Randomized, comparative, double-blind, double-dummy, multicenter trial of miconazole buccal tablet and clotrimazole troches for the treatment of oropharyngeal candidiasis: study of miconazole Lauriad® efficacy and safety (SMiLES)


Vazquez, Jé.A.; Patton, L.L.; Epstein, J.B.; Ramlachan, P.; Mitha, I.; Noveljic, Z.; Fourie, J.; Conway, B.; Lalla, R.V.; Barasch, A.; Attali, P.; Conway, B.; Kilby, D.; LaLonde, R.; Tsoukas, C.; Noveljic, Z.; Ramlachan, P.; Mitha, I.; Fourie, J.; Malan, D.; Kelfkens, Y.; Engelbrecht, J.; Andrews, S.; Van Vuuren, J.; Petit, D.; Vazquez, J.; Lalla, R.; Barasch, A.; L.M.rca, A.; Meiller, T.; Osiyemi, O.; Kutcher, M.; Nichols, C.M.; Sroussi, H.; Muzyka, B.; Beal, J.; Borkert, C.; Patel, S.; Ernst,

HIV Clinical Trials 11(4): 186-196

2010


Oropharyngeal candidiasis (OPC) is the most common opportunistic infection among persons infected with human immunodeficiency virus (HIV). Once-daily miconazole 50 mg buccal tablet (MBT) is a novel delivery system using an extended-spectrum azole with potent in vitro activity against many Candida species, including some that may be resistant to other azoles. This phase 3, double-blind, double-dummy, multicenter trial evaluated 578 randomized patients with HIV infection and OPC. The study compared the efficacy and safety of MBT once daily with clotrimazole 10 mg troches (CT) 5 times daily for 14 days. The co-primary efficacy endpoints were clinical cure at test of cure (TOC) visit (days 17-22) in the intent-to-treat (ITT) and per protocol (PP) populations. Clinical cure rate at TOC visit for MBT-treated patients was statistically noninferior to CT-treated patients in both the ITT (61% vs 65%) and PP (68% vs 74%) populations. Secondary endpoints, safety, and tolerability were similar between treatment groups. In this large trial, once-daily MBT was shown to be noninferior to CT 5 times daily in the treatment of OPC in HIV-positive patients. MBT offers an effective, safe, and well-tolerated topical treatment option for OPC administered as a convenient once-daily dose.

Randomized,
Comparative,
Double-Blind,
Double-Dummy,
Multicenter
Trial
of
Miconazole
Buccal
Tablet
and
Clotrimazole
Troches
for
the
Treatment
of
Oropharyngeal
Candidiasis:
Study
of
Miconazole
Lauriad®
Efficacy
and
Safety
(SMiLES)
Jose
A.
Vazquez,
1,2
Lauren
L.
Patton,
3
Joel
B.
Epstein,
4
Padaruth
Ramlachan,
5
Ismail
Mitha,
6
Zoja
Noveljic,
7
Jan
Fourie,
8
Brian
Conway,
9
Rajesh
V.
Lalla,
1
°
Andrei
Barasch,
11
and
Pierre
Attali
12,13
'Division
of
Infectious
Diseases,
Henry
Ford
Hospital,
Detroit,
Michigan,
USA;
2
Wayne
State
University,
Detroit,
Michigan,
USA;
°University
of
North
Carolina,
Chapel
Hill,
North
Carolina,
USA;
4
University
of
Illinois-Chicago,
Chicago,
Illinois,
USA;
5
NewKwa
Medical
Center,
Durban,
South
Africa;
°Benmed
Park
Clinic,
Benoni,
South
Africa;
'Karl
Bremer
Hospital,
Cape
Town,
South
Africa;
°Medical
practice,
Dundee,
South
Africa;
°University
of
British
Columbia,
Vancouver,
Canada;
'°University
of
Connecticut
Health
Center,
Farmington,
Connecticut,
USA;
"University
of
Alabama-Birmingham,
Birmingham,
Alabama,
USA;
'
2
BioAlliance
Pharma,
Paris,
France;
'
3
1-lopital
de
Bicetre,
Kremlin-Bicetre,
France
Background:
Oropharyngeal
candidiasis
(OPC)
is
the
most
common
opportunistic
infection
among
persons
infected
with
human
immunodeficiency
virus
(HIV).
Once-daily
miconazole
50
mg
buccal
tablet
(MBT)
is
a
novel
delivery
system
using
an
extended-
spectrum
azole
with
potent
in
vitro
activity
against
many
Candida
species,
including
some
that
may
be
resistant
to
other
azoles.
Methods:
This
phase
3,
double-blind,
double-dummy,
multicenter
trial
evaluated
578
randomized
patients
with
HIV
infection
and
OPC.
The
study
compared
the
efficacy
and
safety
of
MBT
once
daily
with
clotri-
mazole
10
mg
troches
(CT)
5
times
daily
for
14
days.
The
co-primary
efficacy
endpoints
were
clinical
cure
at
test
of
cure
(roc)
visit
(days
17-22)
in
the
intent-to-treat
(ITT)
and
per
protocol
(PP)
populations.
Results:
Clinical
cure
rate
at
TOC
visit
for
MBT-treated
patients
was
statistically
noninferior
to
CT-treated
patients
in
both
the
ITT
(61%
vs
65%)
and
PP
(68%
vs
74%)
populations.
Secondary
endpoints,
safety,
and
tolerability
were
similar
between
treatment
groups.
Conclusions:
In
this
large
trial,
once-daily
MBT
was
shown
to
be
noninferior
to
CT
5
times
daily
in
the
treatment
of
OPC
in
HIV-
positive
patients.
MBT
offers
an
effective,
safe,
and
well-tolerated
topical
treatment
option
for
OPC
administered
as
a
convenient
once-daily
dose.
