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Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS—a randomized, placebo-controlled, double-blind trial

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Background Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. Methods This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. Discussion The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. Trial registration This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47 .
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S T U D Y P R O T O C O L Open Access
Safety and preliminary efficacy of
sequential multiple ascending doses of
solnatide to treat pulmonary permeability
edema in patients with moderate-to-severe
ARDSa randomized, placebo-controlled,
double-blind trial
Benedikt Schmid
1
, Markus Kredel
1
, Roman Ullrich
2
, Katharina Krenn
2
, Rudolf Lucas
3
, Klaus Markstaller
2
,
Bernhard Fischer
4
, Peter Kranke
1*
, Patrick Meybohm
1
, Bernhard Zwißler
5,6
, Sandra Frank
5
and and the Solnatide
Collaborators Group
Abstract
Background: Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible
etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar
diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent
(AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to
administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial
investigating the safety and possible future efficacy endpoints in ARDS patients.
Methods: This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to
severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of
solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will
investigate the data from previous patients for any indication of patient safety violations. The intervention
(application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up
period of another 21 days.
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permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: kranke_p@ukw.de
1
Department of Anaesthesiology, Intensive Care, Emergency and Pain
Medicine, University Hospital Wuerzburg, Wuerzburg, Germany
Full list of author information is available at the end of the article
Schmid et al. Trials (2021) 22:643
https://doi.org/10.1186/s13063-021-05588-9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Discussion: The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The
amount of data to be collected upon screening and during the course of the intervention phase is substantial and
the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to
this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to
informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of
inclusion.
Trial registration: This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu).
EudraCT Number: 2017-003855-47.
Keywords: Acute respiratory distress syndrome, Solnatide, Extravascular lung water, Pulmonary edema, Critical care
Administrative information
The order of the items has been modified to group simi-
lar items (see http://www.equator-network.org/
reporting-guidelines/spirit-2013-statement-defining-
standard-protocol-items-for-clinical-trials/).
Title {1} Safety and preliminary efficacy of
sequential multiple ascending doses of
solnatide to treat pulmonary
permeability edema in patients with
moderate-to-severe ARDS - a random-
ized, placebo-controlled, double-blind
trial
Trial registration {2a and 2b}. Primary Registry and trial identifying
number:
clinicaltrialsregister.eu ; EudraCT 2017-
003855-47
Date of registration in primary registry:
2 February 2018
Secondary identifying numbers:
not applicable
Sources of monetary or material
support:
Apeptico Forschung und Entwicklung
GmbH
Primary sponsor:
Apeptico Forschung und Entwicklung
GmbH
Secondary sponsor(s):
not applicable
Contact for public queries:
Apeptico Forschung und Entwicklung
Prof. Dr. Bernhard Fischer
Mariahilfer Str. 136, Top 1.15
1150 Vienna, Austria
00436641432919
b.fischer@apeptico.com
Contact for scientific queries:
Apeptico Forschung und Entwicklung
Prof. Dr. Bernhard Fischer
Mariahilfer Str. 136, Top 1.15
1150 Vienna, Austria
00436641432919
b.fischer@apeptico.com
Public title:
Safety and preliminary efficacy of
sequential multiple ascending doses of
solnatide to treat pulmonary
permeability edema in patients with
moderate-to-severe ARDS - a random-
ized, placebo-controlled, double-blind
trial
Scientific title:
Administrative information (Continued)
Safety and preliminary efficacy of
sequential multiple ascending doses of
solnatide to treat pulmonary
permeability edema in patients with
moderate-to-severe ARDS - a random-
ized, placebo-controlled, double-blind
trial
Countries of recruitment:
Austria, Germany
Health conditions or problems studied:
pulmonary permeability edema in
patients with moderate-to-severe ARDS
Interventions:
Bronchial inhalation of ascending doses
of solnatide vs. placebo for seven days
Key inclusion and exclusion criteria:
Ages eligible: 18 years
Sexes eligible: both
Accepts healthy volunteers: no
Inclusion criteria: diagnosis of moderate
to severe ARDS according to the Berlin
definition, need for mechanical
ventilation, pulmonary edema (EVLWI
10 ml/kg PBW), informed consent
Exclusion criteria: allergy against
solnatide, severe septic shock,
extracorporeal membrane oxygenation
at time of screening
Study type:
interventional
allocation: randomized
intervention model: parallel assignment
masking: double blind (patient,
caregiver, investigator, outcomes
assessor)
Date of first enrolment:
23.05.2018
Target sample size:
95
Recruitment status:
ongoing
Primary outcome:
Safety (mortality, AEs, SAEs, laboratory
data, ECG)
Key secondary outcomes:
extravascular lung water index (EVLWI),
pulmonary vascular permeability index
(PVPI), oxygenation ratio, ventilation
parameters
Protocol version {3} Version 8.0, 2 August 2021
Funding {4} Apeptico Entwicklung und Forschung
GmbH
Schmid et al. Trials (2021) 22:643 Page 2 of 21
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Administrative information (Continued)
Commercial sponsor
Author details {5a} BS, MK, PK, PM: Department of
Anaesthesiology, Intensive Care,
Emergency and Pain Medicine,
University Hospital Wuerzburg,
Wuerzburg, Germany
RU, KK, KM: Department of Anaesthesia,
General Intensive Care and Pain
Medicine, Medical University of Vienna,
Austria
BF: Apeptico Forschung und
Entwicklung GmbH, Vienna, Austria
BZ, SF: Department of Anesthesiology,
University Hospital of Ludwig-
Maximilians-University (LMU), Munich,
Germany
RL: Vascular Biology Center, Division of
Pulmonary Medicine, Medical College
of Georgia, Augusta University, Augusta,
USA
Name and contact information
for the trial sponsor {5b}
Apeptico Forschung und Entwicklung
GmbH
Prof. Dr. Bernhard Fischer
Mariahilfer Straße 136
1150 Vienna, Austria
Role of sponsor {5c} The role of the sponsor was limited to
the study design proposal, obtaining
ethics and agencies approval, as well
trial registration.
The sponsor has no role in the
management, analysis and
interpretation of data, writing of the
report, and the decision to submit the
report for publication.
Introduction
Background and rationale {6a}
Acute respiratory distress syndrome (ARDS)
ARDS is a common pathology seen in intensive care
units globally, with associated significant mortality and
even long-term morbidity. ARDS is a clinical diagnosis
accounting for up to 20% of unplanned ICU admissions.
Mortality in ARDS patients is still high. The LUNG
SAFE study [Belani2016] reports a hospital mortality of
40%, with a significant increase across the ARDS severity
categories, in line with Berlin definition (34.9%, in mild
ARDS; 40.3% in moderate ARDS; 46.1% in severe
ARDS). The socioeconomic burden of the disease of
critical illness is immense. A recent systematic review re-
garding the endpoint return to work after critical ill-
nessreported that approximately two-thirds, two-fifths,
and one-third of previously employed intensive care unit
survivors are jobless up to 3, 12, and 60 months follow-
ing hospital discharge [1].
The most recent Berlin definition of ARDS [2]is
shown in Table 1. The pathophysiology of ARDS is not
completely understood. Initially, a direct pulmonary or
indirect extrapulmonary insult is believed to cause a
release of inflammatory mediators that promotes
neutrophil accumulation in the microcirculation of the
lung. Activated neutrophils migrate in large numbers
across the vascular endothelial and alveolar epithelial
surfaces and release proteases, cytokines, and reactive
oxygen species (ROS). The migration and mediator
release of neutrophils lead to pathologic vascular
permeability, gaps in the alveolar epithelial barrier, and
necrosis of type I and II alveolar cells, resulting in
pulmonary edema, hyaline membrane formation, loss of
surfactant and ultimately alveolar collapse, ventilation/
perfusion mismatch, decrease of pulmonary compliance,
and altered gas exchange. Subsequent infiltration of
fibroblasts can lead to collagen deposition, fibrosis, and
worsening disease [3].
Most cases of ARDS in adults are associated with
pulmonary sepsis (46%) or non-pulmonary sepsis (33%).
Risk factors include those causing direct lung injury
(e.g., pneumonia, inhalation injury, pulmonary contu-
sion) and those causing indirect lung injury (e.g., non-
pulmonary sepsis, burns, polytrauma, transfusion-related
acute lung injury) [4].
ARDS is an orphan condition. The in-hospital mortal-
ity rate for ARDS is estimated to be between 34 and 55%
Table 1 The Berlin definition of acute respiratory distress syndrome
Timing Within 1 week of a known clinical insult or new or worsening respiratory symptoms
Chest imaging Bilateral opacitiesnot fully explained by effusions, lobar/lung collapse or nodules
a
Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload
Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present
Oxygenation
Mild 200 mmHg < P
aO2
/F
iO2
300 mmHg with PEEP or CPAP 5cmH
2
O
b, c
Moderate 100 mmHg < P
aO2
/F
iO2
200 mmHg with PEEP 5cmH
2
O
Severe P
aO2
/F
iO2
100 mmHg with PEEP 5cmH
2
O
Abbreviations: CPAP, continuous positive airway pressure; F
iO2
, fraction of inspired oxygen; P
aO2
, partial pressure of arterial oxygen; PEEP, positive
end-expiratory pressure
a
Chest radiograph or computed tomography scan
b
If altitud e is higher than 1000 m, the correction factor should be calculated as follows: [P
aO2
/F
iO2
× (barometric pressure/760)]
c
This may be delivered noninvasively in the mild acute respiratory distress syndrome group
Schmid et al. Trials (2021) 22:643 Page 3 of 21
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[5]. Risk factors for mortality include older age, multior-
gan dysfunction and presence of pulmonary and non-
pulmonary comorbidities. Most ARDS-related deaths are
due to multiorgan failure. Refractory hypoxemia ac-
counts for only 16 percent of ARDS-related deaths [6].
Treatment of ARDS is supportive, including mechanical
ventilation, prevention of stress ulcers and venous
thromboembolism, nutritional support and treatment of
the underlying disease. Pharmacologic options for the
treatment of ARDS are limited. The use of corticosteroids
is controversial; randomized controlled trials and cohort
studies tend to support the early use of corticosteroids for
decreasing the number of days on a ventilator; however,
no consistent mortality benefit has been shown with this
therapy [7,8]. No targeted pharmacological treatment of
patients with pulmonary permeability edema in ARDS is
currently available, and therefore, new therapeutic
approaches are warranted.
Solnatide (INN, laboratory code AP301)background and
pre-clinical studies
Solnatide (AP301) is a synthetic peptide composed of 17
natural amino acids (CysGlyGlnArgGluThrPro
GluGlyAlaGluAlaLysProTrpTyrCys) with a
molecular mass of about 2000 Da. Basically, solnatide is
a circularized presentation of the lectin-like domain (so
called TIP domain) of human TNF-α. Solnatide lacks
any known pro-inflammatory activity to TNF-α. The In-
vestigational Medicinal Product (IMP) Solnatide 25 mg
powder for reconstitution for solution for inhalationis
a sterile, lyophilized preparation of solnatide and con-
tains no additional ingredients. The clinical route of ad-
ministration is pulmonary delivery by inhalation of a
liquid aerosol.
