ARTICLE
Auteur(s) : Louis Dubertret1, Lavinia
Zalupca2, Tania Cristodoulo3, Vasile
Benea4, Iris Medina5, Sara
Fantin6, Morad Lahfa1, Iñaki
Pérez7, Iñaki Izquierdo7, Eva Arnaiz7,*
1Institute for Skin Research, University Paris VII,
Hôpital Saint-Louis, Paris, France
2CDMTA Nicolae Kretzulescu, Bucharest, Romania
3Clinical Hospital Colentina, Bucharest, Romania
4Clinical Hospital Prof Scarlat Longhin, Bucharest,
Romania
5Centro Medico Vitae, Buenos Aires, Argentina
6Hospital President Peron, Buenos Aires, Argentina
7R+D Clinical Unit, J. Uriach y Compañía, S.A.
Barcelona, Spain
accepté le 22 Decembre 2006
Chronic idiopathic urticaria (CIU) is a debilitating disease which
is characterised by daily, or almost daily, occurrence of wheals
and pruritus, often accompanied by angioedema, for more than 6
weeks, with no obvious aetiology [1, 2]. The wheals and pruritus,
which are not only physiologically bothersome but potentially
stigmatizing due to their very public nature, cause disruption of
sleep and daily activities and fatigue and loss of energy,
resulting in decreased quality of life (QoL) for affected
individuals [3, 4]. While CIU is estimated to affect between 0.1-3%
of the population in Europe and the USA and account for nearly 75%
of all cases of chronic urticaria [1, 5], it is thought that the
world-wide lifelong prevalence for CIU is 0.5% and does not vary
greatly across different populations [1]. Although it is often not
possible to identify the specific cause of CIU, an increasing
amount of evidence suggests that the symptoms of CIU such as
oedema, erythema and pruritus are primarily elicited as a
consequence of histamine released from activated dermal mast cells
and basophils binding to the H1 receptors [6]. This has
consequently advocated the use of oral H1 receptor
antagonists (H1 antihistamines) as the mainstay and only
drugs licensed for therapeutic intervention for CIU [3,
6].Rupatadine is a novel selective and long-acting (24 hour)
histamine H1 receptor and platelet-activating factor
(PAF) receptor antagonist, which binds with a higher affinity to
the H1 receptor than fexofenadine and levocetirizine
[7], and has a long duration (24 hours) of action, as indicated by
prolonged inhibition of histamine and PAF-induced wheal and/or
flare skin reactions in healthy volunteers [8]. A recent study in
patients with seasonal allergic rhinitis treated with rupatadine
10 mg showed that rupatadine also has a fast onset of action
since allergen-induced nasal and non-nasal symptoms were
significantly decreased within 15 minutes of exposure to allergen,
compared with placebo [9]. Indeed, several randomised double-blind,
multicenter studies have demonstrated that rupatadine 10 mg
and 20 mg once daily is highly efficacious in attenuating the
symptoms of rhinitis in adult and adolescent patients with
moderate-to-severe seasonal allergic rhinitis [10-12] and perennial
allergic rhinitis [8]. Rupatadine is currently approved in several
European countries for the symptomatic treatment of seasonal and
perennial allergic rhinitis at a daily recommended dose of
10 mg [13].To date there is no information of the efficacy of
rupatadine in the treatment of symptoms of CIU. The aims of this
dose-ranging study were therefore to assess the clinical efficacy
and safety of rupatadine in the improvement of symptoms and
interference with daily activities and sleep in patients with CIU.
Materials and methods
Patients
Male and female patients, aged 12 to 65 years, with a documented
history of clinical manifestations of CIU (urticarial wheals) with
or without angioedema for at least three days per week over the
last 6 weeks were recruited into the study, mainly during November
2003. All patients had pruritus symptom scores ≥ 2 (i.e. moderate
symptoms classified as annoying or troublesome) for at least 3 days
in the week before inclusion. At randomisation to treatment, none
had been receiving specific H1-receptor antagonists for
3-10 days, H2- receptor antagonists for 2-7 days,
leukotriene antagonists for 4 days, corticosteroids for 7 days and
tricyclic antidepressants for 30 days for their CIU. Patients with
physical urticaria (due to cold, heat, and/or sun), cholinergic
urticaria, and urticaria due to any known aetiology (e.g.
medication, insect bites, food, etc) were excluded as were patients
taking any potential inhibitors of the cytochrome P450 isozyme
CYP3A4.