Key
words:
antifungal
agents,
clotrimazole,
HIV-related
opportunistic
infections,
miconazole,
oral
candidiasis
M
iconazole
is
a
synthetic
imidazole
anti-
fungal
agent
that
has
been
used
since
the
early
1970s
to
effectively
and
safely
treat
fungal
infections.
1
Miconazole
has
a
broad
spectrum
of
activity
against
Candida
albicans
and
non-albicans
species
1-3
and
is
the
only
fungicidal
azole,
a
property
likely
enhanced
by
its
induction
of
reactive
oxygen
species
.
4
Oropharyngeal
candidiasis
(OPC)
is
an
oral
infection
caused
by
the
yeast
Candida.
Although
Candida
is
a
commensal
fungus
of
the
normal
mouth
flora
in
approximately
45%
5
of
healthy
individuals,
under
certain
circumstances
it
can
overgrow,
leading
to
symptomatic
infection.
Immunocompromised
patients,
including
those
individuals
infected
with
human
immunodefi-
ciency
virus
(HIV),
are
highly
susceptible
to
the
186
development
of
OPC.
67
Antiretroviral
agents
have
been
shown
to
decrease
both
the
prevalence
of
OPC
and
the
number
of
OPC
relapses
over
the
course
of
a
year,”
yet
candidiasis
remains
one
of
the
most
common
opportunistic
infections
in
HIV-positive
patients,
with
a
yearly
incidence
of
approximately
20%.
10
Address
for
correspondence:
Jose
A.
Vazquez,
MD,
FACP,
FIDSA,
Henry
Ford
Hospital,
Division
of
Infectious
Diseases,
2799
West
Grand
Boulevard,
CFP-202,
Detroit,
MI
48201
USA.
E-mail:
HIV
Clin
Trials
2010;11(4):186-196
2010
Thomas
Land
Publishers,
Inc.
www.thomasland.com
doi:
10.1310/hct1104-186
MICONAZOLE
BUCCAL
TABLET
FOR
OPC
IN
HIV
VAZQUEZ
ET
AL
187
Clotrimazole
troches
(CT)
and
nystatin
suspen-
sion
or
pastilles
are
topical
antifungal agents,
both
of
which
are
recommended
as
a
first-line
treatment
of
mild
OPC
by
the
Infectious
Diseases
Society
of
America
(IDSA)
candidiasis
clinical
practice
guide-
lines."
In
addition,
the
Centers
for
Disease
Control
and
Prevention
(CDC)
also
recommend
that
initial
episodes
of
OPC
be
managed
by
these
topical
agents
in
HIV-positive
adults.
12
Due
to
low
systemic
drug
concentrations,
topical
antifungal
therapies
result
in
fewer
adverse
events
and
a
low
potential
for
drug-
drug
interactions,
13
making
these
modalities
gener-
ally
preferred
over
antifungal
agents
with
systemic
effects.
14
There
is
currently
an
unmet
need
for
local,
once-daily,
noncariogenic
formulations
of
proven
antifungal
agents
to
treat
OPC,
and
the
miconazole
buccal
tablet
was
designed
to
address
this
need.
Miconazole
has
proven
clinical
efficacy
against
the
organisms
causing
OPC.
The
proprietary
buc-
cal
tablet
used
in
this
study
delivers
miconazole
at
the
local
site
of
infection
with
once-daily
dosing.
This
topical
formulation
adheres
to
the
canine
fossa
of
the
upper
gum;
within
1
hour
after
application,
it
produces
miconazole
levels
in
the
saliva
above
the
minimum
inhibitory
concentration
(>1
pg/mL)
for
most
Candida
species
and
is
able
to
maintain
these
levels
for
more
than
7
hours.
15
The
objective
of
this
study
was
to
evaluate
the
efficacy
and
safety
of
miconazole
50
mg
buccal
tab-
let
(MBT)
once
daily
compared
to
CT
given
5
times
per
day
for
the
treatment
of
OPC
in
HIV-positive
patients.
METHODS
Study
Design
The
efficacy
and
safety
of
MBT
and
CT
for
the
treatment
of
OPC
in
HIV-positive
patients
were
eval-
uated
in
a
noninferiority,
randomized,
double-blind,
double-dummy,
parallel-group
trial.
The
study
was
conducted
at
30
centers
in
the
United
States,
Canada,
and
South
Africa
from
July
2006
to
December
2007.
Eligible
patients
were
randomized
by
block
allo-
cation
to
study
centers
to
either
once-daily
MBT
or
CT
5
times
per
day.
Placebo
buccal
tablets
and
pla-
cebo
troches
were
used
to
maintain
study
blinding.
Each
patient
had
5
scheduled
visits
after
baseline.
After
randomization
(day
1),
patients
received
14
days
of
treatment.
At
the
day
7
and
test
of
cure
(TOC;
days
17-22)
visits,
primary
and
secondary
efficacy
measures
were
assessed.
At
the
end-of-treatment
visit
(day
14),
safety
and
compliance
information
was
gathered.
Relapse
rates
in
patients
with
clinical
cures
at
TOC
visit
were
determined
on
days
35-38.
Patient
Population
Patients
were
eligible
to
be
included
in
the
study
if
they
met
the
following
criteria:
18
years
of
age,
confirmed
as
HIV
positive,
and
with
confirmed
evi-
dence
of
OPC.
For
patients
treated
with
antiretrovi-
ral
agents,
the
regimen
must
have
been
stable
for
2
months
in
the
case
of
treatment
initiation
or
1
month
in
the
case
of
treatment
modification.
Patients
were
maintained
on
their
antiretroviral
therapy
during
the
14-day
antifungal
treatment.
For
patients
not
on
antiretroviral
therapy,
treatment
was
not
to
be
initiated
during
the
course
of
antifungal
therapy.
Patients
were
in
good
general
state
of
health,
defined
by
a
score
<2
on
the
Eastern
Cooperative
Oncol-
ogy
Group
(ECOG)
scale.