Pharmacological studies using rodent models have
indicated that solnatide is an important regulator of
alveolar fluid balance in healthy and injured lungs.
Intratracheally and pulmonary-administered solnatide
improved alveolar liquid clearance (ALC) in in situ
flooded mouse lungs, in ex vivo models of flooded rat
lungs, and in rat lungs prior to transplantation [911].
In a porcine bronchoalveolar lavage model of ARDS, in-
halation of nebulized solnatide resulted in an increased
P
a
O
2
/F
i
O
2
ratio and reduced extravascular lung water
(EVLW) [12].
The alveolar fluid clearing capacity of solnatide is
related to activation of the amiloride-sensitive sodium
channel (ENaC), the major driving force for reabsorption
of water through the alveolar epithelium [1317]. ENaC
is responsible for the maintenance of Na
+
balance, extra-
cellular fluid volume, and blood pressure and is located
at the apical membrane of salt-reabsorbing tight epithe-
lia of the distal nephron, the distal colon, salivary and
sweat glands, and the lung, where it constitutes the rate-
limiting step for vectorial movement of Na
+
ions from
the luminal side into the cell interior. The basolaterally
located Na-K-ATPase actively transports Na
+
out of the
cell, providing the driving force for Na
+
reabsorption. In
the lung, Na
+
transport through apically located ENaC
in the alveolar epithelium is crucial for maintaining the
correct composition and volume of alveolar lining fluid,
enabling optimal gas exchange [18,19]. Disruption of
these processes occurs in pathologies in which perme-
ability of the alveolar epithelium and pulmonary capil-
lary endothelium is increased, leading to excessive
accumulation of alveolar fluid and edema [20].
In addition to its ALC activity, solnatide inhibits
hypoxia-induced reactive oxygen species (ROS) produc-
tion and counteracts various ROS and toxin-mediated
effects: solnatide inhibits protein kinase C (PKC) alpha
activation thereby restoring ENaC activity. Solnatide re-
duces the degree of myosin light chain (MLC) phosphor-
ylation and thus protects and restores the barrier
integrity of endothelial and epithelial cells [21]. Solnatide
lacks pro-inflammatory activity and does not lead to an
increased production of chemokines or an increased in-
filtration of neutrophils in rat lungs upon intratracheal
instillation.
The standard battery of safety pharmacology studies
did not reveal drug-related adverse effects in any of the
animal models. From animal studies in various species
(rodent and non-rodent), it is evident that peptide clear-
ance from blood is quite fast (decrease by a magnitude
of 3 orders within 2 h) after bolus intravenous injection
of 25 mg solnatide/kg BW. In the 14-day toxicity study
in the rat, lung tissue samples were taken after the last
treatment on day 14 and analyzed for the presence of
solnatide; no test item was detected in lung tissue ap-
proximately 30, 60, and 90 min after the end of treat-
ment in the low-, mid-, and high-dose group
respectively.
Solnatide (AP301)clinical studies
The safety, tolerability and preliminary efficacy of
solnatide have been assessed in three placebo-controlled,
randomized, double-blinded clinical studies.
Study 2011-000223-33 was a first in mandose escal-
ation study in healthy male subjects (N= 48; 36 vs 12)
to investigate the safety, tolerability, and systemic expos-
ure of orally inhaled single doses of solnatide. The high-
est tested dose was 171.4 mg per subject (nebulizer
filling dose), which corresponds approximately to the no
observed adverse effect level (NOAEL) dose of the sub-
chronic toxicity (14 days) study in the beagle dog. The
study concluded that doses of up to 171.4 mg were safe
and well tolerated. Consistent with pre-clinical data in
various species, the distribution of inhaled solnatide was
largely confined to the lung, as indicated by very low
Schmid et al. Trials (2021) 22:643 Page 4 of 21
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maximum (C
max
) and total (AUC
0_t
) solnatide systemic
exposure levels. None of the comprehensive safety as-
sessments employed (spirometry, quantification of ex-
haled NO, blood pressure, heart rate, ECG, safety
laboratory variables, adverse event reports) indicated any
clinically meaningful or remarkable dose- or time-
related alterations of safety outcomes [22].
Study 2012-001863-64 was a proof of concept study in
male and female intensive care patients (N= 40; 1:1)
that investigated the clinical effect of repeated orally in-
haled doses of solnatide on alveolar liquid clearance in
acute lung injury. For safety reasons and according to ef-
fective pharmacological doses observed in various animal
models, the second highest dose of the Phase I clinical
study was chosen: 125 mg solnatide (nebulizer filling
dose) twice daily (i.e., every 12 h) delivered per endo-
tracheal inhalation to each subject. The main efficacy
outcome was a positive trend in pulmonary edema
(EVLWI) reduction in the whole study population,
which is significant and more pronounced in patients
with an initial Sequential Organ Failure Assessment
(SOFA) score above 10 inhaling solnatide versus placebo
(P= 0.04; exploratory subgroup analysis). The secondary
endpoint analysis revealed a trend towards an earlier im-
provement of peak, plateau and mean airway pressure,
PEEP, and Murray lung injury score in patients treated
with solnatide. This effect was again most prominent in
patients with an initial SOFA score > 10 (exploratory
subgroup analysis). In addition, a shorter duration of
mechanical ventilation and increased number of
ventilator-free days in patients receiving solnatide inha-
lations versus placebo was observed, which again was
more pronounced in patients with initial SOFA score
above 10 (P= 0.06; exploratory subgroup analysis). No
significant differences in the occurrence of adverse
events and severe adverse events were found between
the study groups that could not be explained by the
underlying diseases [23].
Study 2013-000716-21 was a pilot study that investi-
gated the clinical effect of orally inhaled solnatide on
treatment of primary graft dysfunction (PGD) in mech-
anically ventilated patients (N= 20; 1:1) after primary
lung transplantation. When compared to placebo, oral
inhalation of solnatide in patients with PGD following
lung transplantation led to earlier improvement of gas
exchange, reduction of EVLWI, earlier extubation /
shorter mechanical ventilation, a shorter stay at the ICU,
and earlier discharge from the hospital. No drug-related
adverse events, drug-related serious adverse events, or
deaths were reported.
Inhalation of solnatide provides a novel therapy to
increase alveolar fluid clearance directly, with the
potential to decrease ventilatory pressures earlier and to
improve weaning from mechanical ventilation. The main
cause of death in critically ill patients is underlying
disease and organ failure. Nevertheless, an improvement
in pulmonary function may lead to improvement in
important outcome parameters including length of
mechanical ventilation and ICU stay, hospital stay,
morbidity, and mortality.
Known potential risks
Solnatide is generally well tolerated. No deaths or
serious adverse events occurred during the Phase I study
[22]. Only five possibly solnatide-related adverse events
(AEs) were found in four of the 48 subjects, but all five
were deemed mild and transient by the investigator, did
not require any medical intervention, and were resolved
spontaneously. The cause of the AEs (flatulence, abdom-
inal pain, hiccups, and headache) was likely related to
procedural aspects, as the constant presence of the in-
vestigator, the requirement for continuous uninterrupted
oral inhalation using nose-clips for several minutes and
the large number of examinations during the period of
observation (e.g., frequent drawing of blood samples or
measurement of lung function) could have easily led to
stress and stress-related symptoms in some subjects.
Headachewas generally the most common adverse
event in Phase I trials in healthy subjects and is generally
accepted to be due to the dietary restrictions such as caf-
feine withdrawal [24]. A mild decrease of leucocytes in
one subject could have been due to a congenital disorder
of blood cells and leucocytes, which spontaneously
returned to normal range after 20 days without treat-
ment. No AE led to any subject being withdrawn from
the study. No significant effect of solnatide on vital signs
was detected during the study. Given that patients with
ARDS are sedated and under mechanical ventilation, the
stress-related AEs mentioned above are unlikely to occur
and would in any case be insignificant and pose little
risk considering the clinical condition of the patients.
Solnatide was quantifiable in plasma only at very low
concentrations (i.e., < 2.5 ng/ml) and for a brief period
shortly after inhalation. Systemic bioavailability is
extremely low, so no significant systemic effects are
expected.
During the Phase II proof of concept study, 96 AEs
occurred during the first week of therapy and 59 AEs
occurred within the following 3 weeks of observation.
The most frequent AEs are common conditions in
critically ill patients with acute lung injury and many
AEs were related to the underlying diseases. Other AEs
were related to comorbidities. In the opinion of the
investigators, all AEs were unrelated to study therapy
with one exception: A decreased tidal volume on
pressure-controlled ventilation occurring immediately
after inhalation of solnatide in a 67-year-old male patient
with 60% burn injuries was the only possible treatment-
Schmid et al. Trials (2021) 22:643 Page 5 of 21
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associated AE that could be identified. After bronchos-
copy and treatment with inhaled bronchodilators and
steroids, the patient was weaned to assisted ventilation
on the same day and did not exhibit any adverse reac-
tions to subsequent solnatide treatment.
Currently, there is not enough data available to
consider any event to be expected for the purpose of
regulatory reporting.
Hemodynamic monitoring with systems such as
PiCCO® from Pulsion or VolumeView from Edwards
used in this study requires the application of a central
venous catheter and an arterial catheter via the femoral
artery. Femoral cannulation replaces the routine radial
cannulation used for hemodynamic monitoring. The
procedure is therefore invasive and complications may
occur, although infrequently. A study by Scheer et al.
identified 11 studies that used the femoral artery for
hemodynamic monitoring. Temporary occlusion was
reported in 10 patients (mean incidence 1.45%), and
serious ischemic complications requiring extremity
amputation was reported in three patients (0.18%).
Pseudoaneurysm formation occurred in 6 patients
(0.3%), sepsis in 13 patients (0.44%), and local infection
in 5 patients (0.78%). Bleeding (generally minor) was
observed in 5 patients (1.58%), and hematoma formation
in 28 (6.1%). One patient developed an infected
hematoma and needed blood transfusion and another
patient eventually died from massive retroperitoneal
bleeding. On the basis of this systematic review, the
authors concluded that serious complications of the
radial, femoral, and axillary artery are rare and that
arterial cannulation is a relatively safe procedure [25].
Known potential benefits
Application of solnatide directly into the lower
respiratory tract, in the form of a liquid aerosol, is
expected to activate the pulmonary sodium ion channel
(ENaC) to directly activate alveolar liquid clearance and
to reduce the leakage of blood and fluids from the
capillaries in the airspace, i.e., accelerate the resolution
of alveolar edema and reduce barrier injury in the lung.
Inhalation of nebulized solnatide by patients with
pulmonary edema and ARDS resulted in a reduction of
EVLWI as well as a trend towards a higher number of
ventilator-free days in a subgroup of patients with an ini-
tial SOFA score above 10 [23].