Study design
This was a phase II dose-ranging, randomised, double-blind,
placebo-controlled, parallel-group trial, conducted across France,
Argentina, Hungary and Romania. Following screening, eligible
patients were randomised to receive treatment with either placebo,
rupatadine 5 mg, rupatadine 10 mg or rupatadine
20 mg, as a single tablet once daily for 28 days and provided
with patient diaries at the start of treatment (visit 1). All
patients were subsequently assessed for symptoms, efficacy of
treatment, adverse events (AEs), concomitant medication and
compliance after 14 days (visit 2) and 28 days (visit 3) treatment.
The study protocol and the patients’ informed consent were approved
by local ethics committees/review boards and the study was
performed in accordance with general principles of Good Clinical
Practice and The Declaration of Helsinki, as amended in Edinburgh,
2000.
Evaluation of efficacy
Efficacy was assessed on the basis of change from baseline in i)
mean pruritus severity (MPS) score, ii) mean number of wheals (MNW)
score, iii) mean of total symptoms score (MTSS; calculated as the
sum of MPS and MNW), iv) mean interference with daily activities
score and v) mean interference with sleep score over the 4-week
treatment period. The change from baseline in MPS was investigated
as the primary outcome measure and all remaining variables as
secondary outcome measures.
Patients recorded their symptoms of pruritus and the number of
wheals in daily diary cards in the morning and at bedtime and
scored the severity of pruritus symptoms and the number of wheals
on a 5-point scale of 0-4 (for severity of pruritus: 0 = none; 1 =
mild, not annoying or troublesome; 2 = moderate, annoying or
troublesome; 3 = severe, very annoying, substantially interfering
with sleep/daily activities; 4 = very severe warranting physician
visit; for number of wheals: 0 = no wheals; 1 = 1 to 5; 2 = 6 to
15; 3 = 16 to 25; 4 = >25).
After 14 and 28 days treatment, the investigator and the patient
additionally made a global assessment of efficacy on the basis of
change in symptom severity from pre-study, scored on a 5-point
scale from 0-4 (0 = worse than at pre-study, 1 = no change, 2 =
slight improvement, 3 = good improvement).
Patients also assessed the impact of disease on the extent of
interference with daily activities and interference with sleep by
scoring on a 4-point scale of 0-3 (0= none; 1= mild; 2 = moderate;
3 = severe).
Evaluation of safety
Safety and tolerability of treatment was evaluated according to the
incidence and type of AEs recorded in the patients’ diaries,
results of routine laboratory tests (haematology, blood chemistry
and urinalysis) and clinical examinations, before and at the end of
the treatment period. All AEs were coded using the MedDRA V5
dictionary, and grouped by treatment.
Statistical analysis
A sample size of 248 patients was calculated to detect, with 80%
power and at the 5% significance, a difference > 0.5 units in
the primary efficacy variable, assuming a standard deviation of 0.9
and dropouts of 20%. Differences in MPS, MNW, MTSS, global
assessment of efficacy, interference with daily activities, and
interference with sleep scores, between the treatments groups over
the 4-week treatment period were analysed using ANOVA. The
significance of any differences in these variables was assessed by
pair-wise treatment comparison using the Fisher’s protected Least
Significance Difference (LSD) test. Treatment-emergent AEs were
compared by Chi-square test to check for intolerance to higher
doses. All statistical tests were performed using the
SAS® software version 8.2 for Windows (SAS Institute
Inc, Cary, NC, USA). Analysis of all efficacy parameters was
carried out on intent-to-treat (ITT) basis, which included data
sets of all randomised patients who received any study drug, and
for whom at least one post-baseline value was available,
independent of the degree of adherence to the protocol. Analysis of
safety included data from all randomised patients who received any
study drug.
