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EUROPEAN JOURNAL OF PHARMACEUTICAL
AND MEDICAL RESEARCH
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ABSTRACT
Aim: This study is aimed at evaluating efficacy and safety of Intravenous Aviptadil as an add-on to the Standard
of Care treatment in severe COVID-19 patients with respiratory failure. Design, Setting and Participants: A
randomized, multicentric, double-blind, placebo-controlled, comparative Phase III clinical trial was conducted at 8
geographically distributed sites across India between April 2021 to October 2021. The study enrolled 150
participants who were tested and confirmed cases of severe COVID-19 with respiratory failure and acute
respiratory distress syndrome. Interventions: 12-hour intravenous infusions of Aviptadil over 3 successive days in
ascending doses 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). Methodology: Severe COVID-19 patients with respiratory failure were randomized in
two groups in a ratio of 1:1, to receive either Aviptadil or Placebo. Both the study drugs were given as an add-on to
the standard of care (SOC). The SOC was kept as close as possible to the COVID-19 treatment guidelines specified
by the Government of India. The study site staff, investigator and patients were masked to the treatment allocation.
The primary endpoint of the study was resolution of respiratory failure whereas the secondary endpoints were
improvement in WHO 7-point ordinal scale, improvement in PaO2:FiO2 ratio, survival of the patients and
incidences of adverse events. Results: After the completion of treatment in Aviptadil group, an improvement was
observed in the primary outcome of resolution of respiratory failure. Proportion of patients on Aviptadil
demonstrated statistically significant odds, 2.1-fold, (p=0.0410) of being free of respiratory failure (no oxygen
requirement) at Day 3 and 2.6-fold (p=0.0035) at day 7 as compared to the placebo group. An earlier resolution
from the respiratory failure, with a median duration of 7 days was noted in the Aviptadil-treated group as compared
to 14 days in the placebo group. A higher proportion of patients on Aviptadil shifted to the milder clinical state
(32.43% vs 17.80%; p=0.0410 on Day 3 and 70.27% vs 45.21%; 0.0035 on Day 7) without the requirement of
oxygen than the placebo group. A reduction of severity (based on WHO 7-point ordinal scale) in clinical status
were also observed on Day 14 (p = 0.0005 by Wilcoxon rank sum test) and Day 28 (p = 0.0009 by Wilcoxon rank
sum test). There were 68.42% Aviptadil-treated patients who showed 2 or more points improvement on the WHO
7-point ordinal scale as compared to 44.59% in the placebo group (p=0.003; Pearson chi2 test; odds ratio, 2.69;
95% CI, 1.38-5.24) on Day 7. On day 28, patients in the Aviptadil group had higher odds (1.38) of an improvement
on WHO 7-point ordinal scale as compared to placebo with SOC. Aviptadil reduced the risk of death by 20%
(relative risk 0.80; 95% CI: 0.35, 1.66) in ARDS. Patients treated with Aviptadil demonstrated significant
improvement in PaO2/FiO2 ratio vs. placebo from day 2 to over the week (p<0.05) and beyond. There were 15
deaths in the Aviptadil group and 18 deaths in the placebo group. No deaths were attributed to the Investigational
products. COVID-19related mortality occurred in 22% patients of the study population, due to respiratory failure
caused by underlying medical conditions. Conclusion: Use of Aviptadil was safe and effective in improving the
resolution of respiratory failure, shortening the time to recovery, decreasing respiratory distress and preventing
death in respiratory failure patients. The rapidity and magnitude of clinical effect suggests a highly specific role of
Aviptadil in combating the lethal effects of Acute Respiratory Distress Syndrome associated with COVID-19.
KEYWORDS: COVID-19, Vasoactive Intestinal Peptide (VIP), Acute Respiratory Distress Syndrome (ARDS),
Acute Lung Injury (ALI), Alveolar Type II.
*Corresponding Author: Dr. Bhupesh Dewan
Department of Medical Services, Zuventus Healthcare Ltd., Office No. 5119, Oberoi Garden Estate, Chandivali, Andheri (E), Mumbai-400 072,
India.