In numerous clinical studies, the correlation between
the amount of pulmonary edema (determined as EVLW
I) and outcome parameters in patients with ARDS has
been examined. In these studies, a strong correlation
between elevated pulmonary edema and a worse
outcome has been demonstrated.
Taken together, the alveolar liquid clearance activity of
solnatide as well as its counteracting activity against
various ROS and toxin-mediated effects is expected to
support the alveolar repair process and accelerate restor-
ation of function. In consequence, this should lead to re-
duced airway pressures, increased oxygenation, and
eventually shortened duration of assisted ventilation.
This will limit further lung injury and prevent
ventilator-associated lung injury as well as improve oxy-
genation of vital organs. Both aspects are of importance
as the volume of aerated lung is reduced in patients with
ARDS and normal tidal volumes delivered with airway
pressures that are considered safe for the uninjured lung
may cause regional overdistention. Shortening the dur-
ation of assisted ventilation also limits atelectrauma and
biotrauma.
A rapid improvement of lung function may also lead
to decreased treatment days at ICU and positively
influence survival. However, due to the multifactorial
nature of ARDS, a reduction of mortality can only be
established by a balanced regime of identification and
successful treatment of the underlying cause (or causes),
supportive therapy limiting further lung injury, and
specific therapy reducing lung injury. Nevertheless, a
rapid improvement of pulmonary function is an
important pre-requisite for improved clinical outcomes
in patients with pulmonary permeability edema / ARDS
who have a clinically manageable / curableprimary
disease / condition.
Assessment of potential risks and benefits
Given the good safety and tolerability profile so far
demonstrated in the clinical development program of
solnatide and, given its potential therapeutic effect in
life-threatening pulmonary edema, the benefits of this
trial are expected to outweigh its potential risks.
This Phase IIB trial follows a risk-adjusted procedure
by utilizing a dose escalation scheme of 5 mg, 60 mg and
125 mg solnatide per single administration (nebulizer
filling dose). Escalation from one dose to the next will
occur only once a Data Safety Monitoring Board
(DSMB) has carefully reviewed the safety data emerging
from the last treatment group and has approved the ad-
ministration of the next highest dosage. In contrast to
the previous Phase I study in healthy male volunteers,
this study will investigate safety and preliminary efficacy
in patients with pulmonary permeability edema and
ARDS.
In this Phase II study, seriously ill patients, already on
ventilation, will receive the IMP on top of standard
therapy directly over the ventilation system. These
circumstances and the fact that examinations such as
lung function measurements or blood samplings will be
performed with the patient under sedation, mean that
procedure-related AEs are unlikely to occur. In addition,
Schmid et al. Trials (2021) 22:643 Page 6 of 21
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
assessment of EVLWI is a common procedure in pa-
tients with ARDS and is usually well tolerated.
ARDS patients in this study are under mechanical
ventilation and most likely not able to give their
informed consent prior to enrolment. However, given
the noteworthy potential benefits and limited risks of
the study, participation should not be precluded because
of the sedated/unconscious state of the patient if the
investigator and IRB/IEC believe that it is of potential
benefit to and in the interest of the individual subject.
Patients will be asked to provide consent once they are
fit to do so.
Given the patients conditions and the good safety
profile of solnatide, study procedures will not place any
additional burden on the patient, nor should they create
any foreseeable risks. The patients will nevertheless be
closely and constantly monitored to ensure their health,
safety, and wellbeing.
Aim of the study
The aim of this prospective, randomized, controlled trial
is to identify safe doses of solnatide for inhalative
administration in ARDS patients.
Objectives {7}
The main objective is to assess the local and systemic
safety of 7 days orally inhaled sequential multiple
ascending doses of solnatide in patients with pulmonary
permeability edema and moderate-to-severe ARDS.
Secondary objective is to review potential efficacy
endpoints for a future Phase III pivotal trial.
Trial design {8}
This is a Phase IIb, randomized, placebo-controlled,
double-blind, dose escalation study. The study will be
conducted in up to 10 centers located in Germany
and Austria. Additional European countries may be
involved.
Thirty eligible patients with pulmonary permeability
edema (EVLWI 10 ml/kg PBW) and moderate to
severe ARDS admitted to an intensive care unit (ICU)
and under mechanical ventilation will be randomized in
a 2:1 ratio to receive either a low dose of solnatide (5
mg) (20 patients) or placebo (10 patients). Patients will
be treated for up to 7 days and the study duration for
each patient is of up to 28 days.
Following the end of the study period for these
patients and prior to escalating from the low dose to
the middle dose (60 mg), safety data collected during
the 28-day study period will be reviewed by an inde-
pendent Data Safety Monitoring Board (DSMB), who
will decide whether the safety profile is acceptable for
dose escalation. In case of positive outcome, 25 new
patients will be randomized to solnatide 60 mg or
placebo in a 4:1 ratio in order to have 20 patients
randomized to the middle-dose group and 5 to the
placebo group.
After the end of the study period of these patients and
prior to escalating from the middle dose to the high
dose (125 mg), safety data will again be reviewed by the
DSMB, who will decide whether the safety profile is
acceptable for escalating to the high dose.
If so, 40 new patients will be randomized to solnatide
125 mg and placebo in a 1:1 ratio in order to have 20
patients randomized to the high-dose group and 20 pa-
tients to the placebo group.
The randomization ratios solnatide/placebo (i.e. 2:1; 4:
1; 1:1) will allow to have a total of 35 patients assigned
to placebo. In addition, the randomisation schedule will
provide the DSMB with enough placebo patients to
perform the safety analysis.
To conduct the study, approximately 95 patients will
therefore be randomized (see Fig. 1).
Fig. 1 Trial design flowchart
Schmid et al. Trials (2021) 22:643 Page 7 of 21
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Methods: participants, interventions and
outcomes
Study setting {9}
Patients from 9 academic hospitals in Austria and
Germany will be eligible for enrolment. A list of study
sites can be obtained on request from the Sponsor.
Participating study centers will host intensive care units
specialized in the treatment of moderate and severe
forms of ARDS. Every ARDS patient will be evaluated
for eligibility to participate in this study.
Eligibility criteria {10}
Inclusion criteria
The study will enroll patients with pulmonary
permeability edema (EVLWI 10 ml/kg PBW) and
moderate to severe ARDS admitted to an intensive care
unit and under mechanical ventilation. To be eligible to
participate in this study, an individual must meet all the
following criteria:
Informed consent
1. Male or female 18 years of age
2. Patient has been admitted to an ICU, is
mechanically ventilated and stable in this condition
for at least 8 h.
3. Moderate-to-severe ARDS diagnosis as defined by
the Berlin definition:
Onset of ARDS within 1 week of a known clinical
insult or new or worsening respiratory symptoms.
Bilateral opacities not fully explained by effusions,
lobar/lung collapse, or nodules.
Respiratory failure not fully explained by cardiac
failure or fluid overload (origin of edema).
PaO2/FiO2 200 mm Hg with Positive End-
Expiratory Pressure (PEEP) 5cmH
2
O.
4. Verified ARDS diagnosis (moderate or severe
according to Berlin definition) not older than
48 h.
5. Extravascular lung water index (EVLWI) 10 ml/kg
PBW as assessed with a validated bedside
measurement (single indicator transpulmonary
thermodilution measurement, such as with PiCCO®
from Pulsion or VolumeView from Edwards).
6. Patient who meets criteria for extensive
hemodynamic monitoring as per international
intensive care medicine standards.
Exclusion criteria
Patients must meet none of the exclusion criteria listed
below.
1. History of clinically relevant allergies or
idiosyncrasies to solnatide.
2. Known use of any other investigational or non-
registered drug within 30 days or within 5 half-
livesofthesedrugspriortostudyenrolment,
whichever is longer. No exceptions are allowed
in this study.
3. Severe state of septic shock with a mean arterial
pressure (MAP) 65 mmHg and a serum lactate
level > 4 mmol/L (36 mg/dl) despite adequate
volume resuscitation.
4. An underlying clinical condition that, in the
opinion of the investigator, would make it very
unlikely for the patient to be successfully weaned
from ventilation due to severe underlying diseases
(e.g., severe malnutrition, severe neurological
diseases, pulmonary fibrosis, or COPD).
5. Extracorporeal membrane oxygenation, high-
frequency oscillatory ventilation or any form of
extracorporeal lung support. In no way are patients
to be denied or delayed these procedures to avoid
exclusion from the study.
6. Neutrophil count < 0.3 × 10
9
/L.
7. Cancer treatment (chemotherapy or biological) or
therapy with other immunosuppressive agents for
organ transplantation within 2 weeks.
8. Cachexia (BMI < 18.5 kg/m
2
).
9. Unequivocal cases of cardiogenic pulmonary edema
(if differential diagnosis based on an ARDS
triggering condition and clinical replicability is not
possible, echocardiography may be indicated).
10. Severe skin burns involving more than 15% of body
surface.
11. Subjects who are extremely unlikely to survive
more than 48 h due to the acute conditions of the
patient in the opinion of the investigator.
12. Subjects transferred from a hospital not
participating in this study who are already
planned to be re- transferred during the
observation period.
13.Subjectswhoarenotexpectedtosurvivethe
next month because of an underlying
uncorrectable medical condition or a do not
resuscitate order.
14. Women known to be pregnant, women who are
lactating, women with a positive or indeterminate
pregnancy test, on screening, and males of
reproductive potential and women of childbearing
potential who are not willing to use highly effective
methods of birth control/contraception for a
Schmid et al. Trials (2021) 22:643 Page 8 of 21
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duration defined in the patients Informed Consent
Form.
15. After randomization, drop-out of a participant is
not envisaged by the protocol except for withdrawal
of consent by the participant or his/her legal repre-
sentative, discontinuation of the treatment (e.g., due
to toxicity, or death of the patient during the treat-
ment course).
Who will take informed consent? {26a}
Informed consent will be taken by appointed
investigators, who had been trained beforehand
according to GCP standards. Consent forms describing
in detail the study intervention, study procedures, and
risks are given to the participant/legal representative,
and written documentation of informed consent is
required.
Since ARDS patients in this study are in the ICU
under mechanical ventilation, it is very likely that most
will not be able to give their written informed consent
prior to enrolment in the study.
According to German Law persons unable to give
consent are subject to specific legal regulations and
therefore can be included into medical research projects
only under strict requirements. To obtain consent the
following procedures must be followed:
In case of an emergency, the investigator has to find
out whether a patients representative has been
appointed by power of attorney for personal care
(Vorsorgevollmacht). Usually, this will be done by on-
site interviewing of accompanying persons of the
patient.
If a patients representative appointed by power of
attorney for personal care (Vorsorgevollmacht)is
available, he/she will check whether a patients decree
(Patientenverfügung) exists and whether it is in
accordance with the patients current living and
treatment conditions. If a patients decree is available,
the patients representative will make sure that the
patients specifications will be implemented. If a patients
decree is not available or is not in accordance with the
specific situation, the patients representative is obliged
to act according to the presumed patients will based
upon oral or written statements, values, and ethical or
religious beliefs of the patient concerned. To determine
the presumed will of the patient whether to participate
in a clinical study or not, close relatives, and other
reliable persons might be involved provided that this
process does not lead to any delays being in conflict
with the urgency of the treatment.
