Onset of therapeutic effect of fluticasone.pdf

fluticasone propionate

1. Onset of therapeutic effect of fluticasone
propionate aqueous nasal spray
Eli O. Meltzer, MD*; Kathleen A. Rickard, MD†; Ronald E. Westlund, MS†; and Cindy K. Cook, MS†
Background:The effectiveness of fluticasone propionate (FP) aqueous nasal
spray in the treatment of rhinitis has been demonstrated in multiple controlled
clinical studies. The onset of therapeutic effect of FP in these clinical trials appears
to occur within 12 hours after administration of the initial dose.
Objective:This article presents an analysis from previous clinical trials that
examined the efficacy of intranasal FP in patients with rhinitis to ascertain whether
the time to onset of the therapeutic effect of this medication could be determined.
Methods:Completed randomized, double-blind, placebo-controlled studies with
FP were evaluated to determine whether onset of effect could be evaluated based on
the study designs. A study was deemed acceptable for evaluation of onset of effect
if at least one evaluation of the intensity of nasal symptoms was completed within
12 hours after the initial dose of study medication and daily evaluations were made
thereafter. Adult patients were included in the onset analysis if they received an
initial FP dose of 200
g. Pediatric patients who received an initial FP dose of 100
g were also included. Onset of effect was evaluated by 1) examining the timepoints
at which statistically significant differences were observed between FP and placebo
in mean change from baseline for total nasal symptom score (TNSS); and by 2)
using a binary probability model of success/failure to determine statistically signif-
icant differences from placebo.
Results:Twenty-two studies met the criteria to evaluate onset of therapeutic
effect; 3,605 patients with rhinitis received FP and 2,271 patients received placebo.
This database represents the largest compilation of data ever assembled to determine
the onset of therapeutic effect of a corticosteroid nasal spray. Two studies used a
“park design” to examine onset of effect; statistically significant differences in
TNSS favoring FP were achieved at hours 2 to 4 and at hour 12, respectively. Using
a binary probability model of success/failure for analysis of TNSS in the remaining
20 studies not specifically designed to evaluate onset of effect, numerically greater
improvements in TNSS for FP compared with placebo were found in 19 of the 20
studies within 12 hours of the administration of the first dose (P .001). Pairwise
comparisons showed statistically significant improvement for TNSS within 12 hours
postdose in five of the studies for FP compared with placebo and in none for placebo
compared with FP.
Conclusions:Onset of therapeutic effect occurs within 12 hours, and as early as 2 to 4
hours in some patients, after administration of the first dose of FP aqueous nasal spray.
Ann Allergy Asthma Immunol 2001;86:286–291.
INTRODUCTION
Rhinitis, the inflammation of the mem-
branes lining the nose, is a common
condition characterized by nasal con-
gestion,
1
rhinorrhea including postna-
sal drainage, sneezing, and itching of
the nose. Recent epidemiologic data
indicate that rhinitis affects an esti-
mated 20 to 40 million people in the
United States annually, including 10%
to 30% of adults and up to 40% of
children.
1
Rhinitis is sometimes viewed as a
trivial disease. However, the condition
has significant impact on patients’
quality of life and results in direct and
indirect healthcare costs estimated be-
tween $2.7 and $5.3 billion per year in
the United States.
2
These estimates do
not account for the costs of complica-
tions of the disease that often include
asthma exacerbations, sinusitis, orth-
odontic disturbances, allergic conjunc-
tivitis, and chronic otitis media with
effusion.
2
Further, the 1987 National
Medical Expenditure Survey indicated
that allergic rhinitis resulted in 811,000
missed work days, 824,000 missed
school days, and 4,230,000 reduced ac-
tivity days in the United States annually.
3
In current clinical practice, intrana-
sal corticosteroids are generally con-
sidered the most effective medication
for the treatment of patients with rhi-
nitis.
4
Although intranasal corticoste-
roids are effective in the management
of rhinitis, the onset of effect of these
medications is often thought to be
slow, with symptomatic response not
evident until several days after initia-
tion of therapy.
