Treatment of allergic rhinitis with ectoine containing nasal spray and eye drops in comparison with azelastine containing nasal spray and eye drops or with cromoglycic Acid containing nasal spray


Werkhäuser, N.; Bilstein, A.; Sonnemann, U.

Journal of Allergy 2014: 176597-176597

2014


Objectives. Allergic rhinitis is a common disease with increasing prevalence and high impact on economic burden and comorbidities. As treatment with pharmacological drugs is not always satisfactory due to side effects and incomplete efficacy, alternative treatment strategies are needed. Ectoine is an osmolyte with membrane stabilizing and inflammation reducing capacities. Nasal spray and eye drops containing ectoine are promising new treatment regimens for allergic rhinitis sufferers. Design and Methods. The current two noninterventional trials evaluated the efficacy and safety of ectoine containing nasal spray and eye drops for treating allergic rhinitis in comparison with either azelastine or cromoglycic acid containing products. Nasal and ocular symptom developments as well as judgment of tolerability and efficacy were assessed both by investigators and patients over a time period of one to two weeks. Results. Both trials confirmed that ectoine containing products reduced nasal and ocular symptoms in allergic rhinitis patients. Results clearly demonstrated good safety profiles of the ectoine products comparable to those of azelastine and even better to those of cromoglycate products. Conclusion. Ectoine containing nasal spray and eye drops are interesting new treatment strategies for sufferers of allergic rhinitis, combining both good efficacy and absence of side effects.

Hindawi
Publishing
Corporation
Journal
of
Allergy
Volume
2014,
Article
ID
176597,
13
pages
http://adoi.org/10.1155/2014/176597
Clinical
Study
Treatment
of
Allergic
Rhinitis
with
Ectoine
Containing
Nasal
Spray
and
Eye
Drops
in
Comparison
with
Azelastine
Containing
Nasal
Spray
and
Eye
Drops
or
with
Cromoglycic
Acid
Containing
Nasal
Spray
Nina
Werkhauser,'
Andreas
Bilstein,'
and
Uwe
Sonnemann
2
Bitop
AG,
Stockumer
Strafe
28,
58453
Witten,
Germany
2
Private
Health
Centre,
Institute
for
ENT
Elmshorn,
Hermann-Ehlers-Weg
4,
25337
Elmshorn,
Germany
Correspondence
should
be
addressed
to
Nina
Werkhauser;
werkhaeuser@bitop.de
Received
10
February
2014;
Accepted
29
March
2014;
Published
1
June
2014
Academic
Editor:
Ralph
Mosges
Copyright
CO
2014
Nina
Werkhauser
et
al.
This
is
an
open
access
article
distributed
under
the
Creative
Commons
Attribution
License,
which
permits
unrestricted
use,
distribution,
and
reproduction
in
any
medium,
provided
the
original
work
is
properly
cited.
Objectives.
Allergic
rhinitis
is
a
common
disease
with
increasing
prevalence
and
high
impact
on
economic
burden
and
comorbidities.
As
treatment
with
pharmacological
drugs
is
not
always
satisfactory
due
to
side
effects
and
incomplete
efficacy,
alternative
treatment
strategies
are
needed.
Ectoine
is
an
osmolyte
with
membrane
stabilizing
and
inflammation
reducing
capacities.
Nasal
spray
and
eye
drops
containing
ectoine
are
promising
new
treatment
regimens
for
allergic
rhinitis
sufferers.
Design
and
Methods.
The
current
two
noninterventional
trials
evaluated
the
efficacy
and
safety
of
ectoine
containing
nasal
spray
and
eye
drops
for
treating
allergic
rhinitis
in
comparison
with
either
azelastine
or
cromoglycic
acid
containing
products.
Nasal
and
ocular
symptom
developments
as
well
as
judgment
of
tolerability
and
efficacy
were
assessed
both
by
investigators
and
patients
over
a
time
period
of
one
to
two
weeks.
Results.
Both
trials
confirmed
that
ectoine
containing
products
reduced
nasal
and
ocular
symptoms
in
allergic
rhinitis
patients.
Results
clearly
demonstrated
good
safety
profiles
of
the
ectoine
products
comparable
to
those
of
azelastine
and
even
better
to
those
of
cromoglycate
products.
Conclusion.
Ectoine
containing
nasal
spray
and
eye
drops
are
interesting
new
treatment
strategies
for
sufferers
of
allergic
rhinitis,
combining
both
good
efficacy
and
absence
of
side
effects.
1.
Introduction
Allergic
rhinitis
is
a
common
disease
affecting
10-20%
of
the
population
[1].
Since
it
has
great
impact
on
patients'
quality
of
life,
school
performance,
work
productivity,
and
comorbid
conditions
such
as
asthma,
it
is
considered
as
an
important
health
problem.
Allergic
rhinitis
is
defined
as
an
allergic
reaction
(most
often
IgE-dependent)
to
offending
allergens
such
as
dust
mites,
insects,
animal
dander,
and
pollens.
Symptoms
include
rhinorrhea,
nasal
obstruction,
nasal
and
nasopharyngeal
itching,
sneezing,
and
postnasal
drip.
Often,
allergic
rhinitis
is
accompanied
by
allergic
conjunctivitis
with
ocular
symptoms
such
as
itchy
and
watery
eyes,
resulting
in
the
term
allergic
rhinoconjunctivitis.
According
to
its
length
of
duration,
allergic
rhinitis
is
classified
into
intermittent
(symptoms
present
<4
days
a
week
of
<4
weeks)
and
persistent
(symptoms
present
4
days
a
week
and
for
at
least
4
weeks)
forms.
Symptom
severity
is
used
to
classify
allergic
rhinitis
into
mild
or
moderate-severe
forms.
A
number
of
pharmacological
treatments
of
allergic
rhinitis
exist,
such
as,
for
example,
oral
and
topical
antihis-
tamines,
leukotriene
receptor
antagonists,
intranasal
gluco-
corticoids,
and
cromoglycic
acid
(mast
cell
stabilizers)
[2].
Azelastine
is
a
new-generation
antihistamine
applied
topically
as
nasal
spray
or
eye
drops.
It
is
used
as
treatment
of
allergic
rhinitis,
hay
fever,
and
allergic
conjunctivitis.
Although
azelastine
is
regarded
as
effective
possible
first-line
treatment
for
allergic
rhinitis,
common
side
effects,
such
as
bitter
taste
of
the
drug
and
local
irritation
reactions
and
rare
side
effects
such
as
fatigue
or
headache,
can
occur
[3].
Cromoglycic
acid
is
an
antiallergic
drug
which
inhibits
the
degranulation
of
mast
cells,
thereby
blocking
the
release
of
2
Journal
of
Allergy
inflammatory
mediators
[4].
Thus,
cromoglycic
acid
prevents
the
development
of
allergic
reactions
rather
than
reducing
acute
symptoms
and
its
onset
of
action
is
about
four
to
seven
days.
Due
to
its
short
half-life,
cromoglycic
acid
has
to
be
applied
at
least
4
times
a
day.
Cromoglycic
acid
is
thought
to
be
a
safe
medication,
and
adverse
events
which
might
occur
are
usually
mild,
such
as
sneezing
and
sensation
of
burning.
Due
to
its
good
safety
profile,
cromoglycic
acid
can
be
prescribed
for
treating
rhinitis
in
children
and
pregnant
women.
In
general,
many
allergic
rhinitis
patients
are
still
unsatis-
fied
with
the
control
of
symptoms,
complain
about
incom-
plete
relief
of
symptoms,
and
suffer
from
unwanted
side
effects
[5,
6].
Therefore,
it
is
not
surprising
that
increasing
interest
in
the
use
of
alternative
and
complementary
medicine
(CAM)
for
treating
rhinitis
exists.
Thus,
it
was
demonstrated
that
40%
of
the
American
population
uses
CAM,
17%
of
which
uses
it
for
treating
otorhinolaryngologic
diseases
[7].
However,
so
far
no
general
recommendation
for
the
use
of
CAM
can
be
given
by
ARIA
guidelines
as
ambiguous
study
results
are
available
[8].
The
present
two
individual
studies
compared
treatment
of
allergic
rhinitis
with
ectoine
containing
nasal
spray
and
eye
drops
with
azelastine
containing
products
(study
1)
or
treatment
with
ectoine
containing
nasal
spray
with
that
of
cromoglycic
acid
containing
nasal
spray
(study
2).
Ectoine
is
a
natural
amino
acid
derivate
which
is
pro-
duced
by
bacteria
living
under
extreme
harsh
environmental
conditions
where
it
serves as
osmoregulatory
compatible
solute
[9,
10].
Ectoine
works
via
a
mechanism
called
"prefer-
ential
exclusion"
[11,
12].
If
it
is
present
together
with
proteins
or
lipids,
ectoine
is
expelled
from
their
surfaces,
thereby
increasing
the
hydration
of
the
surface
and
stabilizing
lipid
layers
[13].