Results
A total of 283 patients were randomised to treatment, of whom data
from 277 (69 treated with placebo; 68 with rupatadine 5 mg; 73
with rupatadine 10 mg; 67 with rupatadine 20 mg) were
analysed. Overall 244 completed the study according to protocol and
39 patients withdrew from the study. Of the withdrawing patients,
25 (10 in placebo group; 9 in rupatadine 5 mg group; 3 in
rupatadine 10 mg group, and 3 in rupatadine 20 mg group)
withdrew due to ineffective treatment, 1 due to an AE, 2 due to
incorrect treatment allocation, and 11 for other or personal
reasons. The demographic and clinical characteristics of the
patients are shown in table 1. All
treatment groups were similar with respect to mean age, the male to
female ratio, symptoms scores and impairments in daily activity and
sleep at inclusion.
Table 1 Demographic and baseline clinical
characteristics of patients in the intent-to-treat-population
|
Placebo
|
Rupatadine 5 mg
|
Rupatadine 10 mg
|
Rupatadine 20 mg
|
Total
|
|
(n = 69)
|
(n = 68)
|
(n = 73)
|
(n = 67)
|
(n = 277)
|
|
Age (y) mean ± SD
|
36.91 ± 13.44
|
39.31 ± 13.55
|
39.77 ± 11.78
|
36.45 ± 13.00
|
38.14 ± 12.96
|
|
% Female
|
78.26
|
72.06
|
75.34
|
65.67
|
72.92
|
|
%Caucasian
|
97.10
|
95.59
|
95.89
|
97.10
|
96.39
|
|
Pruritus severity score (mean ± SD)
|
2.49 ± 0.52
|
2.52 ± 0.52
|
2.54 ± 0.52
|
2.52 ± 0.53
|
2.49 ± 0.52
|
|
Number of wheals (mean ± SD)
|
2.06 ± 1.04
|
1.84 ± 1.07
|
1.95 ± 1.14
|
1.93 ± 1.05
|
1.94 ± 1.08
|
|
Interference with sleep score (mean ± SD)
|
1.03 ± 1.00
|
0.94 ± 0.93
|
1.11 ± 1.06
|
0.99 ± 0.95
|
1.02 ± 0.98
|
|
Interference with daily activities score (mean ± SD)
|
1.42 ± 1.03
|
1.24 ± 0.96
|
1.34 ± 1.07
|
1.33 ± 0.98
|
1.33 ± 1.01
|
Efficacy outcome measures
Change in mean pruritus score (MPS)
Over the 4-week treatment period, rupatadine 10 and 20 mg
significantly reduced the MPS from baseline by 1.52 (p < 0.05)
and 1.83 (p < 0.001), respectively, compared to reduction of
1.14 with placebo, reflecting significant reductions in pruritus
severity of 62.7% and 72.3%, respectively, compared with 45.8% with
placebo (figure
1). Although rupatadine 5 mg reduced the MPS by 1.31
from baseline (a reduction of 51.6%), this was not significant
compared to placebo. The treatment effect of rupatadine 20 mg
over the 4 week period was significantly greater compared with
rupatadine 5 mg (p < 0.001) and rupatadine 10 mg (p
< 0.05) (figure
1). Exploratory analyses of the time-dependent effect of
rupatadine showed that rupatadine 10 mg and 20 mg
progressively improved the MPS from week one onward of treatment,
with rupatadine 20 mg providing significant improvements
during each week throughout the entire study, compared with placebo
(table 2). Similarly, rupatadine
10 mg significantly improved the MPS for all weeks except for
week 2, compared with placebo.
Rupatadine decreased pruritus severity in a dose- and
time-dependent manner. Linear trend analysis showed that the trend
in decreased severity was significant over the entire 4-week
treatment period and all time points investigated (p < 0.0001 at
all time points and periods).