5
Because the onset of
rhinitis symptoms rapidly follows ex-
posure to triggers of inflammation, the
need for a treatment regimen that con-
trols the symptoms quickly and effec-
tively is obviously the desire of the
patient and a concern for the treating
physician. Thus, the perception of de-
layed onset of therapeutic effect may
reduce patient adherence to the dosing
schedule and impact physician pre-
scribing practices.
The effectiveness of fluticasone pro-
pionate (FP) aqueous nasal spray in the
treatment of rhinitis has been demon-
strated in numerous controlled studies.
FP has been shown to influence many
* Allergy and Asthma Medical Group and Re-
search Center, San Diego, CA.
† Glaxo Wellcome Inc., Research Triangle Park,
NC.
The data included in this paper were presented in
part at the 1999 American Academy of Allergy
Asthma and Immunology Annual Meeting, Or-
lando, FL, February 26 to March 3, 1995.
Received for publication April 10, 2000. Accepted for publication September 6, 2000.
286 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

2. aspects of the nasal inflammatory pro-
cess, acting on both the early- and late-
phase allergic response by influencing
the immune response to allergens by
downregulation of allergen-specific
antibody production, decreasing the
levels of cellular mediators in nasal
secretions, and inhibiting the influx of
inflammatory cells.
6–8
We evaluated
the time to onset of effect of FP, cur-
rently the most widely prescribed in-
tranasal corticosteroid, on the nasal
symptoms of rhinitis. The results re-
ported here are based on a comprehen-
sive review of 22 clinical trials
9 –27
that
provided information on the time to
onset of therapeutic effect of FP. This
database represents the largest compi-
lationofdataeverassembledtodeter-
mine the onset of therapeutic effect of
a corticosteroid nasal spray.
METHODS
Study Identification
Thirty-three clinical trials conducted in
the United States were identified and
evaluated to determine whether their
design allowed an evaluation of the
onset of therapeutic effect of FP. The
objectives of these studies varied; 11
were not suitable to evaluate onset of
effect either because they did not col-
lect nasal symptom data on an hourly
or daily basis after the first dose of
study medication or they were small
pilot studies. All 22 remaining place-
bo-controlled studies allowed evalua-
tion of onset of effect. Two of these
studies were specifically designed to
study onset of effect in an outdoor
setting in adults and adolescents with
seasonal allergic rhinitis (park studies).
Of the remaining 20 studies also de-
signed in a manner that allowed eval-
uation of onset of effect, 14 were in
adolescents and adults with seasonal
allergic rhinitis (SAR), two were in
children with SAR, two were in ado-
lescents and adults with perennial al-
lergic rhinitis, and two were in adults
and adolescents with perennial nonal-
lergic rhinitis.
Study Design
Studies were included in the evaluation
of onset of effect if they were well-
controlled, double-blind trials in which
patients were randomly assigned to ei-
ther FP or placebo treatment groups.
Efficacy evaluations to determine on-
set of therapeutic effect were collected
from patient-rated nasal symptom
scores recorded at least daily by the
patients on diary cards.
All studies included a screening pe-
riod and a double-blind treatment pe-
riod. In each study, patient eligibility
for the study was determined and se-
verity of baseline nasal symptoms was
established during the screening period.
Patients who met all requirements for
entry into the studies were enrolled into
the double-blind treatment period only if
their symptoms exceeded predetermined
levels immediately preceding assign-
ment to double-blind treatment.
Studies were included in this analy-
sis if they had at least one evaluation of
nasal symptom severity within the first
12 hours after an initial dose of FP or
placebo and had daily evaluations
completed thereafter. In the two stud-
ies designed specifically to evaluate
onset of effect (park studies), nasal
symptoms were evaluated by patients
on optically scanned diary cards. Se-
verity of nasal stuffiness (left and right
nostril), sniffles/runny nose (left and
right nostril), postnasal drip, and itchy
nose was measured using a 10-point
scale ranging from 0 (no symptoms) to
10 (severe symptoms). For nose blows
and sneezes, patients filled in the exact
number of occurrences from 1 to 10, or
10 if the patients experienced more
than 10 of these occurrences. A total
nasal symptom score was calculated
from the sum of all symptoms, with a
total possible maximum score of 80
points. The initial dose of study med-
ication was taken in the park and
symptoms were rated hourly in the
park for 7 hours postdosing and after
leaving the park at 9 and 12 hours
postdosing.