All
patients
had
clinical
evidence
of
OPC, positive
potassium
hydroxide
smear,
and
a
positive
local
Candida
culture.
Isolates
were
sent
to
a
central
reference
laboratory
(Center
for
Medical
Mycology,
Case
Western
Reserve
Uni-
versity,
Cleveland,
Ohio,
USA)
for
all
mycological
analysis
and
susceptibility
testing.
Patients
were
not
eligible
for
enrollment
if
they
presented
with
signs
or
symptoms
of
systemic
can-
didiasis,
perioral
lesions
(angular
cheilitis)
only
or
esophageal
candidiasis
(documented
by
esophageal
endoscopy),
upper
full
or
partial
dentures
with
an
acrylic
border
in
the
canine
fossa;
if
they
used
topi-
cal
or
systemic
antifungal
agents
within
the
past
7
to
15
days,
respectively;
or
if
they
had
a
milk
allergy
or
known
hypersensitivity
to
any
of
the
product
components.
Patients
undergoing
antibiotic
treat-
ment
were
excluded,
except
prophylactic
antibiotics
in
the
management
and
care
of
HIV
and
antituber-
culosis
treatments.
Additional
exclusion
criteria
included
pregnancy
or
breast-feeding
status,
a
life
expectancy
of
<45
days,
or
presence
of
a
clinical
condition
making
study
completion
unlikely.
Treatment
Administration
The
MBT
or
placebo
buccal
tablet
was
applied
in
the
morning
to
the
canine
fossa
depression
of
the
upper
gum,
superolateral
to
the
canine
tooth,
after
the
first
dose
of
CT
or
placebo
troche.
The
MBT
or
placebo
buccal
tablet
was
alternated
daily
between
188
HIV
CLINICAL
TRIALS
11/4
JULY-AUGUST
2010
the
right
and
left
sides
and
was
to
remain
in
position
until
tablet
disintegration
was
complete.
If
the
MBT
or
placebo
buccal
tablet
did
not
adhere
for
a
mini-
mum
of
6
hours,
it
was
replaced
with
a
new
tablet.
To
facilitate
adhesion
of
the
MBT
or
placebo
buccal
tablet
to
the
gum,
slight
pressure
was
applied
over
the
upper
lip
for
30
seconds.
After
application,
patients
were
permitted
to
eat,
drink,
and
chew
any
time
during
the
study.
The
CT
or
placebo
troche
was
administered
as
a
lozenge
to
be
slowly
dissolved
in
the
mouth
5
times
a
day.
Efficacy
Measures
Table
1
defines
efficacy
outcomes
and
populations
for
this
study.
The
co-primary
efficacy
measures
were
clinical
cure,
defined
as
complete
resolution
of
lesions
(signs)
and
symptoms
of
OPC
at
the
TOC
visit,
in
both
the
intent-to-treat
(111)
and
per
proto-
col
(PP)
study
populations.
The
Murray
scale
was
used
to
rate
extent
of
lesions
(0
=
none
to
3
=
exten-
sive)
and
symptoms
(0
=
absent
to
3
=
severe).
16
Secondary
efficacy
measures
included
clinical
cure
at
day
7,
clinical
success
at
day
7
and
at
the
TOC
visit,
along
with
the
mycological
cure
rate
at
the
TOC
visit,
evidence
of
relapse
by
day
35,
and
time
to
relapse.
Safety
and
Tolerability
Treatment
compliance
was
calculated
from
the
number
of
scheduled
doses
per
patient
and
Table
1.
Study
definitions
the
number
of
MBTs
or
troches
returned
at
the
end
of
treatment
visit.
MBT
or
placebo
buccal
tablet
adhesion
time
was
recorded
on
a
daily
patient
questionnaire.
Plasma
miconazole
levels
were
determined
in
40
randomly
selected
patients
after
7
days
of
therapy.
Clinical
and
biological
safety
assessments
were
conducted
at
baseline
and
at
each
visit
throughout
the
trial.
Vital
signs
measured
were
temperature,
pulse,
and
blood
pressure.
Laboratory
variables
included
hematol-
ogy
and
biochemistry
measurements,
CD4+
cell
count,
viral
load,
and
pregnancy
testing
and
were
sent
to
a
local
or
central
laboratory
for
assay.
Local
inflammation
(gingival
index
17
)
and
oral
comfort
(gum
pain
when
brushing
teeth,
taste
of
food,
taste
when
not
eating,
dry
mouth)
were
evaluated
using
a
0
to
3
(none
to
severe)
scale.
In
addition,
patients
were
asked
to
evaluate
daily
oral
discomfort
and
burning
sensation
at
application
site
using
a
10
cm
visual
analog
scale
(VAS).
Statistical
Analyses
To
demonstrate
noninferiority
between
MBT
and
CT
for
the
co-primary
endpoints,
sample
size
was
based
on
a
meta-analysis
15
of
the
clotrimazole
literature,
16,19-22
which
yielded
an
expected
clinical
cure
rate
of
70%
in
the
CT
treatment
group.
The
placebo
clinical
cure
rate
has
been
documented
at
20%.
23-25
Based
on
the
expected
cure
rate
and
pla-
cebo
response,
the
noninferiority
margin
was
set
at
15%,
requiring
a
sample
size
of
243
patients
for
Definition
Complete
resolution
of
OPC
signs
(lesions)
and
symptoms
(soreness/burning)
(Murray
scores
of
0)
Clinical
cure
or
improvement
(Murray
lesion
score
of
0
and
symptoms
score
<2;
no
visible
lesion
and
minimal
symptoms)
Negative
fungal
culture
(no
colonies)
Difference
between
the
time
that
the
tablet
was
applied
and
the
time
that
it
disappeared
from
the
gum
(ie,
dissolved,
accidently
swallowed
or
expectorated)
Percent
of
patients
who
experienced
clinical
cure
at
days
17-22
(TOC
visit)
and
had
reoccurrence
of
OPC
by
day
35
Difference
in
days
between
the
TOC
visit
date
and
the
date
of
clinical
relapse
All
randomized
patients
who
received
at
least
one
dose
of
study
drug
All
ITT
patients
who
did
not
have
a
major
protocol
deviation,
completed
at
least
10
days
of
study
treatment,
and
were
compliant
with
the
study.