Its
membrane
stabilizing
as
well
as
inflammation
reducing
capacities
makes
ectoine
an
interesting
candidate
for
the
treatment
of
allergic
rhinitis.
These
studies
served
to
investigate
the
efficacy
and
safety
of
ectoine
containing
nasal
spray
and
eye
drops
in
patients
with
allergic
rhinitis.
2.
Materials
and
Methods
The
current
paper
describes
two
noninterventional
studies
carried
out
with
ectoine
containing
nasal
spray
and
eye
drops
assessing
their
efficacy
in
comparison
with
azelastine
nasal
spray
and
eye
drops
(study
1,
NCT02131051)
or
cromoglycic
acid
nasal
spray
(study
2,
NCT02131038).
2.1.
Medication.
The
ectoine
eye
drops
contain
an
iso-
osmotic
solution
with
2%
ectoine
and
0.35%
hydroxyethyl
cellulose;
the
ectoine
nasal
spray
is
a
hypertonic
solution
with
2%
ectoine.
Additional
ingredients
of
the
eye
drops
were
sodium
chloride,
sodium
dihydrogen
phosphate
dehydrate,
sodium
monohydrogen
phosphate
dehydrate,
and
water.
Additional
ingredients
of
the
nasal
spray
were
sodium
chlo-
ride
and
water.
In
study
1,
both
nasal
spray
and
eye
drops
were
used,
whereas
only
the
nasal
spray
was
used
in
study
2.
Azelastine
containing
products
were
used
as
com-
parator
in
study
1.
The
azelastine
eye
drops
contain
0.5
mg/mL
azelastine
hydrochloride
with
one
drop
adminis-
tering
0.015
mg
azelastine
hydrochloride,
and
the
azelastine
nasal
spray
contains
1
mg/mL
azelastine
hydrochloride
with
one
puff
administering
0.14
mg
azelastine
hydrochloride.
Additional
ingredients
of
the
eye
drops
were
benzalkonium
chloride
(preservative),
sodium
edetate,
hypromellose,
sor-
bitol,
sodium
hydroxide,
and
water.
Additional
ingredients
of
the
nasal
spray
were
sodium
edetate,
hypromellose,
citric
acid,
sodium
chloride,
sodium
hydrogen
phosphate,
and
water.
During
study
2,
a
cromoglycic
acid
containing
nasal
spray
was
used
as
comparator.
The
spray
contained
20
mg/ml
cro-
moglycic
acid
corresponding
to
2.8
mg
sodium
cromoglycic
acid
per
puff.
In
addition,
the
following
ingredients
were
present
in
the
formulation:
benzalkonium
chloride
(preserva-
tive
0.014
mg/puff),
sodium
edetate,
sodium
chloride,
sodium
dihydrogen
phosphate,
sodium
monohydrogen
phosphate,
sorbitol,
and
water.
2.2.
Treatment
and
Study
Design
2.2.1.
Study
1.
On
day
0
(Visit
1)
patients
were
asked
to
par-
ticipate
in
the
study,
and
upon
signing
the
informed
consent
form
and
patient
information,
they
were
allocated
to
one
of
the
study
groups,
without
any
washout
period.
Antiallergic
medications
used
the
last
two
days
prior
to
inclusion
were
recorded
by
the
physician.
Patients
were
treated
either
with
ectoine
containing
nasal
spray
and
eye
drops
or
with
aze-
lastine
containing
nasal
spray
and
eye
drops.
Patients
of
the
ectoine
group
had
to
apply
one
eye
drop
per
eye
and
one
puff
of
the
nasal
spray
per
nostril
four
times
per
day.
Patients
of
the
azelastine
group
had
to
apply
one
eye
drop
per
eye
and
one
puff
of
the
nasal
spray
per
nostril
twice
per
day.
The
treatment
period
was
7
days,
and
patients
were
asked
to
document
their
symptoms,
together
with
possible
comedication
and
adverse
effects
daily
in
patient
diaries
at
the
evening.
Therefore
the
patients'
assessments
started
after
the
products
had
been
applied
already.
Following
treatment,
patients
came
back
for
Visit
2
(day
7),
during
which
symptom
scores
were
evalu-
ated
and
tolerability,
efficacy
and
compliance,
and
possibly
comedications,
antiallergic
and
others,
were
assessed.
In-
and
Exclusion
Criteria.
Male
or
female
patients
aged
18
-
70
with
proven
allergy
and
acute
symptoms
in
nose
and
eye
(sum
nasal
score
15
and
sum
oral
score
6)
were
allowed
to
take
part
in
the
study.
Allergy
diagnosis
was
based
on
positive
prick
test.
Exclusion
criteria
were
pregnant
and
nursing
women,
drug
addicts
and
persons
unable
to
give
consent
to
study
participation,
patients
with
intolerance
against
ingredients
of
any
of
the
study
treatments,
previous
eye
or
nose
surgery,
concomitant
treatment
with
antiallergic
drugs,
and
diseases
which
might
influence
the
output
of
the
study
according
to
the
physicians'
judgment.
Scoring
of
Nasal
and
Ocular
Symptoms.
Single
nasal
(nasal
obstruction,
rhinorrhea,
and
sneezing)
and
ocular
symptoms
(eye
itching,
tearing,
and
conjunctivitis)
were
scored
with
an
8
point
scale
ranging
from
no
symptoms
(0)
to
very
severe
symptoms
(8).
48
patients
Ectoine:
22
patients
Azelastine:
26
patients
2
dropouts
due
to
AEs
46
patients
completed
treatment
3
patients
excluded
from
analysis
due
to
absence
of
pollen
L
>
43
patients
in
final
analysis
FIGURE
1:
Patient
flow
during
study
1.
Journal
of
Allergy
3
Scoring
of
Efficacy,
Tolerability,
and
Compliance.
Efficacy,
tolerability,
and
compliance
were
judged
by
using
a
scale
ranging
from
0
(very
good)
to
8
(bad).
Thus,
a
general
judgment,
of
either
how
well
to
tolerate
or
how
efficient
the
products
were,
had
to
be
given
by
the
patients
and
documented
in
the
patient
diaries.
Both
scoring
values
were
based
on
the
patients'
personal
opinion/feeling
with
the
products.
Whereas
efficacy
and
tolerability
were
assessed
both
by
patients
and
by
physicians,
compliance
was
solely
judged
by
physicians.
Statistics.
The
statistical
analysis
was
carried
out
with
SPSS
version
18
and
SigmaPlot
version
12.
Both
efficacy
and
safety
analyses
were
performed
on
the
entire
study
population.
Descriptive
statistics
were
used
for
a
quantitative
report
of
the
main
study
population
features.
Continuous
variables
were
tested
for
normal
distribution
via
Kolmogorov-Smirnov
test.
Further
analysis
was
carried
out
with
the
Mann-Whitney
U
test,
Wilcoxon
test,
or
Friedman
test.
The
level
of
significance
was
set
to
P
<
0.05
in
all
tests.
Unavailable
data
were
treated
as
"missing
values"
or
substituted
by
the
"last
value
carried
forward"
method.
2.2.2.
Study
2.
This
study
was
designed
as
a
crossover
study,
without
any
washout
period
within
the
first
week.
Half
of
the
patients
received
ectoine
nasal
spray
whereas
the
other
half
received
cromoglycic
acid
containing
nasal
spray.
After
7
days,
patients
swapped
to
the
other
treatment.
Thus,
patients
who
started
with
one
week
treatment
with
ectoine
nasal
spray
received
cromoglycic
acid
containing
nasal
spray
within
the
second
week
and
vice
versa.
For
simplification
reasons,
patients
starting
their
treatment
with
ectoine
are
termed
group
A,
and
patients
starting
their
treatment
with
cromoglycic
acid
are
termed
group
B
in
this
paper.
The
ectoine
nasal
spray
had
to
be
applied
at
least
5
times
per
day,
whereas
the
cromoglycic
acid
spray
had
to
be
applied
4
times
a
day.
Thus,
patients
had
to
take
the
ectoine
product
at
least
5
times
a
day
but
could
upgrade
dosing
if
they
felt
that
medication
was
not
sufficient.
The
cromoglycic
acid
product
had
to
be
used
according
to
the
instruction
for
use.
Patients
had
to
attend
visits
to
the
investigator
on
day
0
(V1),
day
7
(+2
days)
(V2),
and
day
14
(+2
days)
(V3).
During
those
visits,
the
investigator
assessed
nasal
(nasal
obstruction,
sneezing,
and
rhinorrhea)
and
ocular
symptoms
(eye
itching,
tearing,
and
conjunctivitis)
as
well
as
palate
itching
and
turbinate
hyperplasia.
At
the
end
of
the
study
(V3),
efficacy,
tolerability,
and
compliance
were
determined.
In
addition
to
the
investigator's
assessment,
patients
had
to
document
daily
their
ocular
and
nasal
symptoms
as
well
as
their
judgment
of
tolerability
and
efficacy
in
a
patient
diary
at
the
evening.