The severity of nasal symptoms in
the remaining 20 studies was evaluated
daily by patients using a visual analog
scale. The unmarked scale was a
100-mm line that represented a contin-
uum from 0 (no symptoms) to 100
(most severe symptoms). Patients indi-
cated severity by placing a vertical
mark on the horizontal scale. In sea-
sonal and perennial allergic rhinitis
studies, patients rated nasal obstruc-
tion, rhinorrhea, nasal itching, and
sneezing. A total nasal symptom score
was calculated from the sum of these
symptoms, with a total possible maxi-
mum score of 400 points. In perennial
nonallergic rhinitis studies, total nasal
symptom scores were calculated as the
sum of nasal obstruction, rhinorrhea,
and postnasal drip for a maximum of
300 points. Total daily dosages were
delivered with once daily or twice
daily dosing regimens. In these studies,
the initial dose of medication was ad-
ministered in the investigator’s office
and symptoms were rated in the
evening on the same day and daily
thereafter.
Statistical Analyses
Hypothesis tests were used to analyze
efficacy data collected during double-
blind treatment for all patients who
were exposed to the study drug (intent-
to-treat analysis).
Two methods were used to evaluate
onset of effect. In the first, onset was
evaluated by examining the timepoints
at which statistically significant differ-
ences were observed between FP and
placebo in mean change from baseline
in total nasal symptom score (TNSS)
for data collected from patient diary
cards during the first 4 days of treat-
ment. The null hypothesis (FPpla-
cebo) and the alternative hypothesis
(FPplacebo) were evaluated. How-
ever, it is important to note that the
studies were not originally designed to
study this endpoint and none except
the park studies were powered to show
a difference between the treatment
groups during the first 4 days.
In the second method, each study
was the unit of measurement. A binary
probability model of success/failure
was used to determine statistical sig-
nificance. In this model, a binomial
distribution is used to determine the
probabilities of the possible outcomes
that might be observed when sampled
from a binomial population (ie, either
FP is better than placebo or FP is not
VOLUME 86, MARCH, 2001 287

3. better than placebo). A study was con-
sidered supportive of onset of thera-
peutic effect (success) if the decrease
in TNSS for the FP group was numer-
ically superior to placebo. The null hy-
pothesis (FPplacebo at random) and
the alternative hypothesis (FPplacebo
in an ordered fashion) were evaluated. If
the majority of the studies indicated that
the decrease in TNSS for FP was greater
than placebo, the null hypothesis was
rejected in favor of the alternative hy-
pothesis. Specifically, the probability of
14 or more studies demonstrating a de-
crease in TNSS for FPplacebo is
0.021, and the probability of 13 or more
studies demonstrating FPplacebo is
0.058. Therefore, if 14 or more studies
demonstrated that the change from base-
line in TNSS for FPplacebo, the null
hypothesis was rejected and the superi-
ority of FP over placebo was not a ran-
dom occurrence and was thus supportive
of the onset of effect within 12 hours.
RESULTS
Patient Enrollment
Twenty-two studies met the criteria to
evaluate onset of therapeutic effect. In
these studies, 3,605 patients with rhi-
nitis received FP and 2,271 patients
received placebo.
Studies Designed to Examine Onset
of Effect (Park Studies)
In the two studies designed specifically
to examine time to onset of effect,
treatment with FP resulted in greater
improvements in TNSS compared with
placebo at all timepoints after admin-
istration of the first dose of study med-
ication. In study 1, statistically signif-
icant differences in TNSS favoring FP
over placebo were achieved at 2 to 4
hours after administration of the first
dose and were maintained throughout
the first treatment day (Fig 1A). In
study 2, improvements favoring FP
over placebo were observed at 2 to 4
hours also, but did not reach statistical
significance until 12 hours after the
first dose (Fig 1B). Once achieved,
statistically significant differences be-
tween treatment groups were main-
tained throughout the treatment period.
