected from sodium chloride, disodium edetate, sodium hydroxide/hydrochloric acid q.s. to adjust pH, or water of injection q.s.

4. The Aviptadil composition as claimed in claim 1 is in the form of a lyophilized powder.

5. The Aviptadil composition as claimed in claim 1 is used for the treatment of severe COVID-19 patients with respiratory failure in ascending doses of 0.166 µg/kg/hr on Day 1, 0.332 µg/kg/hr on Day 2 and 0.498 µg/kg/hr on day 3 as 12-hour intravenous infusion on 3 successive days.