Based
on
the
design
the
patients
scoring
started
after
the
study
medication
had
been
applied.
In-
and
Exclusion
Criteria.
Male
or
female
patients
with
diagnosed
allergy
and
moderate
to
severe
acute
symptoms
of
nasal
obstruction,
sneezing,
and
rhinorrhea
were
allowed
to
take
part
in
the
study.
The
diagnosis
of
the
allergy
was
based
on
a
positive
prick
test.
Exclusion
criteria
were
intolerance
against
ectoine
or
cromoglycic
acid,
pregnancy,
previous
nose
surgeries,
or
ongoing
treatment
with
additional
antiallergic
drugs.
Scoring
of
Nasal,
Ocular,
and
Other
Symptoms.
Single
nasal
symptoms
(nasal
obstruction,
rhinorrhea,
and
sneezing)
and
ocular
symptoms
(eye
itching,
tearing,
and
conjunctivitis)
as
well
as
the
symptoms
palate
itching
and
turbinate
hyperplasia
were
scored
with
an
8
point
scale
ranging
from
no
symptoms
(0)
to
very
severe
symptoms
(8).
Scoring
of
Efficacy,
Tolerability,
and
Compliance.
Efficacy,
tolerability,
and
compliance
were
judged
by
using
a
scale
ranging
from
0
(very
good)
to
8
(bad).
Thus,
a
general
broad
judgment,
of
how
well
to
tolerate
and
how
efficient
the
products
were,
had
to
be
given
by
the
patients
and
to
be
documented
in
the
patient
diaries.
Both
scoring
values
were
based
on
the
patients'
personal
opinion/feeling
with
the
products.
Whereas
efficacy
and
tolerability
were
assessed
both
by
patients
and
by
physicians,
compliance
was
solely
judged
by
physicians.
Pollen
Score.
In
order
to
reflect
the
current
pollen
exposure,
data
from
the
online
HEXAL
pollen
calendar
were
used
to
grade
pollen
exposure
into
mild,
moderate,
or
severe
(1,
2,
or
3)
scores
during
the
course
of
the
study.
Statistics.
The
statistical
analysis
was
carried
out
with
SPSS
version
17
and
SigmaPlot
version
12.
Safety
analyses
were
performed
on
the
entire
study
population
whereas
efficacy
analysis
was
performed
on
all
patients
who
completed
the
treatment.
Continuous
variables
were
tested
for
normal
distribution
via
Kolmogorov-Smirnov
test.
Further
analysis
was
carried
out
with
the
Mann-Whitney
U
test,
Wilcoxon
test,
or
Friedman
test.
The
level
of
significance
was
set
to
P
<
0.05
in
all
tests.
Unavailable
data
were
treated
as
"missing
values"
or
substituted
by
the
"last
value
carried
forward"
method.
35
30
Ca
25
+I
g
20
TNSS
(physicians'
assessment)
*
*
T
v
/
4
Journal
of
Allergy
TABLE
1:
Development
of
single
nasal
scores
(mean
±
SD)
during
study
1
according
to
patients'
and
investigators'
assessments.
Symptom
Group
Score
dl
(patient)
Score
d7
(patient)
P
value
Score
V1
(investigator)
Score
V2
(investigator)
P
value
Nasal
obstruction
c
E
toine
4.14
±
1.93
3.38
±
2.20
P
=
0.003
5.29
±
1.15
2.86
±
1.49
P
<
0.001
Azelastine
4.38
±
2.38
3.60
±
2.37
P
=
0.044
5.91
±
1.23
3.0
±
2.13
P
<
0.001
Rhinorrhea
Ectoine
3.81
±
1.86
2.71
±
1.87
P
=
0.054
5.19
±
1.03
2.24
±
1.58
P
<
0.001
Azelastine
3.48
±
2.11
2.8
±
2.02
P
=
0.133
5.45
±
1.01
2.59
±
1.89
P
<
0.001
Sneezing
Ectoine
3.9
±
1.92
2.9
±
1.73
P
=
0.475
6.0
±
1.48
2.43
±
1.58
P
<
0.001
Azelastine
4.05
±
1.43
2.45
±
1.7
P
<
0.001
5.77
±
0.92
2.32
±
2.10
P
<
0.001
Nasal
itching
Ectoine
2.81
±
1.83
2.05
±
1.56
P
=
0.068
4.24
±
2.32
1.00
±
1.41
P
=
0.001
Azelastine
3.90
±
1.70
2.25
±
1.92
P
=
0.002
4.59
±
1.99
1.41
±
1.05
P
<
0.001
3.
Results
Both
studies
were
conducted
in
accordance
with
the
Declara-
tion
of
Helsinki.
All
investigations
were
carried
out
with
the
understanding
and
consent
of
all
participants.
3.1.
Results
Study
1.
This
was
a
noninterventional
trial
taking
place
at
two
German
ear
nose
throat
(ENT)
practices
starting
4
15
in
June
2010
and
being
completed
in
September
2010.
Distri-
bution
of
patients
is
shown
in
Figure
1.
In
total,
48
patients
took
part
in
the
study,
of
which
43
were
included
in
the
final
analysis
(31
females
and
12
males).
Mean
age
of
patients
was
35
5
years,
and
both
groups
were
comparable
in
regard
to
clinical
aspects.
0
cp
10
3.1.1.
Nasal
Symptoms.
Nasal
symptom
scores
were
assessed
both
as
single
symptoms
and
as
sum
of
all
nasal
symptoms
(TNSS).
Details
of
the
development
of
single
scores
are
given
in
Table
1.
Nasal
Obstruction.
The
mean
symptom
score
of
nasal
obstruction
decreased
significantly
by
45.95%
in
the
ectoine
group
and
by
49.23%
in
the
azelastine
group
(V1
to
V2,
P
<
0.001
for
both
groups).
The
documentation
of
the
patient
diaries
also
reflected
a
significant
decrease
by
18.39%
in
the
ectoine
group
(P
=
0.003)
and
by
17.83%
in
the
azelastine
group
(P
=
0.044).
Rhinorrhea.
A
significant
decrease
in
the
symptom
score
was
also
observed
for
rhinorrhea
from
V1
to
V2.
Mean
values
decreased
by
56.88%
in
the
ectoine
group
and
by
52.50%
in
the
azelastine
group
(P
<
0.001
for
both
groups).
The
patient
documentation
showed
a
dear
decrease
of
the
symptom
rhinorrhea
which,
however,
was
not
significant.
Values
decreased
by
28.75%
in
the
ectoine
group
(P
=
0.054)
and
by
19.45%
in
the
azelastine
group
(P
=
0.133).
Sneezing.
The
symptom
sneezing
decreased
significantly
from
V1
to
V2:
values
decreased
by
59.52%
in
the
ectoine
group
and
by
59.84%
in
the
azelastine
group
(P
<
0.001
for
both
groups).
The
patient
documentation
also
reflected
the
symptom
decrease
which
was
not
significant
in
the
ectoine
group
(25.61%,
P
=
0.475)
but
significant
in
the
azelastine
group
(39.47%,
P
<
0.001).
Nasal
Itching.
Nasal
itching
decreased
significantly
from
V1
to
V2:
values
decreased
by
76.40%
in
the
ectoine
group
(P
=
Mean
TNSS
V1
ectoine
EZZ21
Mean
TNSS
V1
azelastine
I
i
Mean
TNSS
V2
ectoine
®
Mean
TNSS
V2
azelastine
FIGURE
2:
Decrease
(mean
±
SD)
of
TNSS
from
V1
to
V2
according
to
the
physicians'
assessment
*
P
<
0.001.
0.001)
and
by
69.31%
in
the
azelastine
group
(P
<
0.001).
According
to
the
patient
documentation,
nasal
itching
scores
decreased
by
27.12%
in
the
ectoine
group
(P
=
0.068)
and
by
42.38%
(P
=
0.002)
in
the
azelastine
group.
3.1.2.
Total
Nasal
Symptom
Score
(TNSS).
The
sum
of
nasal
symptom
scores
(nasal
obstruction,
rhinorrhea,
sneezing,
and
nasal
itching)
showed
a
significant
decrease
from
V1
to
V2
(as
assessed
by
physicians):
sum
scores
in
the
ectoine
group
decreased
from
20.71
±
3.52
to
8.52
±
4.74
(decrease
of
58.85%;
P
<
0.001)
and
sum
scores
in
the
azelastine
group
decreased
from
21.73
±
3.34
to
9.32
±
6.24
(decrease
of
57.11%;
P
<
0.001).
Data
are
depicted
in
Figure
2.
According
to
the
patients'
assessment
(see
Figure
3),
values
decreased
by
23.05%
in
the
ectoine
group
(P
=
0.076)
and
by
33.14%
in
the
azelastine
group
(P
=
0.02).
3.1.3.
Ocular
Symptoms.