Parameter
Clinical
cure
Clinical
success
Mycological
cure
MBT
adhesion
Relapse
rate
Time
to
relapse
Population
Intent-to-treat
Per
protocol
Note:
ITT
=
intent-to-treat;
OPC
=
oropharyngeal
candidiasis;
TOC
=
test
of
cure.
MICONAZOLE
BUCCAL
TABLET
FOR
OPC
IN
HIV
VAZQUEZ
ET
AL
189
each
treatment
arm
to
demonstrate
noninferiority
with
95%
power.
Patient
demographics,
baseline
characteristics,
and
safety
analyses
were
based
on
the
ITT/safety
population.
Efficacy
analyses
were
performed
in
both
the
ITT
and
the
PP
populations.
For
the
primary
efficacy
measure,
the
null
hypothesis
of
noninferiority
of
MBT
to
CT
was
accepted
if
the
treatment
difference
fell
within
the
95%
confidence
interval
(CI).
For
secondary
measures,
a
95%
2-sided
CI
of
the
treatment
difference
between
both
groups
was
calculated
with
significance
if
P
<
.05.
The
improvement
of
signs
and
symptoms
from
baseline
to
the
TOC
visit
was
compared
between
the
2
treatment
groups
by
a
Cochran-Mantel-
Haenszel
test.
Negative
Candida
cultures
were
compared
between
the
treatment
groups
by
chi-
square
test
or
Fisher
exact
test
if
the
conditions
of
the
chi-square
test
were
not
satisfied.
Ethical
Aspects
The
clinical
study
protocol
was
approved
by
each
site's
institutional
review
board
and/or
ethics
com-
mittee.
The
study
was
conducted
in
accordance
with
good
clinical
practice,
the
International
Conference
on
Harmonization
guidelines,
and
the
Helsinki
Declaration
revision
of
2004.
Study
participants
pro-
vided
written
informed
consent.
The
ClinicalTrials.
gov
identifier
for
this
trial
is
NCT00390780.
RESULTS
Patient
Population
Of
the
578
patients
who
were
randomized
(Figure
1),
101
patients
(MBT
50,
CT
51)
had
at
least
1
major
protocol
violation
and
therefore
were
not
included
in
the
PP
population.
Baseline
Enrolled
(N
=
697)
USA
Canada
RSA
n
=
155
n
=
13
n
=
529
Randomized
(N
=
578)
USA
Canada
RSA
n
=
129
n
=
7
n
=
442
MBT
once
daily
(n
=
290)
a
ITT/Safety
Population
CT
5
times
daily
(n
=
287)
Reasons
for
withdrawal:
Reasons
for
withdrawal:
Non-compliance
7
(2.4%)
Screening
failure
1
(0.3%)
Consent
withdrawn
1
(0.3%)
Inclusion
criteria
not
satisfied
.
2
(0.7%)
Adverse
events
1
(0.3%)
Non-compliance
4
(1.4%)
Investigator
decision
Lost
to
follow
up
3
(1.0%)
3
(1.0%)
Consent
withdrawn
Investigator
decision
Lost
to
follow
up
2
(0.7%)
1
(0.3%)
7
(2.4%)
Serious
adverse
event
1
(0.3%)
Serious
adverse
event
7
(2.4%)
Death'
1
(0.3%)
Death
b
5
(1.7%)
Other
reasons
10
(3.4%)
Other
reasons
6
(2.1%)
1
Majo
Protocol
Deviation
(n
=
50)
b
C
;1
Majo
Protocol
Deviation
(n
=
51)
b
MBT
once
daily
(n
=
240)
PP
Population
CT
5
times
daily
(n
=
236)
Figure
1.
Patient
randomization
and
disposition.
CT
=
clotrimazole
10
mg
troche;
ITT
=
intent-to-treat;
MBT
=
miconazole
50
mg
buccal
tablet;
PP
=
per
protocol;
RSA
=
Republic
of
South
Africa.
aOne
randomized
patient
reported
losing
all
study
medication
prior
to
the
initiation
of
treatment
and
withdrew
from
study.
The
patient
is
included
in
the
withdrawal
group
but
not
the
ITT/Safety
population.
bOnly
those
deaths
that
resulted
directly
in
withdrawal
from
the
study.
°The
most
common
protocol
deviations
were
patient
noncompliance,
TOC
visit
outside
the
acceptable
window
(days
17
to
22),
missing
efficacy
data
at
TOC
visit,
less
than
10
days
of
treatment,
and
not
having
stable
antiretroviral
therapy
for
2
months
prior
to
enrollment.
190
HIV
CLINICAL
TRIALS
11/4
JULY-AUGUST
2010
demographics
and
characteristics
in
the
ITT
pop-
ulation
were
comparable
between
both
treatment
groups
(Table
2).
No
statistically
significant
dif-
ferences
were
observed
between
treatment
groups
for
CD4+
cell
count,
history
of
antiretroviral
therapy,
and
extent
of
oral
lesions
at
baseline.
At
baseline,
the
majority
of
patients
exhibited
multi-
ple
lesions
and
mild
to
moderate
OPC
symptoms
(Figure
2).
Mycological
findings
were
not
significantly
dif-
ferent
between
treatment
groups.
The
most
com-
mon
fungal
species
in
baseline
isolates
was
C.
albicans,
which
was
present
in
89%
of
patients
in
each
group,
based
upon
the
ITT
population
for
whom
species
data
were
available
(MBT,
n
=
283;
CT,
n
=
281).