The information and consent process will be carried
out with the patients representative in the same way as
with the patient. The patients representative will sign
the consent form on behalf of the patient. If a patient is
unable to give consent but still able to follow the
information and consent process partially, the patient
must also be informed. Even if expressed non-verbally, a
patients wish either to participate or not to participate
in the trial must be respected.
If a patients representative cannot be asked for
consent to include the patient in the study, the
appointment of a provisional patients representative
must be made by the local district court (Amtsgericht).
If, in cases of urgency, such an appointment is not
possible, a judge may also take the decision for the
benefit of the patient.
If neither the appointment of a patients representative
nor a judicial urgent decision is possible in time, § 41
paragraph 1 clause 2 of the German Drug Law is
applicable. According to this paragraph, treatment
which is necessary without delay to save the life of the
person concerned, restore good health or alleviate
suffering, can be dispensed immediately. Consent for
continued participation must be obtained as soon as it is
possible and reasonable. In this case, the investigator
must consider all known indications regarding the
patients presumed will. It is the responsibility of the
investigator to examine whether, in his view, the patient
could be included in the clinical trial.
The process to determine the patients presumed will
to participate in a clinical study will be documented in
accordance with local procedures. Once the patient
regains his/her ability to consent, he/she shall be asked
to give his/her consent to the continuation of the
clinical trial.
Additional consent provisions for collection and use of
participant data and biological specimens {26b}
Not applicable, biological samples will not be retained
after the study is complete.
Interventions
Explanation for the choice of comparators {6b}
This ascending dose study consists in the sequential
administration of 5 mg, 60 mg, and 125 mg of solnatide.
In cell-based non-clinical pharmacodynamic studies,
the EC
100
of solnatide-induced ENaC activation was
found to be approximately 120 nM. Various models tak-
ing into account lung volume, lung weight, and lung sur-
face area have indicated that a nebulizer filling dose of 5
mg solnatide corresponds most closely with the non-
clinical cell-based experimental setup. A single applica-
tion of 5 mg solnatide corresponds to the lowest dose of
the previous Phase I clinical study (EudraCT: 2011-
000223-33).
A bridging dose of 60 mg was chosen between the low
and high dose. This dose was used in a pharmacological
study in pigs and may be effective in a clinical setting
Schmid et al. Trials (2021) 22:643 Page 9 of 21
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also. In addition, this dose corresponds to the
intermediate dose level of the previous Phase I clinical
study (EudraCT: 2011-000223-33).
In previous clinical Phase II trials, patients received
two daily doses each of 125 mg solnatide
reconstituted in 5 ml water for injection delivered as
aerosol via nebulization for up to 7 days. This dose
level is below the highest dose level used in the
previous Phase I study (EudraCT: 2011-000223-33). It
represents a dose level corresponding to the most ef-
fective dose levels used in previous pharmacologic
studies and showed promising outcomes in the two
previous Phase IIa trials (EudraCT: 2012-001863-64;
2013- 000716-21).
Intervention description {11a}
Active agent
The Investigational Medicinal Product (IMP) is
Solnatide 25 mg powder for reconstitution for solution
for inhalation.The IMP is a sterile lyophilized
preparation of the drug substance solnatide, a synthetic
peptide composed of 17 naturally occurring amino acids.
One N-terminal cysteine and one C-terminal cysteine
form an intra-molecular disulfide bridge. Solnatide con-
tains no post-translational modifications.
Solnatide was manufactured, characterized, and
released based on requirements of the European
Pharmacopoeia, European and international quality and
safety guidelines including ICH guidelines related to
chemical compounds and / or synthetic peptides.
Guidelines and regulations related to recombinant
proteins do not apply to the development compound.
Prior to clinical use, each vial with the IMP is to be
reconstituted with 1 ml of water for injection
(commercial product) resulting in a solnatide solution
with a concentration of 25 mg/ml. Reconstituted IMP in
the required clinical-use concentration is provided as a
clear solution in a closed single-use sterile plastic syringe
for transportation purpose at 28 °C for immediate use
with the nebulizer Aeroneb Solo.
However, in-use storage time of the reconstituted so-
lution in the single-use plastic syringe may be extended
up to 3 days at 2 to 8 °C, if required and a corresponding
Manufacturers Authorization is in place.
The in-use stability of the reconstituted solution is de-
scribed in the investigatorsbrochure. The chemical and
physical in-use stability of the reconstituted solution in
the single-use plastic syringe has been demonstrated for
7 days at 28 °C. Sterility of the reconstituted solution in
the single-use plastic syringe has been demonstrated
after in-use storage times of 4 days at 2 to 8 °C provided
reconstitution has taken place in controlled aseptic
conditions.
Placebo
This is commercially available 0.9% saline solution in
vials.
Patients will receive 5 ml of the study drug containing
5 mg, 60 mg, or 125 mg solnatide or 0.9% saline
according to treatment allocation via endotracheal
nebulization every 12 h for a maximum of 7 days using
an Aeroneb Solo nebulizer.
Reconstituted solnatide as well as placebo solution
(saline) will be supplied in a closed and labelled syringe
to study personnel authorized for administration. Both
solutions are clear and colorless, and thus
indistinguishable in appearance.
Dosing and administration
In this dose ascending study, 3 groups of patients (one
for each dosage) will be randomized to treatment with
either solnatide or placebo. The three doses
administered in this study are 5 mg, 60 mg, and 125 mg
and escalation from one dose to the next will occur only
once a DSMB has carefully reviewed the safety data
emerging from the last treatment group and has
approved the administration of the next highest dosage.
The highest dosage used in this study has already been
tested and has proved to be safe in a Phase I and two
Phase II trials and no dose-limiting effects are expected.
Patients will be treated with solnatide or placebo twice
a day for 7 days via endotracheal inhalation. Inhalations
should be scheduled around 08:00 a.m. 30 min) and
08:00 p.m. 30 min). The 12-h sequence should be
followed as closely as possible. If applicable to the rou-
tine of the ICU, inhalation can be shifted to a later time
until 10:00 a.m. (± 30 min) and 10:00 p.m. (± 30 min), re-
spectively, at the latest.
To enable endotracheal inhalation, reconstituted
solnatide in water for injection is converted into an
inhalable aerosol by the Aeroneb Solo medicinal device.
This device is a product of Aerogen, Galway, Ireland,
and is a commercially available liquid nebulizer. The
Aerogen Solo nebulizer has been approved in the
European Community by CE-marking based on require-
ments of Annex II, Section 3.2. of Directive 93/42/EEC.
The nebulizer unit holds up to 6 ml of liquid
medication. The nebulizer unit is clear to allow visual
monitoring of medication levels and aerosolization.
When the nebulizer unit is connected to the ventilator
circuit, the silicon plug can be opened and closed in
between doses without causing loss of circuit pressure.
The T-piece of the nebulizer connects the unit into
the breathing circuit via standard male and female 22-
mm conical ports. The nebulizer unit together with the
T-piece is placed into the inspiratory limb of the breath-
ing circuit before the patient wye. Various in vitro stud-
ies and laboratory simulation have been conducted to
Schmid et al. Trials (2021) 22:643 Page 10 of 21
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characterize solnatide aerosol generation by the Aeroneb
Solo nebulizer. Solnatide solution of 25 mg/ml showed
effective nebulization and small condensation losses of
solnatide aerosol in the connecting tube system. The
nebulization time for 5 ml ranges between 10 and 20
min. Breath simulator studies showed that approx. 60 to
70% of nebulized solnatide was deposited on the inhal-
ation filter (lung), indicating that the delivered dose of
solnatide corresponds to about 60 to 70% of the nominal
nebulizer filling dose.
Criteria for discontinuing or modifying allocated
interventions {11b}
Discontinuation from treatment does not mean
discontinuation from the study, and remaining study
procedures should be completed as indicated by the
study protocol as described for any treatment day as
well as follow-up period. If a clinically significant finding
is identified (including, but not limited to changes from
baseline) after enrolment, the investigator or qualified
designee will determine if any change in participant
management is needed. Any new clinically relevant find-
ing will be reported as an adverse event (AE).
Every subject, the legal representative or authorized
representative has the right to interrupt or to
discontinue study participation at any time, for any
reason, and every subject may be discontinued from the
study for any reason beneficial to his/her wellbeing.
In addition, individual subjects must discontinue or
withdraw from the study for any of the following
reasons:
Withdrawal of informed consent by the patient or
the legal representative or authorized representative.
Any AE, laboratory abnormality or intercurrent
illness that, in the opinion of the investigator,
indicates that continued participation in the study is
not in the best interest of the subject.
Suspected drug-related serious adverse event (SAE)
Suspected unexpected serious adverse reaction
(SUSAR)
Allergies or idiosyncrasies to solnatide.
Patients withdrawn from the study will not be
replaced with new participants.
If the cause of temporary withdrawal has been
resolved, e.g., informed consent has been re-confirmed,
a suspected drug-related SAE has not been confirmed by
the investigator, a SUSAR has not been confirmed by
the investigator, the patient may resume participation in
the clinical study if the treatment schedule allows it.
Patients who are withdrawn from the study
prematurely by the investigator or the sponsor will
undergo all investigations as described for any treatment
day for the end-of-study interview. Patients, the legal
representative, or authorized representative who with-
draw consent will be asked to accept further safety ex-
aminations in the interest of the patient.
Strategies to improve adherence to interventions {11c}
The study medication will be administered only by
authorized study personnel. Every effort will be made to
ensure timely administration of the IMP as per protocol.
If medication cannot be administered, the reason is to
be documented in the eCRF and a protocol deviation
recorded.
Relevant concomitant care permitted or prohibited
during the trial {11d}
There are no known interactions of solnatide with other
substances. Accordingly, a general list of permitted and
not-permitted concomitant medication is not available.
In previous clinical studies, no drug- related SAEs and
SUSARs have been observed.
As this is an add-on study in patients also receiving
standard treatment, administration of concomitant
medication is subject to the investigators decision and
discretion and may vary for each individual patient due
to the heterogeneity of ARDS and underlying etiologies.
Provisions for post-trial care {30}
Specific post-trial care is not provided. Study partici-
pants are insured against any harm arising from the
study interventions according to legal provisions.