Ocular
symptom
scores
were
also
assessed
as
single
symptoms
and
as
sum
of
all
ocular
symp-
toms
(TOSS).
Details
of
the
development
of
single
scores
are
given
in
Table
2.
Conjunctivitis.
The
symptom
conjunctivitis
dearly
decreased
from
V1
to
V2,
as
reflected
by
decline
of
48.15%
in
the
Journal
of
Allergy
5
TABLE
2:
Development
of
single
ocular
symptom
scores
during
study
1
according
to
patients
and
investigators'
assessments.
Symptom
Group
Score
dl
(patient)
Score
d7
(patient)
P
value
Score
V1
(investigator)
Score
V2
(investigator)
P
value
Conjunctivitis
Ectoine
2.1
±
1.84
1.38
±
1.56
P
=
0.218
2.67
±
0.97
1.71
±
1.62
P
=
0.058
Azelastine
2.05
±
1.77
2.35
±
2.32
P
=
0.885
3.32
±
1.73
1.77
±
1.66
P
=
0.013
Eye
itching
Ectoine
3.24
±
1.89
2.67
±
1.91
P
=
0.604
3.86
±
1.93
2.0
±
1.79
P
=
0.008
Azelastine
2.9
±
1.81
2.75
±
2.1
P
=
0.14
4.05
±
1.89
2.18
±
2.17
P
=
0.002
Tearing
Ectoine
1.71
±
1.35
1.62
±
1.63
P
=
0.886
2.90
±
1.3
1.38
±
1.69
P
=
0.003
Azelastine
1.9
±
1.84
1.55
±
1.67
P
=
0.357
2.14
±
1.67
1.27
±
1.67
P
=
0.039
TNSS
(patients'
assessment
TOSS
(physicians'
assessment)
30
20
25
15
c
q
20
10
-
A
A
Mean
TNSS
dl
ectoine
Mean
TNSS
dl
azelastine
I I
Mean
TNSS
d7
ectoine
ESN
Mean
TNSS
d7
azelastine
FIGURE
3:
Decrease
(mean
±
SD)
of
TNSS
from
day
1
(d1)
to
day
7
(d7)
according
to
the
patients'
assessment
°P
=
0.02.
Mean
TOSS
V1
ectoine
rzz2
Mean
TOSS
V1
azelastine
I I
Mean
TOSS
V2
ectoine
zzO
Mean
TOSS
V2
azelastine
FIGURE
4:
Decrease
(mean
±
SD)
of
TOSS
from
V1
to
V2
as
assessed
by
physicians
in
study
1.
*
1
3
<
0.001.
ectoine
group
(P
=
0.058)
and
of
46.07%
in
the
azelastine
group
(P
=
0.013).
In
the
patients
documentation,
scores
of
conjunctivitis
decreased
by
34.09%
in
the
ectoine
group
(P
=
0.218)
whereas
an
increase
by
14.77%
was
observed
in
the
azelastine
group
(P
=
0.885).
Eye
Itching.
There
was
a
significant
decrease
in
the
symptom
scores
of
eye
itching:
in
the
ectoine
group,
the
mean
decreased
by
48.15%
(P
=
0.008)
whereas
values
of
the
azelastine
group
decreased
by
46.07%
(P
=
0.002).
Corresponding
decreases
as
assessed
by
the
patients
were
17.65%
in
the
ectoine
group
(P
=
0.604)
and
5.33%
in
the
azelastine
group
(P
=
0.14).
Tearing.
A
statistical
decrease
in
the
scoring
of
the
symptom
tearing
was
also
observed
from
V1
to
V2:
in
the
ectoine
group,
values
decreased
by
52.46%
(P
=
0.003)
whereas
values
in
the
azelastine
group
decreased
by
40.43%
(P
=
0.039).
The
patient
documentation
of
the
symptom
tearing
also
showed
a
dear
decrease
of
values
(5.56%
with
P
=
0.886
in
the
ectoine
group
and
18.63%
with
P
=
0.357
in
the
azelastine
group).
3.1.4.
Total
Ocular
Symptom
Score
(TOSS).
The
TOSS
(sum
of
conjunctivitis,
eye
itching,
and
tearing)
decreased
signifi-
cantly
from
V1
to
V2
in
both
groups
(P
<
0.001
for
ectoine,
P
=
0.009
for
azelastine).
Starting
mean
values
at
V1
were
9.43
±3.14
in
the
ectoine
group
and
9.5
±4.22
in
the
azelastine
group
which
decreased
by
45.96%
to
5.10±4.38
in
the
ectoine
group
and
by
44.98%
to
5.23
±
4.36
in
the
azelastine
group.
Decreases
of
TOSS
values
as
assessed
by
patients
were
not
significant
(Figure
4)
(data
not
shown).
Palate
Itching.
As
for
nasal
and
ocular
symptoms,
a
clear
decrease
of
the
symptom
palate
itching
was
observed
from
V1
to
V2:
in
the
ectoine
group,
values
decreased
from
2.52
±
2.71
to
1.19
±
1.72
(P
=
0.024),
and
in
the
azelastine
group,
values
decreased
from
3.36
±
2.68
to
1.5
±
1.92
(P
=
0.018).
Values
of
the
patients'
documentation
did
only
reach
statistical
significance
in
the
azelastine
group:
here,
the
scoring
decreased
from
3.81
±
2.5
to
2.15
±
2.13
(P
<
0.001).
In
the
ectoine
group,
values
decreased
from
1.76
±
2.1
to
1.67
±
2.15
(P
=
0.854).
Correlation
of
Pollen
Count
and
Nasal
Symptoms.
In
order
to
normalize
the
nasal
symptoms
(nasal
constriction,
rhinor-
rhea,
and
sneezing)
to
the
pollen
burden,
a
quotient
from
sum
score
and
pollen
counts
was
determined.
Values
of
quotients
decreased
significantly
from
8.97
±
3.98
to
5.23
±
3.59
in
the
ectoine
group
(P
=
0.002)
and
from
9.73
±
3.59
to
5.76
±
5.26
in
the
azelastine
group
(P
=
0.011),
thus
confirming
the
decrease
of
nasal
symptoms
during
the
pollen
season
upon
treatment.
Efficacy,
Tolerability,
and
Compliance.
The
physicians'
assess-
ment
of
efficacy
of
both
products
was
similar
at
V2,
and
Efficacy
(patients'
assessment)
10
8
-
6
-
4
-
0
-
Ectoine
Azelastine
6
Journal
of
Allergy
TABLE
3:
Correlation
of
differences
of
single
symptoms
(mean
values)
between
V1
and
V2
(based
on
physicians'
evaluations)
in
study
1.
Symptom
Difference
means
Difference
means
P
value
V1-V2
ectoine
V1-V2
azelastine
Nasal
obstruction
2.43
2.91
0.546
Rhinorrhea
2.95
2.86
0.882
Sneezing
3.57
3.45
0.787
Nasal
itching
3.24
3.18
0.768
Conjunctivitis
0.96
1.55
0.409
Eye
itching
1.86
1.87
0.863
Tearing
1.52
0.87
0.254
Palate
itching
1.33
1.86
0.426
FIGURE
5:
Patients'
assessment
of
efficacy
during
study
1
from
day
1
to
day
7.
Lines
within
the
box
mark
the
median;
the
upper
and
lower
ends
of
the
box
indicate
the
75th
and
25th
percentiles,
respectively.
Whiskers
above
and
below
the
box
indicate
the
90th
and
10th
percentiles.
Dots
(.)
represent
outlying
points.
Tolerability
(patients'
assessment)
Ectoine
Azelastine
FIGURE
6:
Patients'
assessment
of
tolerability
during
study
1
from
day
1
to
day
7.
Lines
within
the
box
mark
the
median;
the
upper
and
lower
ends
of
the
box
indicate
the
75th
and
25th
percentiles,
respectively.
Whiskers
above
the
box
indicate
the
90th
percentile.
Dots
(.)
represent
outlying
points.
with
values
of
2.48
(good)
in
the
ectoine
group
and
2.64
(good-satisfactory)
in
the
azelastine
group,
there
was
no
significant
difference
between
groups.
The
general
tolerability
was
assessed
as
very
good
to
good
in
both
groups
(1.33
in
the
ectoine
group
and
1.45
in
the
azelastine
group),
and
the
compliance
was
comparably
good
(values
<1)
in
both
groups.
Values
of
the
patients'
assessments
of
efficacy
and
tolera-
bility
are
shown
in
Figures
5
and
6.
The
patients'
evaluations
resulted
in
comparable
values
of
efficacy
and
tolerability
without
statistical
differences
between
treatment
groups.
Comparison
of
Reduction
of
Symptoms
between
Groups.
In
order
to
calculate
if
reduction
of
symptoms
from
V1
to
V2
was
different
between
the
treatment
groups,
differences
of
mean
V1
and
V2
values
were
compared
via
Mann-Whitney
U
TABLE
4:
Correlation
of
differences
of
single
symptoms
(mean
values)
between
dl
and
d7
(based
on
patients'
evaluations)
in
study
1.