The
only
other
species
present
in
Table
2.
Baseline
patient
characteristics
MBT
(n
=
290)
CT
(n
=
287)
Demographics
Age,
years
Mean
(SD)
37.5
(9.7)
36.5
(9.1)
Range
18-73
18-72
Female,
n
(%)
173
(60)
168
(59)
Concomitant
treatmenta
n
(%)
Yes
236
(81)
238
(83)
No
54
(19)
49
(17)
Extent
of
lesions
at
baseline,
n
(%)
Single,
localized
37
(13)
36
(13)
Multiple,
localized
157
(54)
170
(59)
Confluent
or
extensive
96
(33)
81
(28)
HIV
characteristics
Viral
load,
copies/mL
Mean
(SD)
119,325
116,130
(186,626)
(196,528)
CD4+
cell
count,
cells/mm
3
Mean
(SD)b
254
(186)
Antiviral
therapy,
n
(%)°
Yes
65
(22)
No
225
(78)
Note:
CD4+
=
CD4-positive
lymphocyte;
CT
=
clotrimazole
10
mg
troche;
MBT
=
miconazole
50
mg
buccal
tablet;
SD
=
standard
deviation.
aConcomitant
treatments
were
mainly
used
to
treat
under-
lying
disease;
the
most
common
were
sulfamethoxazole
and
trimethoprim
(Bactrimv),
vitamin
B
complex,
and
medroxy-
progesterone
acetate.
bP
=
.08
between
treatment
groups.
aP
=
.07
between
treatment
groups.
>1%
of
patients
in
both
groups
were
C.
tropicalis
(8.1%
MBT
vs
5.0%
CT),
C.
parapsilosis
(2.1%
MBT
vs
3.2%
CT),
and
C.
dubliniensis
(1.1%
in
each
group).
Efficacy
Clinical
cure
at
TOC
(primary
endpoint)
Clinical
cure
rate
in
the
MBT
group
was
sta-
tistically
noninferior
to
the
CT
group
in
both
the
ITT
and
PP
populations
at
the
TOC
visit
(Table
100
90
80
70
7
60
50
-
a
40
30
20
-
10
0
None
Single
Multiple
Extensive
76
71
59
54
33
28
13
14
13
13
10
11
Baseline
TOG
Baseline
TOG
n
=
290
n
=
268
n
=
287
n
=
260
MBT
CT
100
-
None
Mild
90
Moderate
Severe
80
70
7
60
50
a.
40
Figure
2.
(A)
Comparison
of
extent
of
oropharyngeal
candidiasis
(OPC)
lesions
at
baseline
and
test
of
cure
(TOC)
visit
in
the
MBT
(miconazole
50
mg
buccal
tablet)
and
CT
(clotrimazole
10
mg
troche)
treatment
groups.
(B)
Comparison
of
severity
of
OPC
symptoms
at
baseline
and
TOC
visit
in
the
MBT
and
CT
treatment
groups.
30
224
(170)
20
83
(29)
10
204
(71)
0
58
27
13
L
Baseline
n
=
290
91
87
55
28
12
14
8
TOG
Baseline
TOG
n
=
268
n
=
287
n
=
260
MBT
CT
MICONAZOLE
BUCCAL
TABLET
FOR
OPC
IN
HIV
VAZQUEZ
ET
AL.
191
3).
In
the
ITT
population,
61%
of
patients
treated
with
MBT
experienced
clinical
cure
compared
to
65%
treated
with
CT.
This
corresponds
to
a
treat-
ment
difference
of
-0.045
(95%
CI,
-0.124
to
0.034).
Results
were
similar
in
the
PP
population,
with
a
clinical
cure
rate
of
68%
of
MBT-treated
patients
compared
to
74%
of
CT-treated
patients,
resulting
in
a
treatment
difference
of
-0.059
(95%
CI,
-0.140
to
0.022).
Seconder),
clinical
endpoints
There
were
no
significant
differences
between
treatment
groups
in
clinical
cure
rate
at
day
7,
or
in
clinical
success
rate
at
day
7
or
at
the
TOC
visit,
in
either
the
ITT
or
PP
populations
(Table
3).
Change
in
extent
of
lesions
and
symptoms
of
OPC
from
baseline
to
TOC
visit
are
shown
in
Figure
2.
Mycological
cure.
At
the
TOC
visit,
myco-
logical
cure
was
numerically
higher
in
the
MBT
group
compared
to
the
CT
group
in
both
patient
populations;
however,
this
difference
was
not
statistically
significant.
In
the
ITT
pop-
ulation,
a
total
of
79
(27%)
MBT
patients
and
71
(25%)
CT
patients
experienced
mycological
cure
(P
=
.58).
Similarly,
in
the
PP
population,
73
(30%)
MBT
and
64
(27%)
CT
patients
experi-
enced
mycological
cure
(P
=
.44).
Relapse.
Of
the
172
MBT
patients
in
the
ITT
population
who
experienced
clinical
cure
at
the
TOC
visit
and
had
relapse
data
available,
48
(27.9%)
experienced
a
relapse
by
day
35.
In
the
CT
group,
relapse
occurred
in
52
of
185
(28.1%)
patients
who
were
clinically
cured
at
the
TOC
visit
and
evalu-
able
for
relapse
(P
=
.96;
95%
CI,
-9.5
to
9.1).
In
the
PP
population,
these
numbers
were
43/160
(26.9%)
and
48/174
(27.6%)
for
the
MBT
and
CT
treatment
groups,
respectively
(P
=
.88;
95%
CI,
-10.3
to
8.8).
In
the
ITT
population,
the
mean
time
to
relapse
was
16.0
and
15.5
days
in
the
MBT
and
CT
groups,
respectively
(P
=
.7).
In
the
PP
population,
the
mean
time
to
relapse
was
16.2
days
for
MBT
and
15.9
days
for
the
CT
group
(P
=
.7).