Outcomes {12}
The main objective of this study is to investigate the
safety of solnatide administration. Therefore, no formal
primary and secondary outcomes are defined. Safety will
be assessed by a review of mortality, incidence of
adverse events, and serious adverse events, as well as by
analysis of relevant laboratory data and ECG. The
following parameters will be taken into account when
assessing the safety of solnatide:
Vital signs (i.e., heart rate, systolic and diastolic
blood pressure, and temperature)
Clinical laboratory (i.e., white and red blood cell
count, hematocrit, hemoglobin concentration,
platelet count, creatinine, sodium, potassium,
chloride, blood urea nitrogen, bilirubin, aspartate
and alanine transaminases, lactate dehydrogenase,
amylase, lipase, C-reactive protein, creatine kinase,
arterial pH, PaO
2
, PaCO
2
, bicarbonate, SO
2
as well
as urine pH, specific weight, appearance, color, ni-
trites, proteins, glucose, urobilinogen, bilirubin, ke-
tones, hematic pigments, and leukocytes)
12-lead electrocardiogram
Schmid et al. Trials (2021) 22:643 Page 11 of 21
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Hemodynamic parameters (i.e., mean arterial
pressure, pulmonary blood volume, cardiac index,
and cardiac output
Need for vasoactive drugs
24-h fluid balance
Concomitant medications
All-cause deaths
Utilization of extracorporeal treatments
Adverse events and serious adverse events
The secondary objective of this study is to evaluate
possible endpoints for a future Phase III pivotal trial.
Such endpoints investigated in this study include:
Extravascular lung water index
Pulmonary vascular permeability index
Murray lung injury score
Oxygenation ratio
Ventilation parameters (i.e., plateau pressure, tidal
volume, positive end-expiratory pressure, peak in-
spiratory pressure, respiratory rate, F
i
O
2
, mean air-
way pressure, peak airway pressure, ventilation
mode)
Lung compliance
Ventilation-free days
Days of ICU
Days of hospitalization
Driving pressure
Sequential organ failure assessment
Participant timeline {13}
The intended timeline for each participants study
activities is outlined in Fig. 2.
Sample size {14}
Given that the primary objective of the study is to
investigate the safety of solnatide, the study sample size
of 95 randomized patients is based on feasibility criteria.
Patients will be randomized to 3 groups of 20 patients
each, representing the 3 multiple ascending dose groups
receiving solnatide at doses of 5 mg, 60 mg and 125 mg,
and 35 patients will receiving placebo in total, with 15
patients receiving placebo in Dosing Group A (low dose)
and Dosing Group B (middle dose) and 20 patients
receiving placebo in Dosing Group C (high dose).
Nevertheless, considering the key preliminary
efficacy endpoint and the results of a Phase IIa study
(2012-001863-64), a sample size of 20 evaluable
patients in each treatment group will have
approximately 80% power to detect a difference in
means between solnatide and placebo of 3.2 ml/kg in
thechangefrombaselinetoday7ofEVLWIwitha
Fig. 2 Schedule of activities
Schmid et al. Trials (2021) 22:643 Page 12 of 21
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common SD of 3.5 using a two-group t-test with a
0.05 two-sided significance level and no alpha level
adjustment for multiple testing.
Recruitment {15}
All ARDS patients in participating centers will be
screened for eligibility. In case of slow or insufficient
recruitment, the sponsor will consider increasing the
number of study sites.
Assignment of interventions: allocation
Sequence generation {16a}, concealment mechanism
{16b} and implementation {16c}
A randomization plan will be generated before study
start. No stratification factors are planned. Three
different randomization lists (one for each step of the
study) will be prepared with the following
randomization ratios:
2:1 in the first step of solnatide 5 mg vs. placebo
4:1 in the second step of solnatide 60 mg vs. placebo
4:1 in the third step of solnatide 125 mg vs. placebo
The randomization process will be managed
electronically (block-wise generation of random
numbers) by means of an Interactive Web Response
System (IWRS) to ensure that treatment assignment is
unbiased and concealed from patients and investigator
staff. The results of the randomization are merely
revealed to the responsible study pharmacist, who will
then facilitate the preparation of the respective IMP.
IMP vials are transferred to the investigators in a neutral
container. Solnatide and placebo solutions cannot be
distinguished from one another by the investigators.
Assignment of interventions: blinding
Who will be blinded {17a}
This is a double-blind study. Patients and all clinical
team members involved in the study are blinded. Solna-
tide and saline solution have the same appearance. All
personnel except pharmacy staff directly involved in the
study, including the investigator, are blinded to the
medication codes.
Pharmacy staff in charge of labelling and preparing the
IMP will be unblinded. As soon as a patient is
randomized, an email will automatically be sent to the
pharmacist instructing him or her to prepare a solnatide
or saline (placebo) solution for that randomization
number. The syringe containing 5 ml of either one or
the other solution will be appropriately labelled and
delivered to the ICU for administration. The pharmacist
will then print and sign the email for filing purposes. No
clinical staff member has access to the treatment
preparation instructions except for the study
pharmacists. The trial statistician will be blinded during
the analysis of the data.
Procedure for unblinding if needed {17b}
Individual patient unblinding during the trial may occur
in case of patient emergencies or medically important
adverse events including cases of COVID-19.
The code breaking procedure is managed by means of
an online-specific utility implemented in the eCRF and
is available for the investigator and pharmacovigilance
staff only. Sealed envelopes will also be provided as
backup in the unlikely case of system unavailability.
If during the study the investigator needs to break a
code (for emergency reasons), he/she has to follow the
procedure implemented in the system clicking on ad hoc
icon present on the toolbar.
In case of an individual patient unblinding, an
automatic email will be sent to the study team notifying
the occurrence of a code break reminding the
investigator to discontinue the patient from the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
All data collected for this trial, e.g., eligibility criteria,
demography, medical history, concomitant medication,
physical examinations, vital sign measurements,
laboratory results, and ECG data, is first recorded in site
specific clinical charts based either on electronic or
paper documents. If electronic charts are used, the
electronic system should be compliant with applicable
requirements. No study-related information will be
stored on the eCRF only.
For laboratory tests, each site uses its own certified
routine laboratory, which also provides its own reference
values for each parameter obtained for study purposes.
Measurements like ECG or hemodynamic parameters
will be obtained using medical-grade, certified
equipment.
Clinical scores are assessed based on the following
resources:
Gas exchange, Organ failure, Cause, Associated
disease (GOCA) score [26,27]
Sequential Organ Failure Assessment (SOFA) [28]
Acute Physiology and Chronic Health Evaluation
(APACHE) II score [29]
Simplified Acute Physiology Score (SAPS) 3 [30,31]
Plans to promote participant retention and complete
follow-up {18b}
Not applicable as this is a study of patients with ARDS
in intensive care and under mechanical ventilation.
Schmid et al. Trials (2021) 22:643 Page 13 of 21
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Data management {19}
Designated investigator staff will enter the data required
by the protocol into the eCRF using fully validated
software that conforms to 21 CFR Part 11 requirements
as well as GAMP 5 and PIC/S requirements. Designated
investigator site staff will not be given access to the
Electronic Data Capture (EDC) system until they are
trained.
Web-based software will be used and no installation
procedure is needed. Each site will be authorized by the
administrator to access the eCRF. Each site-qualified
personnel will be allowed to access the eCRF by means
of a login maskrequiring user ID and password and
may read, modify, and update only the information he/
she previously reported. Each page reports site code and
subject code.
Online validation programs will check for data
discrepancies and, by generating appropriate error
messages, allow the data to be confirmed or corrected
before transfer to the CRO working on behalf of the
sponsor. The investigator will certify that the data
entered into the eCRF is complete and accurate.
After database lock, the investigator will receive a CD-
ROM of subject data for archiving at the investigational
site.
Confidentiality {27}
Participant confidentiality and privacy is strictly held in
trust by the participating investigators, their staff, and
the sponsor(s) and their interventions. This
confidentiality is extended to cover testing of biological
samples and genetic tests in addition to the clinical
information relating to participants. Therefore, the study
protocol, documentation, data, and all other information
generated will be held in strict confidence. No
information concerning the study or the data will be
released to any unauthorized third party without prior
written approval of the sponsor.
All research activities will be conducted in as private a
setting as possible.
The study monitor, other authorized representatives of
the sponsor, representatives of the IRB/IEC, regulatory
agencies, or pharmaceutical company supplying study
product may inspect all documents and records required
to be maintained by the investigator, including but not
limited to medical records (office, clinic, or hospital) and
pharmacy records for the participants in this study. The
clinical study site will permit access to such records.
The study participants contact information will be
securely stored at each clinical site for internal use
during the study. At the end of the study, all records will
continue to be kept in a secure location for as long a
period as dictated by the reviewing IRB/IEC,
institutional policies, or sponsor requirements.
Study participant research data, which is for purposes of
statistical analysis and scientific reporting, will be
collected and stored at the OPIS Data Center. This will
not include the participants contact or identifying
information. Rather, individual participants and their
research data will be identified by a unique study
identification number. The study data entry and study
management systems used by clinical sites and by OPIS
Data Center staff will be secured and password protected.
Plans for collection, laboratory evaluation, and storage of
biological specimens for genetic or molecular analysis in
this trial/future use {33}
These are not applicable
Statistical methods
Statistical methods for primary and secondary outcomes
{20a}
Data collected in this study will be listed and summarized
as described below by treatment group. Data from all sites
will be pooled and summarized. Continuous data will be
summarized by mean, standard deviation (SD), median,
first and third quartiles, minimum, and maximum.
Categorical data will be presented by absolute and relative
frequencies (n and %) or contingency tables. All statistical
tables, listings, figures, and analyses will be performed by
means of SAS® release 9.4 or later (SAS Institute, Inc.,
Cary, NC, USA).
A two-sided alpha level 0.05 will be considered. No
alpha level adjustment will be made for secondary pre-
liminary efficacy outcome variables and for multiple
comparisons. Patients will be included in each analysis
based on available assessments. No methodology for
missing data handling will be applied, except for the
EVLWI efficacy endpoint. Censoring rules for time-to-
event analyses will be detailed in the Statistical Analysis
Plan.
There is no primary efficacy endpoint as the primary
objective of the study is to investigate the safety of
solnatide. All efficacy analysis will be considered as
secondary preliminary efficacy analyses. All secondary
preliminary efficacy analyses will be performed based on
the ITT set as primary analysis and on the PP set as
supportive analysis and will be reported by planned
treatment cohort.
No methodology for missing data handling will be
applied for secondary preliminary efficacy endpoints,
except for EVLWI. The homogeneity of treatment
effects across different centers will not be tested.
Change from baseline to day 7 in extravascular lung water
index (EVLWI)
The absolute change from baseline in extravascular lung
water index (EVLWI) after 7 days from randomization,
Schmid et al. Trials (2021) 22:643 Page 14 of 21
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as assessed with a validated bedside measurement (single
indicator transpulmonary thermodilution measurement,
such as with PiCCO® from Pulsion or VolumeView from
Edwards), will be analyzed by means of an analysis of
covariance (ANCOVA) model with baseline value as
covariate and treatment cohort as an independent class
variable. Mean estimates will be provided, together with
their corresponding two-sided 95% confidence intervals.
A hierarchical testing procedure will be carried out to
control multiplicity, where statistical comparison will
first be performed between the highest solnatide dose
cohort and the placebo cohort. Statistical comparison
between the next lower dose(s) and placebo will be
performed only in case of statistical significance of the
comparison between the highest solnatide dose cohort
and the placebo cohort.