Symptom
Difference
means
dl-d7
ectoine
Difference
means
dl-d7
azelastine
P
value
Nasal
obstruction
0.76
0.78
0.814
Rhinorrhea
1.1
0.68
0.446
Sneezing
1.0
1.6
0.54
Nasal
itching
0.76
1.65
0.184
Conjunctivitis
0.72
-0.3
0.42
Eye
itching
0.57
0.15
0.73
Tearing
0.09
0.35
0.826
Palate
itching
0.09
1.66
0.034
test.
As
shown
in
Table
3,
there
were
no
statistical
differences
between
the
ectoine
and
the
azelastine
group,
thus
con-
firming
that
both
substances
worked
comparably
well.
The
same
calculation
was
performed
for
the
patient
data.
Here,
no
statistical
difference
was
shown
except
for
the
symptom
palate
itching.
Details
are
shown
in
Table
4.
Adverse
Events
(AEs).
In
total,
8
AEs
occurred
during
the
study
(see
Table
5).
2
AEs
occurred
in
the
ectoine
group,
whereas
6
AEs
occurred
in
the
azelastine
group.
2
AEs
in
the
azelastine
group
led
to
dropout
of
the
study.
No
serious
adverse
event
(SAE)
occurred
during
the
study.
3.2.
Results
Study
2.
This
was
a
noninterventional
trial
taking
place
at
a
German
ear
nose
throat
(ENT)
practice
starting
in
May
2009
and
being
completed
in
September
2009.
Distribution
of
patients
is
shown
in
Figure
7.
In
total,
50
patients
(33
females
and
17
males)
with
an
average
age
of
34
years
took
part
in
the
study.
Both
treatment
groups
were
homogeneous
from
a
clinical
point
of
view.
3.2.1.
Nasal
Symptoms
Nasal
Obstruction.
Both
patient
groups
started
with
a
com-
parable
mean
nasal
obstruction
score
of
5.80
in
group
A
and
5.64
in
group
B
(physician's
assessment).
The
symptom
scores
10
8
0
TNSS
(physician's
assessment)
*
*
*
*
T
I
N
V1
=
Group
A
I
i
Group
B
i
V1
V2 V2
V3 V3
Journal
of
Allergy
7
TABLE
5:
Adverse
events
during
study
1.
N
Description
Outcome
Ectoine
group
2
#1:
burning
of
eyes
#2:
itching
of
throat
during
application
of
products
Recovered
#1-4:
burning
of
eyes
(n
=
4)
Azelastine
group
6
#5:
nausea
#6
headache
(n
=
1)
1
premature
determination
of
study
due
to
AE
1
premature
determination
of
study
due
to
AE
25
50
patients
20
1 1
Group
A:
Group
B:
15
En
En
25
patients
25
patients
Ectoine
treatment
Cromoglycic
acid
treatment:
10
7(+2)
days
7(+2)
days
Crossover
5
Ectoine
treatment
Cromoglycic
acid
treatment:
7(+2)
days
7(+2)
days
0
50
patients
in
final
analysis
FIGURE
7:
Patient
flow
during
study
2.
FIGURE
8:
TNSS
development
according
to
the
physician's
assess-
ment.
TNSS
scores
decreased
from
16.64
(V1,
group
A)
to
8.16
(V2,
group
A)
and
further
to
6.20
(V3,
group
A).
In
group
B,
values
decreased
from
16.28
(V1)
to
8.92
(V2)
and
to
8.28
(V3).
*P
<
0.001.
decreased
to
3.2
(group
A)
and
3.44
(group
B)
after
a
week,
and
a
further
decrease
to
2.52
(group
A)
and
2.92
(group
B)
was
observed
after
2
weeks.
Decreases
were
significant
in
both
groups
with
P
values
both
for
1
week
and
for
2
weeks
of
P
<
0.001.
Similarly,
patient
scores
of
the
symptom
nasal
obstruction
decreased
from
4.08
(group
A)
and
3.60
(group
B)
on
day
0
to
2.84
(group
A,
P
=
0.009)
and
3.24
(group
B,
P
=
0.464)
on
day
7
and
further
to
2.52
(group
A,
P
=
0.004)
and
2.56
(group
B,
P
=
0.041)
on
day
14.
Rhinorrhea.
The
symptom
rhinorrhea
decreased
significantly
(P
<
0.001)
for
both
groups
both
from
V1
to
V2
and
from
V1
to
V3
according
to
the
physician's
assessment.
Values
decreased
from
5.12
to
2.40
(V2)
and
further
to
1.88
(V3)
in
group
A
and
from
4.96
to
2.68
(V2)
and
to
2.76
(V3)
in
group
B.
According
to
the
patients'
evaluation,
scoring
of
rhinor-
rhea
decreased
from
3.12
to
2.32
(d7,
P
=
0.104)
and
further
to
2.04
(d14,
P
=
0.010)
in
group
A.
In
group
B,
values
decrease
from
3.80
to
3.08
(d7,
P
=
0.115)
and
further
to
2.28
(d14,
P
<
0.001).
Sneezing
The
symptom
sneezing
also
decreased
significantly
(P
<
0.001)
from
V1
to
V2
and
from
V1
to
V3
in
both
groups.
Baseline
scores
from
group
A
were
5.72
and
decreased
to
2.56
(V2)
and
further
to
1.80
(V3),
whereas
values
in
group
B
decreased
from
5.68
to
2.80
(V2)
and
to
2.6
(V3).
According
to
the
patients'
evaluation,
scoring
of
the
symptom
sneezing
decreased
from
3.16
to
2.44
(P
=
0.20)
on
day
7
to
2.12
(P
=
0.265)
on
day
14
in
group
A,
whereas
values
decreased
from
4.04
to
2.64
(P
=
0.018)
on
day
7
to
2.40
(P
<
0.001)
on
day
14
in
group
B.
3.2.2.
Total
Nasal
Symptom
Score
(TNSS).
To
reflect
the
development
of
the
sum
of
nasal
symptoms,
the
total
nasal
score
(nasal
obstruction,
rhinorrhea,
and
sneezing)
was
calculated.
Results
are
depicted
in
Figures
8
and
9.
According
to
the
physician's
assessment,
TNSS
scores
decreased
signif-
icantly
for
both
groups
both
from
V1
to
V2
(P
<
0.001)
and
from
V1
to
V3
(P
<
0.001).
Scores
assessed
by
patients
showed
that
decreases
in
TNSS
from
dl
to
d7
were
not
significant
whereas
significant
decreases
in
TNSS
scores
from
dl
to
d14
were
shown
both
for
group
A
(P
<
0.001)
and
group
B
(P
<
0.001).
3.2.3.
Ocular
Symptoms.
To
investigate
the
development
of
ocular
symptoms
during
the
treatment
period,
the
single
symptoms
eye
itching,
tearing,
and
conjunctivitis/redness
of
eyes
were
assessed
both
by
the
investigator
and
by
Ess!,
Group
A
I I
Group
B
FIGURE
10:
Assessment
of
sum
of
ocular
symptoms
(TOSS)
accord-
ing
to
physician's
assessments
in
study
2.
*
P
<
0.001,
°
P
=
0.008,
and
+
P
=
0.003.
16
TOSS
(physician's
assessment)
+
*
*
T
\
V1 V1
V2
V2
V3 V3
6
-
14
-
12
-
8
Journal
of
Allergy
25
TNSS
(patients'
assessment)
20
15
co
c
'
D
E-
,
10
5
/
/
0
4
4
4
dl dl
d7 d7
d14
d14
EZZ
Group
A
I I
Group
B
FIGURE
9:
TNSS
development
according
to
the
patients'
assessment.
TNSS
scores
decreased
from
10.36
(dl,
group
A)
to
7.60
(d7,
group
A)
and
further
to
6.68
(d14,
group
A).
In
group
B,
values
decreased
from
11.44
(dl)
to
8.96
(d7)
and
to
7.24
(d14).
*
P
<
0.001.
the
patients.
Details
of
scores
are
listed
in
Tables
6
and
7.
According
to
the
investigator's
assessment,
all
observed
ocular
symptoms
improved
significantly
from
V1
to
V3
in
group
A,
whereas
only
the
symptoms
eye
itching
and
tearing
improved
significantly
in
group
B.
The
patients'
assessment
of
ocular
symptoms
showed
that
the
symptoms
eye
itching
and
eye
redness
improved
significantly
in
group
A,
whereas
decreases
in
symptom
scores
from
day
1
to
day
14
were
not
significant
in
group
B.
3.2.4.
Total
Ocular
Symptom
Score
(TOSS).
The
development
of
the
sum
of
ocular
symptoms
(eye
itching,
conjunctivitis,
and
tearing)
as
assessed
by
the
investigator
is
depicted
in
Figure
10.