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1. INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a
devastating clinical syndrome of acute respiratory failure
that presents with progressive arterial hypoxemia,
dyspnea, and a marked increase in the work of breathing
with a need for mechanical ventilation.[1] ARDS is the
rapid onset of progressive malfunction of the lungs, that
quickly evolves into respiratory failure. The condition is
associated with extensive lung inflammation and
accumulation of fluid in the alveoli (air sacs) that affects
the lung‟s gas exchange capability.[2] ARDS is a
manifestation of acute injury to the lung, associated with
sepsis, pneumonia, severe pulmonary infections,
aspiration of gastric contents, and major trauma.[3,4]
ARDS has been widely recognized as a major clinical
problem worldwide. Globally, ARDS affects
approximately 3 million patients annually, accounting for
10% of intensive care unit (ICU) admissions, and 24% of
patients receiving mechanical ventilation in the ICU[5]
with an estimated mortality rate of approximately 40-
60% depending on disease severity.[6,7] The incidence of
ARDS in patients with risk factors is 30% in India with
the mortality of 41.8%.[8]
In the setting of lung injury, neutrophils accumulate in
the lung microvasculature, get activated and migrate in
large numbers across the vascular endothelial and
alveolar epithelial surfaces, releasing several toxic
mediators, including proteases, cytokines, and reactive
oxygen species which result in increased vascular
permeability and a sustained loss of normal endothelial
barrier function.[1,9] This migration and mediator release
lead to pathologic vascular permeability gaps, in the
alveolar epithelial barrier and necrosis of type I and II
alveolar cells. Type I alveolar cells are irreversibly
damaged and the denuded space is replaced by the
deposition of proteins, fibrin, and cellular debris,
producing hyaline membranes, while injury to the
surfactant-producing alveolar type II (ATII) cells
contributes to alveolar collapse. In the proliferative
phase, ATII cells proliferate with some epithelial cell
regeneration, fibroblastic reaction, and remodeling. In
some patients, this progresses to an irreversible fibrotic
phase involving collagen deposition in alveolar, vascular,
and interstitial beds with the development of
microcysts.[4]
Vasoactive Intestinal Peptide (VIP) is a gut peptide
hormone, containing 28-residue amino acid peptides.
VIP is highly localized in the lungs (70%) and binds with
ATII cells via VIP receptor type-1 (VPAC1).[10] Its action
is mediated through VPAC1 and VIP receptor type-2
(VPAC2), which are activated by Pituitary Adenylate
Cyclase-Activating Polypeptide (PACAP) belongs to the
glucagon-secretin superfamily.[11] VIP was awarded
Orphan Drug Designation in 2001 by USFDA for
treatment of Acute Respiratory Distress Syndrome.[12]
Aviptadil, a synthetic form of human VIP was awarded
Orphan Drug Designation for treatment of Pulmonary
Arterial Hypertension (in 2005 by USFDA), Acute Lung
Injury (in 2006 by EMA) and Sarcoidosis (in 2007 by
EMA and in 2020 by USFDA).[13-16]
Aviptadil acts as a potent anti-cytokine in the lung that
provides a key defense against numerous forms of acute
lung injury. Aviptadil blocks apoptosis, caspase-3
activation in the lung, inhibits inflammatory cytokines
like IL6 and TNF-alpha production and reverses
CD4/CD8 ratio. Aviptadil increases surfactant
production by up-regulation of choline phosphate
cytidylyltransferase, which increases the incorporation of
methyl choline into phosphatidylcholine[17,18], the major
component of pulmonary surfactant.[19] Surfactant
reduces the alveolar surface tension, thereby preventing
alveolar collapse and allows for breathing with minimal
efforts. Furthermore, pulmonary surfactant enhances
phagocytes function and maintains immune response in
patients with ARDS.[20] Aviptadil prevents the activation
of NMDA‐induced caspases, inhibits IL‐6 and TNF‐α
production and protects against HCl‐induced pulmonary
oedema.[21] In a clinical study, Aviptadil reduced the
mortality rate to 12.5% during intensive care and 25% at
30 days which is lower than the expected mortality in
sepsis-related ARDS.[22]
ARDS is a global threat with significant health and
economic burden as it needs intensive medical and
pharmaceutical care. Treatment of ARDS is mainly
supportive, and it encompasses all measures such as
supplemental oxygen, inflammation management
(corticosteroids), fluid management, decrease oxygen
consumption and increase oxygen delivery.[23] Current
managements of ARDS are hampered by the failure to
diagnose the condition and to prevent iatrogenic harms
such as hospital-acquired infections, ICU acquired
weakness, delirium, risk of bleeding and thrombosis,
acute kidney injury, hypotension and renal
dysfunction.[2]
Severe COVID-19 represents viral pneumonia from
severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection leading to ARDS. Its manifestations
can be viewed as a combination of the two events,
namely viral pneumonia and ARDS.[24] The mechanism
appears for lung involvement are a combination of both
direct viral-mediated injury and host inflammatory
response. The pathological features of COVID-19 greatly
resemble those seen in SARS and Middle Eastern
respiratory syndrome (MERS) coronavirus infections.
COVID-19 ARDS causes the typical ARDS pathological
changes of diffuse alveolar damage in the lung[25,26] but
the mortality is increased up to 61.5%.[24] A lethal SARS-
CoV-2 infection that specifically attacks the ATII cells
which perform an important role during breathing. This
highly specific role of Aviptadil in the lung may be the
key to combating the lethal effects of SARS-CoV-2
infection.
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Considering the benefits and need of therapeutic option
for the treatment of ARDS, this study was conducted in
India, to evaluate the safety and efficacy of Aviptadil in
severe COVID-19 patients with respiratory failure.
2. MATERIAL AND METHODS
2.1 Design and Setting
The study was a multicentric, randomized, double-blind,
comparative placebo-controlled, Phase III clinical trial to
evaluate the efficacy and safety of intravenous Aviptadil,
as an add-on to the Standard of Care‟ (SOC) treatment
in severe COVID-19 patients with respiratory failure.