The analysis described above will be performed on
data where the Last Observation Carry Forward
approach is applied for handling missing data.
Additional imputation methodologies for missing data
may be applied as sensitivity analysis (further details to
be provided in the Statistical Analysis Plan).
1. Secondary preliminary efficacy endpoints
Change from baseline to day 7 in Pulmonary Vascular
Permeability Index (PVPI)
The absolute value and the change from baseline will be
analyzed by treatment group for PVPI by means of
summary descriptive statistics at each time point until
day 7.
Lung compliance during mechanical ventilation
Static lung compliance is the change in volume for any
given applied pressure and is derived as the ratio
between tidal volume (V
t
) and the difference between
plateau pressure and positive end-expiratory pressure
(PEEP).
The absolute value and the change from baseline will
be analyzed for static lung compliance by means of
summary descriptive statistics at each time point
through day 14, if patient is mechanically ventilated
(controlled mechanical ventilation).
Murray lung injury score (LIS)
The absolute value and the change from baseline will be
analyzed for Murray Lung Injury Score by means of
summary descriptive statistics at each time point until
day 7 if chest X-ray is available.
Sequential Organ Failure Assessment (SOFA)
The absolute value and the change from baseline will be
analyzed for SOFA score by means of summary
descriptive statistics at each time point until day 7.
Oxygenation ratio (P
a
O
2
/F
i
O
2
ratio)
The absolute value and the change from baseline will be
analyzed for oxygenation ratio (P
a
O
2
/F
i
O
2
) by means of
summary descriptive statistics at each time point during
first 7 days.
Ventilation parameters
The absolute value and the change from baseline will be
analyzed for each ventilation parameter (ventilatory
plateau pressure, V
t
, PEEP, respiratory rate, F
i
O
2
, PIP,
mean airway pressure, peak airway pressure) by means
of summary descriptive statistics at each time point
through day 14 for patients mechanically ventilated
(controlled mechanical ventilation, assisted breathing,
non-invasive ventilation).
Driving pressure (P
plat
PEEP)
The absolute value and the change from baseline will be
analyzed for driving pressure (P
plat
PEEP) by means of
summary descriptive statistics at each time point
through day 14 for patients mechanically ventilated
(controlled mechanical ventilation, assisted breathing,
non-invasive ventilation).
Spontaneous Breathing Trial
The time (in days) from the first spontaneous breathing
trial to the first successful extubation / unassisted
breathing will be calculated. Summary descriptive
statistics will be provided.
In addition, patients will be classified according to the
following outcome definitions [32]:
Simple
Successful SBT after the first attempt
Difficult
Failed SBT at first attempt and
Required up to three trials or
Required < 7 days to reach successful SBT
Prolonged
Required > 7 days to reach successful SBT
Time to extubation through day 28
Time to extubation (in days) is defined as the difference
between the first extubation date and the randomization
date. Patients still intubated at day 28 or who die while
still intubated will be censored at day 28. Summary
descriptive statistics will be provided for the time to
extubation.
Ventilator-free days (VFD) through day 28
VFD is defined as the number of days from
randomization to day 28 after achieving unassisted
breathing for patients who maintained unassisted
breathing for at least two consecutive calendar days. If a
Schmid et al. Trials (2021) 22:643 Page 15 of 21
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patient survived for more than 48 consecutive hours of
unassisted breathing but required assisted breathing (for
any reason) before day 28, the number of VFD is the
number of days of successful unassisted breathing
through day 28. All periods of successful unassisted
breathing (> 48 consecutive hours) are taken into
account. Unassisted breathing is defined as being
extubated with face mask, with nasal prong oxygen or
room air or T-tube breathing or tracheostomy mask
breathing or CPAP breathing with 8cm H
2
O pressure
support of assisted ventilator support, according to wean-
ing protocol. Patients who die before day 28 will be
assigned the number of days of successful unassisted
breathing. If a patient required more than 28 days of
mechanical ventilation, the value for VFD will be set to 0.
The parameter of ventilator-free days will be analyzed
by means of an analysis of variance (ANOVA) model
with treatment cohort as an independent class variable.
Mean estimates will be provided, together with their cor-
responding two-sided 95% confidence intervals.
No multiplicity adjustment for multiple comparison
will be applied, given that statistical comparison will be
performed only between the highest solnatide dose
cohort and the placebo cohort. A statistical comparison
between lower dose(s) and placebo will be performed
only in case of statistical significance of the comparison
between the highest solnatide dose cohort and the
placebo cohort.
Days of hospitalization through day 28
Length of hospital stay (in days) is defined as the
difference between the discharge date and the
randomization date. Patients still in the hospital at day
28 or who die during hospitalization will be censored at
day 28. Days of outpatient hospitalization will not be
included. Summary descriptive statistics will be provided
for the number of days of hospitalization.
Days of stay at ICU through day 28
Length of stay at ICU (in days) is defined as the number
of calendar days a patient was in the ICU. Patients still
in the ICU at day 28 or who die during the stay at ICU
will be censored at day 28. Summary descriptive
statistics will be provided for the number of days of stay
at the ICU.
2. Safety analyses
Safety analyses will be conducted on the Safety Set and
will be reported by actual treatment cohort. No
methodology for missing data handling will be applied
for safety parameters.
Drug-related adverse events through day 14
The incidence of treatment-emergent drug-related AEs
through day 14 after randomization, both in terms of
number of events and in terms of patients with at least
one event, will be tabulated by MedDRA System Organ
Class (SOC) and Preferred Term (PT).
All adverse events through day 28
According to the onset date of the event, AEs will be
defined as follows:
Treatment-emergent AEs are those events with an
onset date after treatment initiation;
Non-treatment-emergent AEs are those events with
an onset date between screening and treatment
initiation.
Non-treatment-emergent adverse events will be listed
only. The incidence of treatment-emergent adverse
events (TEAE) will be tabulated by MedDRA System
Organ Class (SOC) and Preferred Term (PT). The inci-
dence of TEAEs will also be summarized by system
organ class, preferred term, and severity (based on inves-
tigators judgment).
The same analysis will be repeated for SAEs regardless
of drug relationship, for drug-related SAEs, AEs with an
outcome of death, and AEs leading to discontinuation of
treatment. Deaths reportable as SAEs will be listed by
patient and tabulated by MedDRA SOC and PT.
All-cause deaths through day 28
The number and proportion of deceased patients will be
reported. In addition, the time (in days) from
randomization to the event will be used for analysis.
Subjects without an event will be censored at the earlier
of the last contact date or day 28. The Kaplan-Meier es-
timates of the survival functions for each treatment co-
hort will be plotted and summarized.
Vital signs
The absolute value and the change from baseline will be
analyzed for each parameter (including heart rate,
systolic and diastolic blood pressure and body
temperature) by means of summary descriptive statistics
at each time point through day 14 after randomization.
ECG parameters
Evaluation of ECG data will be performed by an external
provider.
The absolute value and the change from baseline will
be analyzed for each cardiac parameter (PQ, QRS, QT,
and QTc intervals [Fridericias formula] and heart rate)
by means of summary descriptive statistics at each time
point (first 7 days of study). Based upon these
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parameters, heart rhythm anomalies / conduction
abnormalities and changes/abnormalities in ECG
morphology will be assessed and summarized.
Laboratory parameters
The absolute value and the change from baseline will be
analyzed for each laboratory parameter (separately for
hematology, clinical chemistry, blood gases, and
urinalysis) by means of summary descriptive statistics at
each time point through day 14. In addition, shift tables
using the low/normal/high classification according to
the laboratory normal ranges to compare baseline to the
worst on-treatment value will be provided.
Listings of all laboratory data with values flagged to
show the classifications relative to the laboratory normal
ranges will also be generated.
Twenty-four-hour fluid balance
The absolute value and the change from baseline will be
analyzed for the 24-h fluid balance parameter by means
of summary descriptive statistics at each time point
through day 7. Twenty-four-hour fluid balance at a given
timepoint will be determined as the difference, at the
timepoint, between the complete amount of fluid sup-
plied to the patient over 24 h and the complete amount
of fluid lost by the patient over the same period.
Hemodynamic parameters
The absolute value and the change from baseline will be
analyzed for each hemodynamic parameter (i.e., mean
arterial pressure, pulmonary blood volume (PBV),
cardiac index and cardiac output) by means of summary
descriptive statistics at each time point until the end of
treatment.
Need for vasoactive drugs
The number and proportion of patients who required
vasoactive drugs at any time through the end of
treatment will be reported.
3. Baseline descriptive statistics
Patient demographics and baseline characteristics will
be summarized on the ITT set, overall and by treatment
cohort, and by means of summary descriptive statistics.
A complete description of subject disposition will be
provided, overall and by treatment cohort specifying the
number of randomized subjects, number of subjects at
each visit, and completed and discontinued subjects and
the reason for the discontinuation. The analysis
populations will be described and the reasons for
excluding the subject from any analysis set will be
provided with the number of protocol violators per each
criterion. Medical history data will be presented by
MedDRA System Organ Class and Preferred Term.
4. Treatments
The Safety Set will be used for the following analyses.
Investigational treatment
Duration of exposure to study treatment, defined as the
time (days) elapsed from the date of the first treatment
administration to the date of the last treatment
administration and number of administrations will be
summarized. Cumulative dose (mg), defined as the total
dose given during treatment exposure, will be
summarized. The number of patients with dose
interruptions/permanent discontinuation will be
presented along with the reasons for the dose
interruptions/discontinuation.
Concomitant treatments
Concomitant medications or procedures taken
concurrently with the study treatment will be listed and
summarized by WHO Anatomical Therapeutic
Chemical (ATC) Class and Preferred Term. These
summaries will include medications starting on or after
the start of study treatment, or medications starting
prior to the start of study treatment and continuing after
the start of study treatment. Prior medications starting
and ending prior to the start of study treatment will be
listed only.
Interim analyses {21b}
No formal interim efficacy analysis is planned.
Methods for additional analyses (e.g., subgroup analyses)
{20b}
Additional subgroup analyses will be detailed in the
Statistical Analysis Plan.
Methods in analysis to handle protocol non-adherence
and any statistical methods to handle missing data {20c}
Patients will be included in each analysis based on
available assessments. No methodology for missing data
handling will be applied, except for the EVLWI efficacy
endpoint.
Plans to give access to the full protocol, participant-level
data, and statistical code {31c}
These are not applicable.
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Oversight and monitoring
Composition of the coordinating center and trial steering
committee {5d}
The clinical study is coordinated by a professional
Clinical Research Organization (CRO). The CRO and
the sponsor form the trial steering committee.
The data management is part of the responsibility
of the CRO and cannot accessed by the sponsor. No
unblinded data are submitted from the data
management to the sponsor and to the investigators.
There is no endpoint adjudication committee foreseen.