Table
3.
Clinical
efficacy
of
MBT
compared
to
clotrimazole
troches
MBT
CT
P
value
Treatment
difference
95%
CI
Co-primary
efficacy
endpoints:
clinical
cure
at
TOC
visits
ITT
population
n
=
290
n
=
287
Clinical
cure,
n
(%)
176
(61)
187
(65)
NAb
-0.045
-0.124
to
0.034
PP
population
n
=
240
n
=
236
Clinical
cure,
n
(%)
164
(68)
175
(74)
NAb
-0.059
-0.140
to
0.022
Secondary
efficacy
endpoints
ITT
population
n
=
290
n
=
287
Clinical
cure°
at
day
7,
n
(%)
67
(23)
71
(25)
NAb
-0.016
-0.086
to
0.054
Clinical
successd
at
day
7,
n
(%)
92
(32)
89
(31)
0.90
-0.007
-0.069
to
0.083
Clinical
successd
at
TOC,
n
(%)
188
(65)
199
(69)
0.10
-4.5
-12.2
to
3.2
PP
population
n
=
240
n
=
236
Clinical
cure°
at
day
7,
n
(%)
60
(25)
63
(27)
NAb
-0.016
-0.086
to
0.054
Clinical
successd
at
day
7,
n
(%)
82
(34)
78
(33)
0.80
-0.011
-0.074
to
0.096
Clinical
successd
at
TOC,
n
(%)
173
(72)
185
(78)
0.11
-6.3
-14.0
to
1.4
Note:
CI
=
confidence
interval;
CT
=
clotrimazole
10
mg
troche;
ITT
=
intent-to-treat;
MBT
=
miconazole
50
mg
buccal
tablet;
NA
=
not
applicable;
PP
=
per
protocol;
TOC
=
test
of
cure
visit
(day
17-22).
aDefined
as
complete
resolution
of
signs
and
symptoms
of
OPC
in
ITT
and
PP
populations.
bNoninferiority
of
clinical
cure
confirmed
if
treatment
difference
within
the
95%
Cl.
aComplete
resolution
of
signs
and
symptoms
of
OPC.
dNo
visible
lesions
and
minimal
symptoms,
includes
those
with
clinical
cure.
192
HIV
CLINICAL
TRIALS
11/4
JULY-AUGUST
2010
Safety
and
Tolerability
Treatment
compliance
The
overall
compliance
in
the
study
population
was
high
and
comparable
between
the
treatment
groups;
253
(87.2%)
patients
in
the
MBT
group
and
250
(87.1%)
patients
in
the
CT
group
were
compliant
(range,
71%-120%)
with
the
treatment.
The
mean
compliance
rate
with
MBT
was
97.6%
compared
to
95.5%
for
the
CT
group.
Duration
of
MBT
or
placebo
buccal
tablet
adhesion.
The
mean
duration
of
adhesion
was
comparable
between
the
MBT
group
(12
hours,
37
minutes)
and
the
CT
group
that
received
placebo
buccal
tablets
(13
hours,
10
minutes).
Total
number
of
tablets
that
detached
within
the
first
6
hours
after
placement
was
6.3%
of
the
MBTs
and
5.7%
of
the
placebo
buccal
tablets.
An
equal
number
of
active
and
placebo
buccal
tablets
were
replaced
in
each
treatment
group
(216
tablets/group).
Plasma
miconazole
levels.
In
all
40
patients
tested
(20
patients
in
each
group),
miconazole
plasma
levels
at
day
7
were
below
the
limit
of
assay
quantification
(0.1
pg/mL),
indicating
that
systemic
exposure
to
miconazole
from
the
MBT
is
very
low.
Adverse
events
(AEs).
AEs
were
comparable
between
treatment
groups
with
respect
to
total
inci-
dence
and
severity
of
AEs
reported
(Table
4).
All
AE-related
withdrawals
were
not
related
to
study
drug.
A
total
of
313
patients
(54%)
reported
n
AE
during
the
study:
161
(56%)
in
MBT
group
and
152
(53%)
in
the
CT
group.
The
types
of
treatment-
emergent
adverse
events
(TEAEs)
were
similar
between
the
2
treatment
groups
(Table
4).
The
most
frequently
reported
TEAEs
were
diarrhea,
head-
ache,
nausea,
and
vomiting.
Nineteen
patients
reported
29
serious
adverse
events
(SAEs),
including
11
deaths
(Table
4).
Eight
patients
experienced
nonfatal
SAEs,
which
included
multiple
falls,
worsening
of
AIDS
demen-
tia,
shigellosis,
lower
respiratory
tract
infection
(2
patients),
and
worsening
anemia
in
the
MBT
treatment
group
and
pneumonia
and
tuberculosis
(2
patients)
in
the
CT
treatment
group.
All
of
the
nonfatal
SAEs
were
deemed
not
related
to
study
drug.
Of
the
11
deaths
reported
during
the
study,
1
patient
in
the
MBT
group
died
during
treatment,
another
died
2
days
following
discontinuation
of
treatment
due
to
renal
failure
and
dehydration,
and
3
died
during
follow-up.
All
6
of
the
deaths
Table
4.
Summary
of
adverse
events
MBT
(n
=
290)
CT
(n
=
287)
Adverse
event
overview,
n
(%)
Adverse
events
161
(56)
152
(53)
Treatment-emergent
AEs
158
(55)
146
(51)
Treatment-related
AEs
69
(24)
65
(23)
Serious
AEs
10
(3)
9
(3)
Discontinuations
due
to
AEs
2
(1)
3
(1)
TEAEs
reported
in
3%
of
patients
in
any
treatment
group
by
preferred
term,
n
(%)
Diarrhea
26
(9)
23
(8)
Headache
22
(8)
19
(7)
Nausea
19(7)
22
(8)
Vomiting
11
(4)
9
(3)
Anemia
8
(3)
5
(2)
Cough
8
(3)
5
(2)
Dry
mouth
8
(3)
5
(2)
Fatigue
8
(3)
6
(2)
Upper
abdominal
pain
5
(2)
8
(3)
Gastroenteritis
4
(1)
8
(3)
GGT
increased
3
(1)
8
(3)
Pain
3
(1)
8
(3)
Note:
AE
=
adverse
event;
CT
=
clotrimazole
10
mg
troche;
GGT
=
gamma-glutamyltransferase;
MBT
=
miconazole
50
mg
buccal
tablet;
TEAE
=
treatment-emergent
adverse
event.