It
could
be
confirmed
that
ocular
symptoms
decreased
significantly
from
V1
to
V2
(P
<
0.001
for
group
1;
P
=
0.008
for
group
B)
as
well
as
from
V1
to
V3
(P
<
0.001
for
group
1;
P
=
0.003
for
group
B).
The
development
of
total
ocular
symptom
score
as
assessed
by
patients
is
shown
in
Figure
11.
Here,
a
significant
decrease
of
symptom
score
was
only
observed
in
group
A
from
day
1
to
day
14
(P
=
0.026).
Palate
Itching
and
Turbinate
Hyperplasia.
In
addition
to
nasal
and
ocular
symptoms,
the
development
of
the
symptom
palate
itching
was
determined
both
by
the
investigator
and
the
patients.
As
shown
in
Table
8,
significant
decreases
in
the
symptom
palate
itching
were
observed
by
the
investigator
from
V1
to
V3.
In
contrast,
patients'
assessment
of
this
symptom
showed
only
small
decreases
in
this
symptom
which
were
not
significant.
Additionally,
the
development
of
turbinate
hyperplasia
was
determined
by
the
investigator.
As
shown
in
Table
8,
treatment
resulted
in
a
significant
improvement
of
this
symptom
within
the
first
week
of
treatment
which
was
still
significantly
improved
after
two
weeks
of
treatment.
No
TOSS
(patients'
assessment)
#
/
/
x
4
4
4
dl dl
d7 d7
d14
d14
eZZi
Group
A
I
I
Group
B
FIGURE
11:
Assessment
of
sum
of
ocular
symptoms
TOSS
develop-
ment
according
to
the
patients'
assessment
during
study
2.
#
P
=
0.026.
differences
between
groups
could
be
determined
for
this
symptom
(Table
9).
Correlation
of
Pollen
Count
and
Nasal
Symptoms.
In
order
to
rule
out
that
results
might
be
influenced
by
the
existence
of
pollens,
data
reflecting
the
current
pollen
count
were
included
in
the
analysis.
The
quotient
of
TNSS
values
and
pollen
count
scores
confirmed
a
significant
decrease
of
TNSS
values
both
from
V1
to
V2
(P
<
0.001)
and
from
V1
to
V3
(P
<
0.001)
(data
not
shown).
Efficacy,
Tolerability,
and
Compliance.
According
to
the
physi-
cians'
judgment,
the
efficacy
of
treatment
was
rated
"good
to
satisfactory"
with
a
score
of
2.68
±
1.89
(group
A)
and
16
14
12
10
FA
0
8
E-
,
6
4
2
0
Journal
of
Allergy
9
TABLE
6:
Development
of
ocular
rhinitis
symptoms
(mean
values)
during
study
2
(physician's
assessment).
Symptom
Group
Mean
V1
Mean
V2
Mean
V3
P
value
Vi
versus
V2
P
value
V2
versus
V3
Eye
itching
A
3.80
±
2.29
1.68
±
1.84
1.00
±
1.38
P
<
0.001
P
<
0.001
B
2.72
±
2.05
1.60
±
1.63
1.48
±
1.78
0.046
0.003
Tearing
A
2.32
±
1.95
0.76
±
1.13
0.68
±
0.95
0.002
P
<
0.001
B
1.32
±
1.35
0.84
±
1.37
0.64
±
1.35
0.107
0.006
A
1.80
±
2.06
0.80
±
1.19
0.40
±
0.58
0.086
0.011
Conjunctivitis
B
1.12
±
1.13
0.75
±
1.22
0.72
±
1.21
0.094
0.383
TABLE
7:
Development
of
ocular
rhinitis
symptoms
(mean
values)
during
study
2
(patients'
assessment).
Symptom
Group
Mean
dl
Mean
d7
Mean
d14
P
value
di
versus
d7
P
value
dl
versus
d14
Eye
itching
A
2.68
±
1.99
1.56
±
1.58
1.48
±
1.81
0.044
0.019
B
2.04
±
1.93
1.48
±
1.61
1.28
±
1.74
0.250
0.014
Tearing
A
1.24
±
1.36
1.20
±
1.26
0.92
±
1.08
0.992
0.382
B
1.12
±
1.36
1.30
±
1.24
0.68
±
1.41
0.271
0.297
Eye
redness
A
2.00
±
2.02
1.12
±
1.24
0.88
±
1.20
0.150
0.003
B
1.12
±
1.42
0.80
±
1.32
0.84
±
1.31
0.337
0.292
2.96
±
1.72
(group
B)
at
V2
and
a
score
of
3.12
±
2.11
(group
A)
and
2.80
±
2.06
(group
B)
at
V3.
There
were
no
significant
differences
between
both
groups.
Similarly,
the
patients'
assessment
of
efficacy
was
"good
to
satisfactory"
both
on
day
7
(group
A:
2.76
±
1.89;
group
B:
2.96
±
1.81)
and
on
day
14
(group
A:
2.56
±
2.00;
group
B:
2.44
±
2.16)
without
statistical
differences
between
groups.
Following
1
week
of
treatment,
the
tolerability
was
judged
as
"very
good"
in
group
A
(1.24
±
1.30)
and
as
"good"
(2.40
±
1.53)
in
group
B.
Following
crossover
of
groups,
tolerability
of
the
treatment
was
judged
as
"satisfactory"
(3.0
±
2.16)
in
group
A
and
as
"very
good"
(0.88
±
1.05)
in
group
B.
The
changes
of
tolerability
between
both
groups
were
highly
significant
(P
<
0.001),
thus
indicating
that
tolerability
was
significantly
better
following
a
7-day
treatment
with
ectoine
containing
nasal
spray
in
comparison
to
7-day
treatment
with
cromoglycic
acid
nasal
spray.
Those
differences
in
tolerability
scoring
were
also
clearly
visible
in
the
patients'
assessment
of
tolerability.
Whereas
tolerability
was
judged
as
"very
good"
(1.30
±
1.48)
within
the
first
days
of
treatment
in
group
A,
scoring
for
the
second
week
decreased
to
a
mean
score
of
2.65
±
1.89
corresponding
to
"good
to
satisfactory"
Group
B
showed
the
opposite
development
with
a
tolerability
scoring
of
2.35
±
1.68
("good")
within
the
first
7
days
which
improved
to
a
mean
score
of
0.97
±
1.24
("very good")
within
the
second
half
of
the
treatment.
Details
of
the
patients'
tolerability
assessment
are
depicted
in
Figure
12.
In
summary,
patients
judged
the
tolerability
significantly
better
under
treatment
with
ectoine
containing
nasal
spray
compared
to
treatment
with
cromoglycic
acid
nasal
spray
(P
<
0.001).
Tolerability
(patients'
assessment
§
4
3
2
2
7
7
7
0
/,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Treatment
day
=I
Group
A
I
I
Group
B
FIGURE
12:
Patients'
assessment
of
tolerability
of
treatments
during
study
2.
The
compliance
was
assessed
as
very
good
by
the
physi-
cian,
and
values
were
not
statistically
different
between
groups
(see
Table
10).
Adverse
Events
(AEs).
During
the
study,
no
serious
adverse
events
(SAEs)
occurred.
No
adverse
events
were
observed
during
treatment
with
ectoine
containing
nasal
spray.
In
contrast,
13
patients
complained
about
a
burning
sensation
during
treatment
with
cromoglycic
acid
nasal
spray.
One
10
Journal
of
Allergy
TABLE
8:
Physician's
assessment
of
palate
itching
and
turbinate
hyperplasia
during
study
2.
Symptom
Group
Mean
V1
Mean
V2
Mean
V3
P
value
V1
versus
V2
P
value
V1
versus
V3
Palate
itching
A
2.32
±
2.54
1.12
±
2.05
0.84
±
1.52
0.054
0.003
B
2.20
±
2.36
1.24
±
2.13
0.92
±
1.80
0.048
0.002
Turbinate
hyperplasia
A
4.68
±
1.25
3.56
±
1.08
3.76
±
1.69
<0.001
0.007
B
4.80
±
1.15
3.84
±
1.25
3.56
±
1.19
0.005
0.001
TABLE
9:
Patients'
assessment
of
palate
itching
during
study
2.
Symptom
Group
Mean
dl
Mean
d7
Mean
d14
P
value
dl
versus
d7
P
value
dl
versus
d14
Palate
itching
A
1.80
±
2.35
B
1.56
±
1.89
1.56
±
1.87
1.24
±
2.09
1.12
±
1.62
0.962
0.425
0.92
±
1.78
0.053
0.035
TABLE
10:
Compliance
scores
(assessed
by
the
investigator)
following
1
week
(V2)
and
2
weeks
(V3)
of
treatment
during
study
2.
Group
Mean
V2
Mean
V3
A
1.28
±
1.24
1.12
±
0.97
B
0.88
±
0.93
1.16
±
1.03
patient
complained
about
displeasing
smell,
and
another
patient
complained
about
dehydration
effect.