Table 2 Effect of treatment time on pruritus severity
over the course of the study for all treatment groups
|
Treatment period
|
Mean % change in 24 hour reflective pruritus score in
patients
|
|
treated with
|
|
Placebo
|
Rupatadine 5 mg
|
Rupatadine 10 mg
|
Rupatadine 20 mg
|
|
Week 1
|
– 38.33
|
– 49.17*
|
– 55.07*
|
– 63.59†§¶
|
|
Week 2
|
– 51.69
|
– 51.29
|
– 64.46
|
– 74.58†§¶
|
|
Week 3
|
– 48.18
|
– 51.88
|
– 65.48*
|
– 75.46†§
|
|
Week 4
|
– 44.96
|
– 53.40
|
– 65.72*
|
– 74.65†§
|
|
Day 1 to day 14
|
– 45.01
|
– 0.23
|
– 59.77‡
|
– 69.09†§¶
|
|
Day 1 to day 21
|
– 46.07
|
– 50.78
|
– 61.67*
|
– 71.21†§¶
|
|
4 weeks
|
– 45.83
|
– 51.56
|
– 62.74*
|
– 72.32†§¶
|
Change in mean number of wheals (MNW)
After 4 weeks treatment, the scores for MNW were decreased from
baseline by 0.64 (30.1%) for placebo, 0.66 (34.3%) for rupatadine
5 mg, 0.92 (45.2%) for rupatadine 10 mg, and 1.16 (57.8%)
for rupatadine 20 mg (figure 1). The comparison
between groups was not statistically significant. However, there
was a tendency for a time-dependent effect of rupatadine, because
assessment of changes at different time points demonstrated a
linear trend for suppression of wheal at week 3 and week 4, with
significant suppression in MNW by about 60% in patients treated
with rupatadine 20 mg, compared with placebo (p < 0.01).
Change in mean total symptoms score (MTSS)
Assessment of the MTSS indicated that this was significantly
reduced from baseline by 2.44 (54.8%; p < 0.05) and 2.99 (65.9%;
p < 0.001) over the 4-week study period in patients treated with
rupatadine 10 mg and 20 mg, respectively, compared with a
reduction of 1.78 (38.6%) in placebo-treated patients (figure 1). Although
rupatadine 5 mg reduced the MTSS by 1.97 (44.1%) from baseline
over the 4-week period, this reduction was not significant compared
with placebo. The effect of treatment with rupatadine 20 mg on
MTSS over the 4 weeks, was also shown to be significantly greater
than for rupatadine 5 mg (p < 0.01) (figure 1). Assessment of
the time-dependent effects of rupatadine on MTSS demonstrated that
there was a significant linear trend in the reduction of MTSS at
all times in patients treated with rupatadine 20 mg (p <
0.005 at all time points). Similarly, a significant trend for a
reduction in the MTSS by around 58% was noted in patients treated
with rupatadine 10 mg during weeks 3 and 4 of treatment (p
< 0.05 at both time points), compared with placebo.
Global assessment of efficacy
Figure 2
demonstrates the overall efficacy of treatment as assessed by the
investigators and the patients over the 4-week treatment period.
Approximately 20-30% of the investigators assessed symptom severity
to be worse or unchanged from pre-study levels in patients treated
with placebo, compared with between 5-15% of investigators who
assessed it to be worse or unchanged in patients treated with any
dose of rupatadine investigated (figure 2A). In contrast, a
significantly greater number of between 13-50% of the investigators
assessed the symptom severity to be improved from pre-study with
any dose of rupatadine investigated, compared with between 10-22%
who assessed it to be improved with placebo (p < 0.005 vs
rupatadine 5 mg and p < 0.001 vs rupatadine 10 mg and
20 mg) (figure
2A). Indeed, 40-50% of the investigators assessed symptom
severity to be greatly improved in patients treated with rupatadine
10 mg and 20 mg, while only about 6% assessed symptoms to
be worse in these treatment groups.
The patients’ assessment of the global efficacy of treatment
followed very similar trends, with only 5-14% of patients treated
with rupatadine assessing symptom severity to be worse or unchanged
from pre-study levels compared 21-28% of placebo-treated patients
(figure 2B).
Similarly, a significantly greater number of patients (13-48%)
treated with any dose of rupatadine assessed symptom severity to be
improved from pre-study, compared with placebo-treated patients
(10-25%; p < 0.005 vs rupatadine 5 mg and p <
0.001 vs rupatadine 10 mg and 20 mg) (figure 2B).
The global improvement in efficacy was accompanied by clear
trends in dose-dependent reductions in daily activities and sleep
scores with rupatadine, although the reductions were not
significantly different over the 4-weeks, compared with placebo.