Figure 1. Patient-rated mean total nasal symptom scores for study 1 (panel A) and study 2 (panel B)
during the course of 12 hours after the first dose of study medication.indicates statistically significant
difference (P.05) between FP and placebo based on ANOVA test on change from baseline, controlling
for investigator.
288 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

4. Onset of Effect-Binary Probability
Model
Twenty additional studies conducted to
evaluate the efficacy of FP compared
with placebo provided total nasal
symptom score data for the first 4 days
of study therapy. In these 20 clinical
studies, the administration of FP re-
sulted in numerically greater improve-
ments in TNSS compared with placebo
within 12 hours of the first dose of
study medication in 19 of the 20 stud-
ies (Fig 2). For patients treated with
FP, the mean absolute change from
baseline in TNSS within 12 hours of
the first dose ranged from15.8 to
67.2. For patients in the placebo
group, change from baseline in TNSS
ranged from3.0 to44.9. Using a
binomial probability model, FP was
statistically superior to placebo in re-
ducing symptoms in these studies (P
.001) within 12 hours after administra-
tion of study medication, and this ef-
fect was maintained throughout the
study periods. These data provide fur-
ther evidence that the onset of the ther-
apeutic effect of FP in comparison to
placebo occurs within 12 hours of ad-
ministration of the first dose.
Efficacy was evaluated in these
studies based on pairwise comparisons
of mean change from baseline in pa-
tient-rated TNSS. Although these stud-
ies were not specifically designed to
evaluate onset of effect, and thus were
underpowered to detect statistically
significant differences within the first
4 days, 5 of the 20 studies resulted in
statistically significant differences fa-
voring FP over placebo within the first
12 hours after the initial dose of study
medication. Patterns of significance
over time for individual nasal symp-
toms generally matched those of the
TNSS. In these clinical studies, the
differences favoring FP over placebo
were generally maintained for the re-
mainder of the study period once sta-
tistically significant differences were
achieved.
DISCUSSION
Our data from 22 clinical studies pro-
vide strong evidence that onset of ther-
apeutic effect of FP occurs within 12
hours of administering the first dose of
medication. In two studies specifically
designed to examine onset of effect,
statistically significant differences in
TNSS favoring FP were achieved at
hours 2 to 4 (P .021) and at hour 12
(P.029), respectively. In 19 of 20
additional studies, treatment with FP
resulted in greater numerical improve-
ments in TNSS compared with placebo
by 12 hours postdose, and a binary
probability model of success/failure in-
dicated that onset of effect within 12
hours after the first dose could not be
attributable to chance (P.001). Pair-
wise comparisons of change from
baseline in TNSS from these 20 addi-
tional studies showed statistically sig-
nificant differences in TNSS favoring
FP over placebo by 12 hours postdose
in five studies, even though the studies
were not powered to show differences
in TNSS at these timepoints.
Park studies have been shown to be
sensitive models for the study of onset
of effect of drugs used to treat allergic
rhinitis.
28 –32
They provide the advan-
tage of a tightly controlled direct com-
parison of medications because they
are conducted in a setting where many
potential variables, such as exposure of
allergen during the day, are standard-
ized in a real-life setting. Berkowitz et
al
33
also showed that the onset of ac-
tion of another intranasal corticoste-
roid (mometasone furoate) occurred
within the first 12 hours of therapy in
patients with seasonal allergic rhinitis
in a study designed similarly to the two
FP park studies that we report. These
studies, specifically designed to mea-
sure time to onset of effect, indicate
that the effects of intranasal corticoste-
roids begin to occur and are substantial
during the first day of use.