The
correlation
between
the
observed
AEs
(burning
sensation,
displeasing
smell,
and
dehydration
effect)
was
judged
as
probable.
4.
Conclusions
The
current
studies
investigated
the
efficacy
and
safety
of
ectoine
containing
nasal
spray
and
eye
drops in
comparison
with
commonly
applied
pharmacological
treatments
of
aller-
gic
rhinitis.
In
two
noninterventional
trials,
ectoine
products
were
compared
with
either
azelastine
or
cromoglycic
acid
containing
products.
Although
this
paper
covers
results
of
two
separate
studies,
they
were
summarized
in
one
document
as
the
indication
was
very
similar
and
both
studies
aimed
to
compare
ectoine
containing
products
with
other
topical
medications.
As
the
study
with
cromoglycic
acid
was
one
of
the
first
studies
with
ectoine
products,
dosage
was
slightly
higher
than
in
the
study
comparing
ectoine
and
azelastine
products.
As
a
placebo-controlled,
randomized
trial
with
ectoine
nasal
spray
and
eye
drops
which
was
conducted
after
the
study
2
had
confirmed
that
the
dose
of
4
uses
per
day
was
sufficient
to
show
significant
superiority
over
placebo
treatment,
this
dosage
was
chosen
in
study
1
[14].
Both
studies
demonstrated
that
allergic
rhinitis
can
be
successfully
and
safely
treated
with
ectoine
containing
products,
thus
offering
a
potential
new
treatment
strategy
for
allergic
rhinitis
sufferers.
Both
studies
were
intentionally
designed
as
noninterven-
tional
studies
based
on
German
law.
Although
this
study
design
forbids
randomization
of
patients,
use
of
placebo,
and
blinding
of
study
medication,
it
still
reflects
the
most
real-
istic
standard
clinical
practice.
Thus,
patients
were
included
independently
on
their
prior
medication
and
no
washout
period
had
to
be
kept.
In
order
to
ensure
homogeneity
of
patients,
all
had
to
show
a
certain
degree
of
symp-
toms
at
inclusion
reflected
by
a
minimum
of
TNSS
values.
Additionally,
symptom
scores
were
correlated
with
pollen
count
scores
in order
to
include
objective
measures
into
the
analysis.
Importantly,
sites
specialized
in
the
area
of
ear
nose
throat
practice
were
chosen
to
warrant
a
very
precise
assessment
of
symptoms
by
specialized
physicians
and
to
have
a
homogeneous
patient
population.
Although
we
believe
that
valuable
results
can
be
drawn
from
noninterventional
trials,
one
drawback
of
this
study
design
is
the
fact
that
one
cannot
include
a
placebo
group
into
the
study
population.
On
the
other
hand,
it
has
been
demonstrated
that
double-
blind
randomized
placebo-controlled
trials
clearly
have
their
limitations
and
disadvantages
and
that
particularly
patients'
awareness
of
a
placebo
arm
can
lead
to
modifications
of
results
due
to
patients'
expectations
and
interpretations
[15].
This
was
confirmed
by
a
comparison
of
open
and
controlled
study
designs
in
neuroleptic
studies,
indicating
that
results
of
well
performed
open
studies
earn
more
attention
[16].
In
study
1,
it
was
shown
that
both
the
ectoine
and
the
aze-
lastine
products
resulted
in
a
clear
decrease
of
symptoms
of
allergic
rhinitis
over
the
study
period
of
7
days.
According
to
the
physicians'
evaluation,
the
symptoms
nasal
obstruction,
rhinorrhea,
sneezing,
nose
itching,
conjunctivitis
(azelastine
group
only),
eye
itching,
and
tearing
were
significantly
reduced.
The
mean
decrease
of
TNSS
was
-58.85%
in
the
ectoine
group
and
-57.11%
in
the
azelastine
group,
thus
demonstrating
a
strong
clinical
relevance.
Similarly,
mean
decreases
in
TOSS
were
-45.96%
in
the
ectoine
group
and
-44.98%
in
the
azelastine
group
and
therewith
reflect
strong
clinical
relevance,
too.
Study
2
also
demonstrated
a
significant
decrease
of
symp-
tom
scores
upon
treatment:
within
the
first
week
of
the
study,
TNSS
values
decreased
by
-50.96%
(group
A)
and
by
-45.21%
(group
B),
and
decreases
within
the
entire
study
period
of
2
weeks
were
-62.74%
(group
A)
and
-49.14%
(group
B)
according
to
the
physician's
assessment.
Nasal
obstruction
is
often
caused
by
an
enlargement
of
the
nasal
turbinates
which
are
located
on
the
lateral
walls
on
each
side
of
the
nose.
Journal
of
Allergy
11
Thus,
the
significant
improvement
of
turbinate
hyperplasia
as
assessed
by
the
physician
underlined
the
efficacy
of
both
treatments
in
reducing
nasal
obstruction.
In
comparison
to
the
physicians'
assessment
of
symp-
toms,
generally
less
strong
symptom
decreases
were
observed
by
patients.
This
might
be
most
likely
due
to
the
fact
that
starting
symptom
values
as
assessed
by
patients
themselves
were
lower
than
the
physicians'
values.
This
in
turn
is
at
least
partly
accredited
to
the
fact
that
patients'
first
assessments
of
symptoms
were
documented
at
the
end
of
the
first
treatment
days
whereas
physicians
documented
baseline
symptoms
during
the
first
site
visit
prior
to
the
start
of
treatment.
A
recent
placebo-controlled
study
in
an
environmental
challenge
chamber
showed
that
3
hours
after
application
of
the
ectoine
nasal
spray
and
eye
drops
the
symptoms
were
decreased
by
—20%.
This
decrease
reflects
roughly
the
difference
between
the
first
assessment
by
the
physicians
and
the
first
patient
diary
entry
[14].
In
addition,
physicians
are
able
to
carry
out
ranking
of
symptoms
based
on
their
experience
with
many
patients;
thus,
their
judgment
might
be
considered
more
objectively.
On
the
other
hand,
symptoms
such
as
itching
of
eyes,
nose,
and
palate
cannot
be
measured
with
a
scientifically
valid
method
and
are
thus
prone
to
personal
perception
and
difficult
to
be
assessed
by
physicians
together
with
patients.
Taken
together,
an
overestimation
by
the
physician
or
an
underestimation
by
the
patients
is
not
likely.
In
study
1,
the
patients'
assessment
showed
that
for
the
azelastine
group,
decreases
were
significant
for
the
symptoms
nasal
obstruction,
sneezing,
and
nasal
itching.
For
the
ectoine
group,
values
decreased
significantly
in
the
symptom
nasal
obstruction,
whereas
a
clear
but not
significant
decrease
in
the
symptoms
nasal
itching,
sneezing,
and
rhinorrhea
was
observed.
In
total,
decreases
of
TNSS
were
—24.68%
in
the
ectoine
group
and
—35.26%
in
the
azelastine
group,
thus
confirming
a
clinical
relevance
of
the
treatment.
Clear
decreases
in
the
ocular
symptoms
tearing
and
eye
itching
were
assessed
by
patients
of
both
groups;
however,
values
did
not
reach
significance.
The
symptom
conjunctivitis
was
clearly
(but
not
significantly)
decreased
in
the
ectoine
group,
whereas
it
became
slightly
worse
in
the
azelastine
group.
In
total,
TOSS
as
assessed
by
patients
decreased
by
—19.57%
in
the
ectoine
group
and
by
—11.81%
in
the
azelastine
group.
Although
no
ocular
treatment
was
applied
in
study
2,
ocular
symptoms
of
allergic
rhinitis
clearly
improved
upon
treatment
with
ectoine
or
cromoglycic
acid
nasal
spray.
According
to
the
physicians'
assessment,
TOSS
values
decreased
by
—59.09%
in
group
A
and
by
—39.32%
in
group
B
after
1
week
of
treatment
and
by
—73.74%
in
group
A
and
by
—45.47%
in
group
B
after
2
weeks
of
treatment.
It
is
not
surprising
that
local
and
nonpharmaceutical
nasal
treatment
might
also
influence
ocular
symptoms
as
recent
studies
suggest
a crosstalk
between
the
nose
and
eyes.
The
mechanism
of
the
influence
of
symptoms
via
the
nasolacrimal
duct
is
not
fully
understood
but
thought
to
be
via
a
mucosal
connection,
possibly
via
a
nose-eye
reflex.
The
patients'
assessment
of
ocular
symptom
development
in
study
2
confirmed
a
significant
decrease
in
the
symptom
eye
itching
after
two
weeks'
treatment
in
both
groups.
A
significant
reduction
of
the
symptom
eye
redness
was
observed
in
group
A
but
not
in
group
B.
However,
as
ocular
symptom
scores
were
generally
rather
small
in
this
study
and
treatment
aimed
mainly
to
reduce
nasal
symptoms,
further
studies
will
be
needed
to
evaluate
the
efficacy
of
treatments
on
ocular
symptoms.