After an approval from the Drug Controller General of
India, the study was conducted in eight geographically
distributed sites across India. The protocol was approved
by the institutional ethics committee at each study site.
The study was performed in accordance with
International Council for Harmonization for Good
Clinical Practice, Declaration of Helsinki and New
Drugs and Clinical Trials, Rules, 2019, The study was
registered with the Clinical Trial Registry of India
(CTRI/2021/04/033118).
2.2 Participants
Patients admitted in hospital were evaluated as per the
study eligibility criteria. Patients aged 18 years or older
admitted to hospital with laboratory confirmation of
SARS-CoV-2 infection and severe disease condition as
per COVID-19 treatment guideline specified by
Government of India (severe condition defined as
respiratory rate >30 breaths/min or SpO2 <90% on room
air or ARDS or septic shock)[27] were considered eligible.
Patients were excluded if the investigator judged that
they had any serious medical conditions or irreversible
condition (other than COVID-19) with projected fatal
course. Patients were also excluded if they were
receiving immunosuppressive therapy or having a recent
history of myocardial infarction, congestive heart failure.
All patients or their legally acceptable representatives
provided written informed consent to participate in the
study. The details of the disposition of patients in the
study are given in Figure 1.
Figure 1: Disposition of patients in the study.
2.3 Randomization and Blinding
Eligible patients were randomly assigned using block
randomization in a ratio 1:1 to receive Aviptadil plus
SOC (Aviptadil group) or placebo plus SOC (Placebo
group). Participants from Aviptadil group received 12-
hour intravenous infusions of Aviptadil over 3 successive
days in ascending doses 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). Since
it was a double-blind study, the assigned treatment arm
was not known to the site staff, investigator and the
patients.
The SOC treatment was administered along with
investigational products as per the COVID-19 treatment
guidelines specified by the Government of India, in both
the treatment groups. SOC included, symptomatic
treatment, adequate hydration, oxygen support,
conservative fluid management, anticoagulation,
corticosteroids, anti-viral, control of co-morbid condition
and regular monitoring for breathing, hemodynamic
stability and oxygen requirement. The SOC was kept as
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close to the Government treatment protocol as possible
in all the study sites.
2.4 Outcome Measures
The clinical status of patients was assessed using the
World Health Organization‟s (WHO) 7-point ordinal
scale recommended by the WHO R&D Blueprint
Group.[28] Clinical status score on WHO 7-point ordinal
scale were defined as follows: 0‟: No clinical or
virological evidence of infection; 1‟: No limitation of
activities; 2‟: Limitation of activities 3‟: Hospitalized,
no oxygen therapy; 4‟: Oxygen by mask or nasal
prongs, 5‟: Non-invasive ventilation or high flow
oxygen, 6‟: Intubation and mechanical ventilation; 7‟:
Ventilation + additional organ support- pressors,
receiving renal replacement therapy, extracorporeal
membrane oxygenation; 8‟: Death.
The primary efficacy outcome of the study was
resolution of respiratory failure up to day 28. Resolution
of respiratory failure was defined as clinical status ≤3
(No Oxygen Requirement) on the WHO 7-point ordinal
scale. The secondary outcomes were two or more points
improvement in WHO 7-point ordinal scale, survival of
the patients, improvement in PaO2:FiO2 ratio and
incidences of adverse events (AEs). The outcomes were
assessed up to Day 28 and patients were followed for
survival status at Day 60. Safety was assessed by the
number of patients reporting incidences of AEs.
2.5 Statistical Analysis
A sample size of 150 patients in the study was estimated
to provide 80% power, with a 5% level of significance,
to establish a difference between the Aviptadil group and
the Placebo group. The mortality with PaO2/FiO2≤100
mmHg were reported in 56% of severe COVID-19
patients with the SOC.[29] We assumed add-on treatment
of Aviptadil to the SOC‟ would reduce the mortality rate
by 30% in COVID-19 patients. Based on the above
assumptions, the sample size required per group was
found to be 62. Considering a drop-out rate of 20%, 75
patients were randomized in each group.
Descriptive statistics was used to summarize baseline
characteristics; data was represented in terms of number
of observations (n), mean ± standard deviation (SD) for
continuous variables whereas frequency counts and
percentages were established for categorical variables.
Baseline and demographic characteristics of two
treatment groups were assessed using unpaired Student‟s
t-test or Pearson-chi2 test.
The primary endpoint was assessed as the proportion of
patients who progressed on WHO 7-point ordinal scale
and significance tested using Pearson-chi2 test.
Improvement on WHO 7-point ordinal scale and
PaO2/FiO2 ratio of two treatment groups was assessed
using unpaired Student‟s t-test and Pearson-chi2 test.
Time to resolution from respiratory failure and survival
probability were calculated on Kaplan Meier Survival
method. All analysis results were presented with a
significance level at 0.05 and 95% confidence intervals.
Safety was summarized descriptively, and AEs and
serious adverse events (SAEs) were assessed as the
frequency and proportion of patients reporting the event.
3. RESULTS