In the two park studies with FP, a
significant and variable placebo effect
was evident. In these two studies, similar
improvements in nasal symptoms were
seen from baseline for patients treated
with FP in both studies, whereas vehicle
placebo in study 2 showed approxi-
mately twice as much effect on symptom
scores as vehicle placebo in study 1 (Fig
1, A and B). The placebo effect in the
park studies that we report here was sim-
ilar to the effect noted in other outdoor
park studies with intranasal corticoste-
roids and in park studies with antihista-
mines.
29 –33
The response rates (improve-
Figure 2. Mean change from baseline in patient-rated total nasal symptom score within 12 hours after
the first dose of study medication.P.001 for binomial probability model of success/failure.
VOLUME 86, MARCH, 2001 289

5. ment in symptom scores) for patients
who are treated with nasal saline or pla-
cebo vehicle have been shown to exceed
30%.
29 –32
These large placebo effects
have been attributed in part to a true
placebo effect, to the excipients such as
propylene and polyethylene glycol, to
statistical regression to the mean, or to
the flushing action of the spray that may
clear secretions and remove mediators of
rhinitis located on or near the surface of
the nasal mucosa.
34,35
Clearly, the placebo in these studies
was not a pure placebo because vehicle
is a recognized treatment for allergic
rhinitis. Although there were statistical
differences in symptom scores be-
tween FP and vehicle placebo within
12 hours of treatment, the large pla-
cebo effect may have confounded the
interpretation of statistical analyses
and blunted the time to onset of the FP
nasal spray. Our binomial probability
evaluation of the magnitude of im-
provement of symptoms over a large
number of studies provides important
additional information in the evalua-
tion of onset of effect. In this model, a
binomial distribution was used to de-
termine the probabilities of the possi-
ble outcomes that might be observed
(ie, either FP is better than placebo, or
FP is not better than placebo). In the
analysis of these outcome data, the null
hypothesis assumes that the probabili-
ties of the outcomes are equal. In the
testing of this hypothesis, the question
is not the probability of obtaining ex-
actly the values that were observed,
but rather, the probability of obtaining
values as extreme or more extreme
than the observed values. In fact, it is
extremely unlikely that the results ob-
tained from our study (ie, that FP onset
is superior to placebo in the vast ma-
jority of studies) are primarily because
of chance. Because the studies were
conducted independently and because
the probabilities of success and failure
are based on a binomial distribution,
one would expect FP to be numerically
superior to placebo in only approxi-
mately half of the studies. Our data
from multiple studies show that FP
provides consistently greater improve-
ment (19 of 20 studies) in TNSS com-
pared with placebo within 12 hours of
the first dose.
CONCLUSION
Studies conducted in the clinical devel-
opment program of FP aqueous nasal
spray consistently showed that FP was
safe and efficacious in the treatment of
patients with rhinitis. A large volume
of data from additional studies has
been obtained since initial approval of
the drug, and these data continue to
provide evidence of the safety and ef-
fectiveness of FP. These additional
data have also provided substantial ev-
idence that confirms the rapid onset of
effect of FP following initiation of
treatment. The weight of the available
evidence clearly shows that onset of
therapeutic effect occurs within 12
hours, and perhaps as early as 2 to 4
hours in some patients, after initiation
of FP treatment, and that symptoms
continue to improve until maximal
beneficial effects occur after several
days of continued dosing with FP.
ACKNOWLEDGMENTS
The analyses of these data were spon-
sored by Glaxo Wellcome Inc., Re-
search Triangle Park, NC. We ac-
knowledge the contributions of John
M. Weiler, MD for his assistance in the
design and conduct of the park studies
described. We also wish to thank Larry
E. East for his expert assistance in the
writing and editing of the manuscript.
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nasal spray in subjects with ragweed-
induced allergic rhinitis. J Allergy Clin
Immunol 1996;97:1050 –1057
Answers to CME Questions
1. e
2. e
3. d
4. e
5. d
Requests for reprints should be addressed to:
Eli O. Meltzer, MD
Allergy and Asthma Medical Group and
Research Center
9610 Granite Ridge Drive, Suite B
San Diego, CA 92123
E-mail: [email protected]
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