Composition of the data monitoring committee, its role
and reporting structure {21a}
The sponsor has appointed an independent Data and
Safety Monitoring Board. The DSMBs role is defined
in the DSMB Charter of clinical trial EudraCT 2017-
003855-47 of March 2018. The DSMB is composed
of individual experts in the field of ARDS from the
following countries: Germany, Spain, USA. All mem-
bers of the DSMB have no competing interest in the
trial.
The DSMB is responsible for reviewing the safety and
tolerability after completion of each dose group and
confirmation in writing that the study can proceed with
the next higher dose group (dose escalation). After
completion of the study, the DSMB will make a final
statement concerning overall safety (the primary
objective of the study). Overall safety will be assessed in
a final session of the DSMB by a summarizing review of
the incidence of mortality, adverse events, and serious
adverse events, as well as by analysis of relevant
laboratory data and ECGs. The DSMB will provide
advice to the Sponsor which will be responsible for
promptly reviewing the DSMB recommendations,
deciding whether to continue, modify, or terminate the
trial; and determining whether amendments to the
protocol or changes in study conduct are required.
The DSMB is required to act in accordance with the
ethical principles derived from the Declaration of
Helsinki.
Communication with DSMB members will be
primarily through an independent statistician not
involved in the management and performance of this
study. It is not expected that study investigators or co-
investigators will directly communicate with DSMB
members.
Adverse event reporting and harms {22}
All identified non-serious AEs (related and unrelated)
must be recorded and described on the non-serious AE
page of the eCRF.
Serious adverse event reporting
Every SAE, regardless of suspected causality, occurring
after screening and until at least 28 days after
randomization must be reported to the sponsor within
24 h of site awareness. Any SAE experienced after this
28-day period should only be reported to the sponsor if
the investigator suspects a causal relationship to the
study treatment. Recurrent episodes, complications, or
progression of the initial SAE must be reported as
follow-up to the original episode within 24 h of the in-
vestigator receiving the follow-up information. Informa-
tion about all SAEs will be recorded on the AE page of
the eCRF and transmitted through the SAE tool. In case
of technical difficulties, SAE notification can be carried
out by sending a paper SAE form to the Pharmacovigi-
lance Officer via email or by fax.
All SAEs still ongoing at end of study will be followed
up by means of queries requesting updates. Other
supporting documentation of the event may be
requested by the study sponsor and should be provided
as soon as possible. The study sponsor will be
responsible for notifying Health Authorities of any
unexpected fatal or life-threatening suspected adverse
reaction as soon as possible, but in no case later than 7
calendar days after the sponsors initial receipt of the
information.
Suspected unexpected serious adverse reactions (SUSA
Rs) will be collected and reported to the competent
authorities and relevant ethics committees in accordance
with Directive 2001/20/EC or as per national regulatory
requirements in participating countries.
Reporting events to participants
Should an event occur that changes the overall benefit/
risk ratio of the study, the Sponsor shall evaluate if a risk
minimization measure is needed. Should this measure
require a substantial amendment to the protocol, the
informed consent and patient information will be
revised and submitted to the patient for written consent.
Frequency and plans for auditing trial conduct {23}
Clinical site monitoring will be conducted to ensure that
the rights and wellbeing of human subjects are
protected, that the reported study data are accurate,
complete, and verifiable, and that the conduct of the
study complies with the currently approved protocol,
with Good Clinical Practice (GCP), and with applicable
regulatory requirements. Monitoring for this study will
be performed by a Contract Research Organization
(CRO), OPIS. Details of clinical site monitoring are
documented in a Monitoring Plan (MP). The MP
describes in detail who will conduct the monitoring, at
what frequency monitoring will be done, at what level of
detail monitoring will be performed, and the distribution
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of monitoring reports. Further audits are at the
discretion of the respective authorities in charge of
overseeing medicinal products trials.
Plans for communicating important protocol
amendments to relevant parties (e.g., trial participants,
ethical committees) {25}
Important protocol modifications will be reported to the
responsible ethics committees and, after approval, made
accessible to the study centers. As far as the ICF is
subject to any revision, all future participants will be
provided with an updated version of the ICF. Protocol
amendments will not be communicated to past
participants.
Dissemination plans {31a, b, c}
This study will ensure that the public has access to the
published results of the research. The International
Committee of Medical Journal Editors (ICMJE) member
journals have adopted a clinical trials registration policy
as a condition for publication. The ICMJE defines a
clinical trial as any research project that prospectively
assigns human subjects to intervention or concurrent
comparison or control groups to study the cause-and-
effect relationship between a medical intervention and a
health outcome. Medical interventions include drugs,
surgical procedures, devices, behavioral treatments,
process-of-care changes, and the like. Health outcomes
include any biomedical or health-related measures ob-
tained in patients or subjects, including pharmacokinetic
measures and adverse events. The ICMJE policy requires
that all clinical trials be registered in a public trials regis-
try such as ClinicalTrials.gov, which is sponsored by the
National Library of Medicine. Other biomedical journals
are considering adopting similar policies.
Access to participant-level datasets and statistical code
can be granted upon request to the sponsors discretion.
Discussion
This protocol describes the process of a Phase II clinical
trial investigating the safety of a novel inhaled agent for
the treatment of moderate to severe ARDS. In addition
to the challenges one faces with every pharmaceutical
investigation, this study has some peculiarities which
shall be discussed here briefly.
The route of administration of the IMP is bronchial
inhalation. One major advantages of this way of
administration is the possibility to bring the IMP
straight to the desired site of action (i.e., the lungs) with
minimal plasmatic absorption, depending on the agents
pharmacokinetic properties. The latter was shown for
solnatide in a first-in-man study [22], which may indi-
cate a low risk of undesired systemic effects. However,
inhalative administration, unlike intravenous or oral use,
is fraught with some degree of variation in terms of the
amount of agent that actually reaches the alveolae. This
is due to each individuals anatomical and physiological
features of the respiratory tract and has been addressed
systematically in earlier research [33]. To minimize this
effect as best as possible, standardization of the proce-
dures is key. Therefore, all patients in this study will be
treated using the same model of bronchial inhaler and
great care was taken to make the setup of the respirator,
tubes, suction devices, and tubes as similar as possible
between patients and study centers.
Another issue to keep in mind is the relatively narrow
timeframe for inclusion of a patient. The protocol
requires a diagnosis of moderate to severe ARDS not
older than 48 h, yet the patient needs to be stable in this
condition for at least 8 h. In practice, potential study
patients will initially often be treated in peripheral
hospitals, deteriorate there until they meet the required
criteria, and then be transferred to one of the study
centers for further treatment in a more or less unstable
condition. Therefore, once the patient is stable enough
to be enrolled in the trial, there will possibly be only
little time left to get informed consent and have all data
necessary for inclusion ready. In order to respond to this
challenge, proper preparation of the required
examinations and procedures is advised. Also,
determination of the exact point in time of the ARDS
diagnosis is key. Respiratory deterioration alone does not
fulfill the Berlin criteria definition of ARDS, so
technically, the 48 h from diagnosis until possible
enrolment will frequently not start until appropriate
chest imaging was performed.
The patients possible need for extracorporeal
membrane oxygenation (EMCO) therapy during the
course of the intervention phase of the trial should also
be considered early on. While ECMO therapy at
screening leads to exclusion of the patient, once a
patient is enrolled, extracorporeal therapy will be
initiated as is clinically appropriate. This is, for ethical
reasons, not to be disputed. However, quality of the
collected data will be compromised in patients on
ECMO therapy during the first 7 days of the trial. In
particular, extravascular lung water (index) was found to
be estimated significantly higher in such patients due to
the altered hemodynamics caused by the extracorporeal
circuit [34]. The responsible investigator will have to
make an individual decision for every patient about to
be included in the trial, considering both quality of data
on the one hand and potential selection bias against the
most severely sick patients on the other hand.
A last point to consider might be the fact that
basically all patients will be unable to give informed
consent themselves at the time of screening. Inclusion
criteria demand that any patient needs to be
Schmid et al. Trials (2021) 22:643 Page 19 of 21
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mechanically ventilated at screening, and this will
usually go along with the use of some form of sedative
medication. So, having the procedures for enrolling such
patients in place according to local legal requirements
must be taken care of beforehand. Moreover, it is
assumed that patients will be hospitalized in the study
facility over the entire course of the observational period
due to the severity of their conditions. In case a patient
is transferred sooner than 28 days after enrolment,
individual measures need to be found in order to ensure
data assessment.
We present here the protocol for a randomized,
double-blind, parallel-group clinical trial investigating
the safety of a novel inhaled agent for the treatment of
pulmonary permeability edema in patients with moder-
ate to severe ARDS. As was laid out, especially during
screening and the intervention phase (days 0 to 7), the
coordination of tasks and procedures can be demanding
at times. However, with proper preparation of the re-
quired processes and some consideration of the possible
pitfalls discussed above, reliable, high-quality data can be
collected throughout the 28-day intervention and follow-
up period.
Trial status
Current protocol version: 8.0, 2 August 2021
Start of recruitment: 23.05.2018
Approx. date of completion: start + 4 years
Abbreviations
AE: Adverse event; ALC: Alveolar liquid clearance; ANCOVA: Analysis of
covariance; ANOVA: Analysis of variance; APACHE: Acute Physiology and
Chronic Health Evaluation (score); ARDS: Acute respiratory distress syndrome;
ATC: Anatomical therapeutic chemical; ATP: Adenosine triphosphate;
AUC: Area under the curve; BMI: Body mass index; BW: Body weight; CD-
ROM: Compact disc read-only memory; C
max
: Maximum concentration;
COPD: Chronic obstructive pulmonary disease; COVID-19: Coronavirus disease
2019; CPAP: Continuous positive airway pressure; CRO: Contract research
organization; DSMB: Data safety monitoring board; ECG: Electrocardiogram;
ECMO: Extracorporeal membrane oxygenation; eCRF: Electronic case report
form; EDC: Electronic data capture; ENaC: Epithelial sodium channel;
EVLWI: Extravascular lung water index; F
i
O
2
: Inspiratory fraction of oxygen;
GCP: Good clinical practice; GOCA: Gas exchange, Organ failure, Cause,
Associated disease (score); ICH: International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use;
ICMJE: International Committee of Medical Journal Editors; ICU: Intensive care
unit; IEB: Independent ethics committee; IMP: Investigational medicinal
product; IRB: Institutional review board; ITT: Intention-to-treat;
IWRS: Interactive web response system; LIS: Murray lung injury score;
MAP: Mean arterial pressure; MLC: Myosin light chain; NO: Nitrogen oxide;
NOAEL: No observed adverse effect level; P
a
CO
2
: Arterial carbon dioxide
partial pressure; P
a
O
2
: Arterial oxygen partial pressure; PBV: Pulmonary blood
volume; PEEP: Positive end-expiratory pressure; PGD: Primary graft
dysfunction; PKC: Protein kinase C; PP: Per-protocol; PVPI: Pulmonary vascular
permeability index; ROS: Reactive oxygen species; SAE: Serious adverse event;
SAPS: Simplified Acute Physiology Score; SBT: Spontaneous breathing trial;
SD: Standard deviation; SO
2
: Oxygen saturation; SOFA: Sequential Organ
Failure Assessment; SUSAR: Suspected unexpected serious adverse reaction;
TEAE: Treatment-emergent adverse event; TNF-m: Tumor necrosis factor e;
VFD: Ventilator-free days; V
t
: Tidal volume; WHO: World Health Organization
Acknowledgements
We want to thank the members of the Solnatide Collaborators Group for
their support:
Division of Anaesthesiology for Cardiovascular Surgery and Intensive Care
Medicine, Medical University of Graz, Austria:
Michael Schörghuber, MD; Christoph Klivinyi, MD; Ines Lindenau, MD
Department of Anesthesiology, Medical Center of the Johannes Gutenberg-
University, Mainz, Germany:
Erik Kristoffer Hartmann, MD; Marc Bodenstein, MD; Robert Rümmler, MD
Department of Intensive Care and Intermediate Care, University Hospital
RWTH Aachen, Germany:
Thomas Breuer, MD; Tim-Philipp Simon, MD; Gernot Marx, MD
Department of Anaesthesia, General Intensive Care and Pain Medicine,
Medical University of Vienna, Austria:
Petra Höbart, MD; Alexander Gartenmayer, MD; Luana Mandroiu, MD
Division of Intensive Care and Emergency Medicine, Department of Internal
Medicine, Medical University Innsbruck, Austria:
Michael Joannidis, MD; Andreas Peer, MD; Romuald Bellmann, MD;
Department of Anesthesiology and Intensive Care Medicine, University
Medical Center Schleswig Holstein, Campus Kiel, Germany:
Norbert Weiler, MD; Dirk Schädler, MD; Christine Eimer, MD
Department of Anesthesiology, University Hospital of Ludwig-Maximilians-
University (LMU), Munich, Germany:
Bernhard Zwißler, MD; Thomas Weig, MD; Michael Irlbeck, MD.