MICONAZOLE
BUCCAL
TABLET
FOR
OPC
IN
HIV
VAZQUEZ
ET
AL
193
in
the
CT
group
occurred
during
the
treatment
period.
Ten
of
the
11
deaths
were
classified
as
unrelated
to
study
drug
and
1
death,
in
the
CT
group,
was
considered
unlikely
related
to
study
drug.
All
deaths
occurred
at
South
African
sites
and
were
generally
due
to
complications
of
underlying
disease.
The
causes
of
the
5
deaths
in
the
MBT
treatment
group
were
renal
failure/
dehydration,
pneumonia,
meningitis,
retroviral
infection,
and
intravascular
coagulation.
In
the
CT
group,
the
causes
of
the
6
deaths
were
sepsis,
meningitis,
pneumonia
(2
patients),
gastroenteri-
tis/dehydration,
and
1
unknown.
Local
tolerability.
The
majority
of
patients
(81%)
in
each
treatment
arm
had
no
gingival
inflamma-
tion
at
the
application
site
at
end
of
treatment.
Patient-rated
assessments
for
oral
comfort
were
similar
in
both
groups,
with
marked
decreases
in
severity
for
gum
pain,
dysgeusia,
and
dry
mouth
over
the
treatment
period
with
97%
to
99%
of
patients
having
a
score
of
0
(absent)
or
1
(mild)
by
day
14,
depending
on
the
symptom.
The
10
cm
VAS
patient-rated
scores
for
oral
discomfort
and
burning
sensation
at
application
site
were
low
(mean
<2)
at
randomization
and
were
<1
for
all
patients
at
end
of
treatment.
DISCUSSION
Results
of
this
study
demonstrate
that
the
effi-
cacy
of
MBT
50
mg
once
daily
is
comparable
to
CT
10
mg
given
5
times/day
for
the
treatment
of
OPC
in
HIV-positive
patients.
There
were
no
significant
differences
between
treatment
groups
in
any
of
the
clinical
efficacy
or
safety
endpoints.
The
efficacy
of
MBT
in
this
study
is
consistent
with
those
results
reported
with
other
topical
agents
currently
used
to
treat
OPC162126,27
and
are
consistent
with
the
medical
literature
upon
which
the
study
design
and
power
were
based.
Similar
to
previous
reports,
mycological
cure
rates
in
this
study
were
lower
than
clinical
cure
rates.
2829
This
is
not
unexpected
as
Candida
species
are
commensal
organisms
and
are
very
difficult
to
completely
eradicate
from
the
oral
cav-
ity,
which
has
large
areas
of
protected
niches.
In
addition,
HIV-infected
patients
have
a
diminished
cell-mediated
immune
function,
thus
making
it
dif-
ficult
to
eradicate
any
fungal
organisms
from
the
mucosal
surfaces.
Candida
may
be
present
before
clinical
signs
and
symptoms
of
OPC
develop
and
after
they
resolve.
Signs
and
symptoms
of
OPC
were
reduced
with
either
treatment.
From
baseline
to
the
TOC
visit,
the
percentage
of
all
patients
with
no
lesions
increased
from
0%
to
73%,
and
the
per-
centage
of
patients
with
no
symptoms
improved
by
75%.
Relapse
rates
were
similar
in
both
treatment
groups,
and
the
time
to
relapse
of
approximately
2
weeks
is
consistent
with
the
published
report
of
another
topical
agent.
3
°
Overall,
both
agents
were
safe
and
well
tolerated,
with
<1%
of
patients
dis-
continuing
treatment
due
to
an
adverse
event.
The
IDSAll
and
the
CDC
12
endorse
the
use
of
topi-
cal
antifungal
agents
for
the
treatment
of
mild
cases
of
OPC.
However,
systemic
agents
are
frequently
used,
due
in
part
to
limitations
of
currently
avail-
able
topical
agents,
including
frequent
daily
dosing
(4-5
times/day),
transient
drug
delivery
during
the
dosing
period,
and
oral
discomfort.
6,31
Addition-
ally,
many
are
highly
sweetened
with
sugar,
which
may
negatively
affect
dental
health.
32
These
draw-
backs
can
result
in
poor
treatment
compliance
and
may
have
contributed
to
the
continued
use
of
systemic
agents
6.33
Despite
the
inconveniences
detailed
previously,
topical
agents
are
recommended
because
there
is
increased
potential
for
hepatic
injury
and
drug-drug
interactions
with
systemic
agents,
which
can
be
major
concerns
in
patients
with
HIV
infection.
13,14
Systemic
fluconazole
use
has
been
specifically
shown
to
impact
the
development
of
azole-resistant
Candida
species
and
the
shift
of
a
susceptible
Candida
species
to
the
less
susceptible
non-albicans
Candida
species.
34
In
a
study
published
by
Bassetti
et
al,
the
investigators
showed
that
the
proportion
of
nosocomial
infections
due
to
non-
albicans
Candida
species
markedly
increased
from
38%
in
1999
to
76%
in
2003.
34
This
is
important
because
patients
suffering
from
relapsing
OPC
are
frequently
given
repeated
courses
of
fluconazole
as
primary
therapy
or
low-dose
fluconazole
for
secondary
prophylaxis.