Interestingly,
another
published
study
with
azelastine
eye
drops,
cromoglycate
eye
drops,
or
placebo
eye
drops
showed
superiority
of
both
active
treatments
versus
placebo
without
significant
differences
between
the
two
active
treatments
[17],
and
a
future
study
comparing
treatment
with
ectoine
eye
drops
only
with
other
pharmaco-
logical
eye
drop
formulations
would
be
desirable.
The
current
studies
both
showed
that
ectoine
nasal
spray
and
eye
drops
can
safely
be
applied
in
patients
with
allergic
rhinitis.
Patients
judged
the
tolerability
of
the
products
as
similarly
good
as
the
azelastine
products
and
significantly
better
than
cromoglycic
acid
nasal
spray,
and
the
very
low
numbers
of
AEs
reflected
a
very
good
safety
profile
of
the
used
treatments.
The
crossover
design
of
study
2
bears
difficulties
as
no
washout
period
between
the
crossover
was
carried
out.
However,
as
symptoms
were
assessed
on
a
daily
basis,
effects
following
one
treatment
only
(after
one
week)
can
be
analyzed
separately
from
the
results
following
two
treatments.
As
clear
improvements
of
symptoms
were
already
observed
after
one
week
of
treatment,
this
time
span
seems
sufficient
to
evaluate
effects
of
either
treatment
A
or
B.
As
the
efficacy
and
safety
of
azelastine
has
been
studied
in
a
huge
range
of
clinical
trials
during
the
last
decades,
one
can
use
historical
data
to
bring
the
results
of
the
current
study
into
a
broader
context
(for
results
from
comparator
studies
see
Table
11).
In
addition,
results
from
placebo
groups
of
comparator
studies
can
be
used
in
order
to
rank
the
current
results.
Thus,
comparable
data
confirmed
a
superiority
of
azelastine
versus
placebo
treatment,
and
values
indicate
that
effects
of
azelastine
are
usually
about
2-3-fold
higher
than
placebo.
However,
comparing
the
actual
values
of
the
current
study
with
other
studies
is
rather
difficult
as
design
(e.g.,
ran-
domized
versus
nonrandomized,
placebo-controlled
versus
not
placebo-controlled,
differences
in
length
of
treatment,
and
differences
in
scaling
of
symptoms)
and
dose
(azelastine
concentration
and
number
of
daily
applications)
of
available
studies
differs
enormously.
In
addition,
most
studies
used
nasal
spray
only
and
assessed
solely
nasal
symptoms,
whereas
the
current
study
is
one
of
few
studies
acknowledging
also
ocular
symptoms
of
allergic
rhinitis.
Taken
together,
results
of
the
current
study
1
showed
that
effects
of
ectoine
containing
products
are
almost
comparable
with
those
of
azelastine,
a
well-studied
drug,
which
has
a
proven
superiority
to
placebo
treatment
and
is
commonly
prescribed
against
allergic
rhini-
tis.
Cromoglycic
acid
has
been
a
common
drug
in
treating
allergic
rhinitis,
and
although
it
is
thought
not
to
be
as
effective
as
intranasal
steroids
or
antihistamines,
it
has
been
shown
to
reduce
both
nasal
and
ocular
symptoms
and
it
is
therefore
a
reasonable
therapy
option.
In
particular,
its
good
safety
profile
makes
it
an
interesting
treatment
option
both
for
children
and
pregnant
women.
As
no
published
studies
were
identical
with
the
current
study
design
(study
12
Journal
of
Allergy
TABLE
11:
Comparison
of
the
current
study
1
with
other
azelastine
studies.
Study
Treatment
%
improvement
from
baseline
to
end
of
treatment
TNSS
TOSS
Current
study
1
1
Ectoine
58.85
45.96
Azelastine
57.11
44.98
Current
study
1
2
Ectoine
24.68
19.57
Azelastine
35.26
11.81
Lumry
et
al.
2007
Azelastine
14.1
n.d.
(study
1)
3
[18]
Placebo
4.5
n.d.
Lumry
et
al.
2007
Azelastine
22.1
n.d.
(study
2
)
3
[18]
Placebo
12.0
n.d.
Azelastine
0.1%
24.4
n.d.
Shah
et
al.
4
[19]
Azelastine
0.15%
29.7
n.d.
Placebo
12.0
n.d.
Howland
et
al
.
3
[20]
Azelastine
0.15%
19.3
16.7
Placebo
11.4
6.0
Van
Bavel
et
al.
6
[21]
Azelastine
0.15%
18.7
n.d.
Placebo
10.5
n.d.
Falser
et
al.
2
[22]
Azelastine
83.56*
n.d.
Levocabastine
70.42*
n.d.
Charpin
et
al.
8
[23]
Azelastine
60.2
65.0
Cetirizine
(tablet)
63.3
60.8
1
Physicians
assessment;
2
patients'
assessment;
3
one
spray
of
0.1%
azelastine
nasal
spray
per
nostril
twice
daily
for
14
days;
4
two
sprays
of
0.1%
or
0.15%
azelastine
nasal
spray
per
nostril
twice
daily
for
14
days;
3
two
sprays
of
0.15%
azelastine
nasal
spray
per
nostril
once
daily
for
14
days;
6
tWO
sprays
of
0.15%
azelastine
nasal
spray
per
nostril
once
daily
for
2
weeks;
7
azelastine
1.12
mg/day
and
levocabastine
0.4
mg/day
nasal
spray
administered
twice
daily
for
4
weeks,
*TNSS:
sneezing,
nasal
itching,
and
rhinorrhoea;
B
one
spray
of
0.1%
azelastine
nasal
spray
per
nostril
twice
daily
for
14
days.
n.d.:
not
determined.
2)
in
terms
of
treatment
duration
and
analysis
of
end
points,
only
general
comparisons
to
cromoglycic
acid
studies
can
be
drawn.
Several
studies
have
confirmed
that
cromoglycic
acid
is
superior
to
placebo
in
patients
with
allergic
rhinitis
[24].
Thus,
Schuller
and
colleagues
[25]
investigated
the
efficacy
of
Cromolyn
sodium
in
comparison
to
nedocromil
sodium
and
placebo.
Over
a
treatment
period
of
8
weeks,
it
was
demonstrated
that
Cromolyn
resulted
in
a
dear
improvement
of
nasal
symptoms,
particularly
in
the
symptom
"stuffy
nose'
A
further
placebo-controlled
study
confirmed
that
cromoglycate
acid
nasal
spray
provided
significant
relief
of
nasal
symptoms
within
2
weeks
of
treatments
which
were
significant
for
the
symptoms
sneezing
and
nasal
congestion
and
clearly
visible
but
not
significant
for
the
symptoms
rhinorrhea
and
nasal
pruritus
[26].
Taken
together,
ectoine
containing
nasal
spray
and
eye
drops
have
been
demonstrated
to
be
promising
alternatives
to
pharmacological
drugs
with
both
good
efficacy
and
a
very
good
safety
profile.
As
the
ectoine
nasal
spray
and
eye
drops
act
purely
physically
on
the
nasal
and
ocular
mucosa,
it
makes
those
products
particularly
interesting
for
patients
with
reservations
about
pharmacological
therapy.
An
addi-
tional
study
in
children
and
adolescents
with
seasonal
allergic
rhinitis
(data
not
yet
published)
has
confirmed
the
safety
of
ectoine
containing
nasal
spray
and
eye
drops
in
the
pediatric
population.
Further
studies
should
be
undertaken
to
further
investigate
the
onset
of
action
and
compare
it
to
commonly
applied
pharmacological
drugs.
Quick
relief
of
symptoms
is
crucial
for
patients
and
understood
to
be
advantageous
when
comparing,
for
example,
azelastine
with
intranasal
corticosteroids
[27]
and
should
therefore
be
assessed
for
the
ectoine
products.
A
controlled,
ramdomised
study
which
was
carried
out
using
a
controlled
environmental
exposure
chamber
showed
a
quick
onset
of
action
of
ectoine
nasal
spray
and
eye
drops
and
confirmed
the
efficacy
in
reducing
both
nasal
and
ocular
symptoms
[14].
Additional
studies
applying
the
ectoine
eye
drops
only
are
needed
to
further
elucidate
their
impact
on
ocular
symptoms
during
allergic
rhinitis.
Conflict
of
Interests
Dr.
Nina
Werkhauser
and
Dr.
Andreas
Bilstein
are
employees
of
bitop
AG,
a
company
where
medical
devices,
including
the
ectoine
nasal
spray
and
eye
drops,
are
developed
and
registered.
bitop
AG
sponsored
the
trials
discussed
in
this
paper.
Dr.
Uwe
Sonnemann
received
sponsorship
by
bitop
AG
to
conduct
the
studies.
Acknowledgment
The
authors
thank
Dr.
T.
Kottmann
for
statistical
analysis
of
data.
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