Authorscontributions {31b}
BS, MK, PK, and PM drafted and revised the current manuscript. BZ and SF
critically reviewed and revised the draft report. RU and KK critically reviewed
and revised the draft report. BF and RL critically reviewed and revised the
draft report. All authors have read and approved the final version which was
also approved by the sponsor.
Funding {4}
The study is funded by APEPTICO Forschung und Entwicklung GmbH
(Mariahilfer Straße 136, 1150 Vienna, Austria) and is also supported, in part,
by the European Commission (EC), Grant No. 101003595, and by the Austrian
Research Promotion Agency (FFG), Grant No.880862. Both EC and FFG have
no role in the design of the study and collection, analysis, and interpretation
of data and in writing the manuscript. The study was designed jointly by the
sponsor and the investigators. The funder has insurance to cover any study-
related injuries according to national legislation and local laws. Open Access
funding enabled and organized by Projekt DEAL.
Availability of data and materials {29}
Only the designated trial investigators will have access to the personal data
of participants and to the final data set. The original eCRF pages generated
during the study will become the property of the sponsor.
Declarations
Ethics approval and consent to participate {24}
The Local Ethics Committees at each site have approved the study protocol.
Any modifications to the protocol will be immediately communicated to all
responsible authorities. All patients, or their legal representative, must give
written informed consent before study participation (Germany, model form,
Additional file from APEPTICO), or as soon as possible (Austria, model form,
additional file from APEPTICO).
Consent for publication {32}
Not applicable, as no individual patient data are published.
Competing interests {28}
The participating study centers receive a per-patient enrollment fee compen-
sating for the expenses to conduct the study. BF is employed by Apeptico
Forschung und Entwicklung GmbH.
Author details
1
Department of Anaesthesiology, Intensive Care, Emergency and Pain
Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.
2
Department
of Anaesthesia, General Intensive Care and Pain Medicine, Medical University
of Vienna, Vienna, Austria.
3
Vascular Biology Center, Division of Pulmonary
Schmid et al. Trials (2021) 22:643 Page 20 of 21
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Medicine, Medical College of Georgia, Augusta University, Augusta, USA.
4
Apeptico Forschung und Entwicklung GmbH, Vienna, Austria.
5
Department
of Anesthesiology, University Hospital of Ludwig-Maximilians-University
(LMU), Munich, Germany.
6
Comprehensive Pulmonary Center Munich
(CPC-M), Member of the German Center for Lung Research (DZL), Munich,
Germany.
Received: 4 April 2021 Accepted: 24 August 2021
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... Solnatide, AP301) is currently being conducted in eight university hospitals in Germany and Austria (ClinicalTrials.gov Identifier: NCT03567577] (Schmid et al., 2021). Moreover, a phase 2a clinical trial in moderate to severe COVID-19 patients is being conducted at the Medical University Vienna (EudraCT 2020-001244-26). ...
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Background Survivors of critical illness often experience poor outcomes after hospitalisation, including delayed return to work, which carries substantial economic consequences. Objective To conduct a systematic review and meta-analysis of return to work after critical illness. Methods We searched PubMed, Embase, PsycINFO, CINAHL and Cochrane Library from 1970 to February 2018. Data were extracted, in duplicate, and random-effects meta-regression used to obtain pooled estimates. Results Fifty-two studies evaluated return to work in 10 015 previously employed survivors of critical illness, over a median (IQR) follow-up of 12 (6.25–38.5) months. By 1–3, 12 and 42–60 months’ follow-up, pooled return to work prevalence (95% CI) was 36% (23% to 49%), 60% (50% to 69%) and 68% (51% to 85%), respectively ( τ² =0.55, I ² =87%, p=0.03). No significant difference was observed based on diagnosis (acute respiratory distress syndrome (ARDS) vs non-ARDS) or region (Europe vs North America vs Australia/New Zealand), but was observed when comparing mode of employment evaluation (in-person vs telephone vs mail). Following return to work, 20%–36% of survivors experienced job loss, 17%–66% occupation change and 5%–84% worsening employment status (eg, fewer work hours). Potential risk factors for delayed return to work include pre-existing comorbidities and post-hospital impairments (eg, mental health). Conclusion Approximately two-thirds, two-fifths and one-third of previously employed intensive care unit survivors are jobless up to 3, 12 and 60 months following hospital discharge. Survivors returning to work often experience job loss, occupation change or worse employment status. Interventions should be designed and evaluated to reduce the burden of this common and important problem for survivors of critical illness. Trial registration number PROSPERO CRD42018093135.
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Introduction: The aim of this study was to describe the epidemiology and management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in Ireland. Methods: As part of a 10-week prospective national audit of patient demographics and organ failure incidence in intensive care in Ireland, all patients with ALI/ARDS in 14 participating centres were prospectively identified using American European Consensus Conference definitions. Results: There were 1,029 admissions during the study period; of these, 728 patients were invasively ventilated. A total of 196 (19%) patients had ALI/ARDS, and 141 of these (72%) had ALI/ARDS on admission and a further 55 (28%) developed ALI/ARDS after admission. For the patients with ALI/ARDS, the mean (+/- standard deviation) age was 58 +/- 17 years and 62% were male. The most common predisposing risk factors were pneumonia (50%) and nonpulmonary sepsis (26%). Mean (+/- standard deviation) tidal volume/kg was 7.0 +/- 1.7 ml/kg. Median (interquartile range) duration of ventilation was 6.8 (2.0 to 12.8) days. Median (interquartile range) length of stay in the intensive care unit was 10.0 (5.0 to 18.5) days. The overall intensive care unit mortality for ALI/ARDS was 32.3%. Lower baseline arterial oxygen tension/fraction of inspired oxygen ratio and higher Sequential Organ Failure Assessment scores were associated with increased mortality. Although not significant, patients receiving treatment with a statin during admission had a 73% lower odds of death (odds ratio 0.27, 95% confidence interval 0.06 to 1.21; P = 0.09). Conclusion: The incidence of ALI/ARDS is high and is associated with significant mortality. Protective lung ventilation is used commonly throughout participating centres. With low tidal volume ventilation, the degree of hypoxaemia is associated with outcome. These data will inform future multicentre clinical trials in ALI/ARDS in Ireland.
Article
AP301 is an activator of ENaC-mediated Na(+) uptake for the treatment of pulmonary permeability edema in acute respiratory distress syndrome (ARDS). The purpose of this "first-in-man" study was to examine local and systemic safety and systemic exposure of ascending single doses of AP301, when inhaled by healthy male subjects. In a double-blind, placebo-controlled study, 48 healthy male subjects were randomized to 6 ascending dose groups (single doses up to 120 mg) of 8 subjects each (3:1 randomization of AP301: placebo). Serial assessments included spirometry, exhaled nitric oxide (eNO), vital signs, ECG, safety laboratory, adverse events (AE), and blood samples for the quantification of AP301 in plasma. Descriptive statistics was applied. All 48 subjects received treatment, and completed the study as per protocol. No serious, local (e.g., hoarseness, cough, bronchospasm), or dose-limiting AEs were noted. None of the assessments indicated notable dose or time-related alterations of safety outcomes. Observed AP301 systemic exposure levels were very low, with mean Cmax values of <2.5 ng/mL in the highest dose groups. Inhaled AP301 single doses up to 120 mg were safe and well tolerated by healthy male subjects. Distribution of inhaled AP301 was largely confined to the lung, as indicated by very low AP301 systemic exposure levels.
Article
Introduction: The lectin-like domain of TNF-α enhances the fluid clearance across the alveolar barrier. For experimental purposes, the lectin-like domain can be mimicked by a synthetic peptide representing the TIP-motif of TNF-α. The present study aims to assess the acute effect of TIP on the pulmonary function in a porcine model of acute respiratory distress syndrome (ARDS). Methods: Lung injury was induced in 16 pigs (25-27 kg) by bronchoalveolar lavage followed by injurious ventilation. Following randomisation, either nebulised TIP (1 mg/kg; AP301, APEPTICO, Vienna, Austria) or water for injection (control group) was administered. During 5 h of monitoring, the extravascular lung water index (EVLWI), the quotient of partial pressure of oxygen and inspired oxygen concentration (PaO(2) /FiO(2) ) and the pulmonary shunt fraction were repetitively assessed. The data were evaluated by an analysis of variance including Bonferroni-Holm correction. Results: Comparable baseline conditions in both groups were achieved. Ventilatory parameters were standardised in both groups. In the TIP group, a significant reduction of the EVLWI and a simultaneous increase in the PaO(2) /FiO(2) ratio was shown (each P < 0.0001). No changes in the control group were observed (EVLWI: P = 0.43, PaO(2) /FiO(2) : P = 0.60). The intergroup comparison demonstrates a significant advantage of TIP inhalation over placebo (EVLWI: P < 0.0001, PaO(2) /FiO(2) : P = 0.004, shunt fraction: P = 0.0005). Conclusions: The inhalation of TIP induces an amelioration of clinical surrogate parameters of the lung function in a porcine lung injury model. By mimicking the lectin-like domain, the synthetic TIP peptide AP301 is an innovative approach as supportive therapy in ARDS.