Both
of
these
regimens
have
resulted
in
the
development
of
infections
due
to
resistant
Candida
species,
especially
C.
glabrata
or
C.
krusei,
which
are
inherently
less
susceptible
to
fluconazole
and
itraconazole
4
and
have
been
increasing
in
frequency
in
relapsing
patients.
35
In
some
studies,
more
than
30%
of
Candida
clinical
isolates
have
been
found
to
have
decreased
suscep-
tibility
to
systemic
antifungal
agents.
35-37
The
current
study
is
the
largest
clinical
trial
evaluating
a
treatment
regimen
for
OPC
and
shows
194
HIV
CLINICAL
TRIALS
11/4
JULY-AUGUST
2010
that
MBT
is
as
effective
and
safe
as
CT
for
OPC
treatment
in
HIV-positive
patients.
Although
the
lack
of
a
comparator
arm
receiving
only
placebo
treatment
may
be
a
limitation,
the
observation
of
noninferiority
of
MBT
relative
to
CT
was
robust
and
consistent
across
all
efficacy
outcomes.
A
previous
study
evaluating
MBT
for
OPC
in
head
and
neck
cancer
patients
found
it
to
be
an
effective
treatment.
38
The
current
study
extends
these
findings
by
supporting
MBT
use
as
an
OPC
treatment
in
HIV-positive
patients.
Although
both
MBT
and
CT
are
topical
agents,
the
high
and
sustained
levels
of
salivary
miconazole
concentrations
with
MBT,
15
combined
with
the
unique
mode
of
administration,
will
increase
its
role
and
utility
as
a
local
therapeutic
alternative
for
OPC
ranging
from
mild
to
moderate
infection.
Compliance
is
typically
higher
in
clinical
trials
than
daily
practice,
390
and
the
convenience
of
once-daily
dosing
may
translate
into
increased
routine
adherence
to
the
treatment
regimen,
another
reason
the
MBT
is
an
important addition
to
the
thera-
peutic
armamentarium
of
antifungal
agents
that
have
been
shown
to
be
effective
against
OPC.
In
addition,
another
contrasting
but
important
difference
is
that
MBT
does
not
contain
any
cariogenic
sugars
as
do
CT
(dextrose)
and
nystatin
solution
(sucrose).
The
results
reported
here
indicate
that
MBT
may
offer
a
beneficial
and
safe
alternative
to
other
topical
and
systemic
antifungal
agents.
ACKNOWLEDGMENTS
The
authors
would
like
to
express
sincere
thanks
to
all
members
of
the
SMILES
Study
Group
for
their
participation
in
this
trial,
with
special
recognition
of
the
South
African
colleagues
whose
dedication
to
gathering
these
data
in
the
field
was
extraordinary.
BioAlliance
Pharma
(Paris,
France)
provided
assis-
tance
with
the
study
design,
data
acquisition,
and
sta-
tistical
analysis.
Prescott
Medical
Communications
Group
(Chicago,
Minois,
USA)
and
Strativa
Pharma-
ceuticals
(Woodrliff
Lake,
New
Jersey,
USA),
devel-
opment
partner
with
BioAlliance
Pharma,
assisted
with
preparation
of
the
first
draft
of
the
manuscript
and
coordinated
revision
of
the
manuscript
on
the
basis
of
the
comments
from
all
of
the
co-authors.
These
data
were
previously
presented
at
the
Interscience
Conference
on
Antimicrobial
Agents
and
Chemotherapy
(ICAAC),
September
12-15,
2009,
San
Francisco,
California;
Infectious
Diseases
Society
of
America
(IDSA),
October
29
November
1,
2009,
Philadelphia,
Pennsylvania,
USA;
American
Society
of
Health-System
Pharmacists
Mid-Year
Clinical
Meeting
(ASHP-Midyear),
December
6-10,
2009,
Las
Vegas,
Nevada,
USA.
Members
of
the
SMiLES
Study
Group
Principal
Investigators.
Canada:
B.
Conway
(Vancouver,
BC),
D.
Kilby
(Ottawa,
ON),
R.
LaLonde
(Montreal,
QC),
C.
Tsoukas
(Montreal,
QC).
South
Africa:
Z.
Noveljic
(Cape
Town,
WC),
P.
Ramlachan
(Durban,
KN),
I.
Mitha
(Benoni,
GT),
J.
Fourie
(Dundee,
KN),
D.
Malan
(Port
Elizabeth,
EC),
Y.
Kelfkens
(Potchefstroom,
NW),
J.
Engelbrecht
(Western
Cape),
S.
Andrews
(Kenilworth,
EC),
J.
Van
Vuuren
(Bloemfontein,
FS),
D.
Petit
(Cape
Town,
WC).
United
States:
J.
Vazquez
(Detroit,
MI),
R.
Lalla
(Farmington,
CT),
A.
Barasch
(Birmingham,
AL),
A.
La
Marca
(Fort
Lauderdale,
FL),
T.
Meiller
(Baltimore,
MD),
0.
Osiyemi
(West
Palm
Beach,
FL),
M.
Kutcher
(Chapel
Hill,
NC),
C.
M.
Nichols
(Houston,
TX),
H.
Sroussi
(Chicago,
IL),
B.
Muzyka
(Greenville,
NC),
J.
Beal
(Tampa,
FL),
C.
Borkert
(Oakland,
CA),
S.
Patel
(Norfolk,
NJ),
J.
Ernst
(New
York,
NY),
R.
Bolan (Los
Angeles,
CA),
J.
Bartczak
(Fort
Lauderdale,
FL).
Medical
Advisory
Board
and
Data
Monitor-
ing
Committee.
L.
Patton
(Chapel
Hill,
NC),
J.
Epstein
(Chicago,
IL),
J.
Sobel
(Detroit,
MI),
J.
Perfect
(Durham,
NC),
M.
Thorn
(Durham,
NC),
S.
Frederick
(Baltimore,
MD),
G.
Lucas
(Baltimore,
MD).
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