Linear trend analysis showed significant trends in the 10 and 20-mg
treated groups compared to placebo in the reduction of daily
activities over the entire 4-week treatment period and at all time
points investigated (p < 0.05 at all time points and periods).
Similarly, a trend in the 10 and 20-mg groups was observed in the
reduction of sleep interference over week 3 (p < 0.05) and week
4 (p < 0.05) of treatment, but not over the entire 4-week
treatment period.
Safety evaluation
A total of 214 AEs were reported during the study, of which 95 were
considered to be treatment related. The two most frequently
reported AEs were somnolence (2.90% for placebo, 4.29% for
5 mg-, 5.41% for 10 mg- and 21.43% for
20 mg-rupatadine-treated group) and headache (4.35% for
placebo, 2.86% for 5 mg-, 4.05% for 10 mg- and 4.29% for
20 mg-rupatadine-treated group). The only reported SAE was an
asymptomatic and transient increase in serum creatine kinase (CPK)
at the end of the study (visit 3) in the 5-mg treatment group. The
patient performed fitness sessions twice a week. One week follow-up
after the study finalization showed that the patient was
asymptomatic and had normal serum CPK and ECG, and neither muscular
nor chest pains.
No clinically relevant AEs of rupatadine were observed on vital
signs.
Overall, there were no differences between the incidence or the
type of any other AEs noted in any of the rupatadine-treated groups
and the placebo-treated group, and all AEs were resolved
completely.
Discussion
Rupatadine 10 mg and 20 mg significantly decreased the
severity of pruritus over 4-weeks treatment, the primary outcome
measure of the study, by 62.7% and 72.3%, respectively, compared
with 45.8% with placebo. Similarly, treatment for 4 weeks with
rupatadine 10 mg and 20 mg significantly reduced the mean
total symptom score from baseline by 54.8% (p < 0.05) and 65.9%
(p < 0.001), compared with 38.6% with placebo, and additionally
showed linear trends in wheal suppression. The pruritus severity
reducing effect of rupatadine was significant from the first week
of treatment and progressive over the entire study period, with
increased reductions in pruritus severity being noted after each
week of treatment.
A blinded global assessment of the overall efficacy of treatment
showed that about 50% of the investigators and patients judged the
symptoms of CIU to be greatly improved with rupatadine 10 mg
and 20 mg, compared with a much small number of between 5-15%
who assessed the symptoms to be either improved with placebo or to
be worse from pre-study levels in rupatadine-treated patients.
Indeed, the greater improvements in symptoms and overall global
efficacy of rupatadine were reflected by linear trends in larger
reductions in interference with daily activities and sleep,
compared with placebo-treated patients. The present study also
demonstrated that treatment with rupatadine 5-20 mg was well
tolerated in patients with moderate-to-severe CIU.
Collectively, these results suggest that there is a linear
relationship between the treatment dose and the main efficacy
variable, with constant dose rises producing constant decreases in
pruritus scores and that a therapeutic dose from 20- and 10 mg
once daily is likely to provide fast onset of action with
long-lasting improvements in both the symptoms and quality of life
indices in patients with moderate-to-severe CIU.
There was a clear symptom reduction in patients under rupatadine
20 mg over time.
While several studies have shown rupatadine 10 mg once
daily to be efficacious for the symptomatic treatment of
moderate-to-severe allergic rhinitis [10-12] and perennial allergic
rhinitis [7], this is the first study to investigate the effect of
rupatadine in patients with CIU. The findings of the present study,
however, are in accordance with the findings of the few documented
studies that have investigated the effect of treatment in CIU and
shown also fexofenadine [14, 15] and desloratadine [16, 17] to be
more effective than placebo in reducing both the symptoms of CIU
and interference with daily activities and sleep. One study
demonstrated that, although mizolastine and cetirizine were also
significantly more effective than placebo in decreasing the
severity of pruritus, the effects of these agents were significant
after 2 weeks treatment [18]. Whilst this difference in the onset
of action noted for rupatadine and mizolastine/ loratadine may
possibly be explained on the basis of differences in pruritus
severity scales employed in the two studies (5-point scale for
rupatadine versus 0-100 mm visual analogue scale (VAS) for
mizolastine and loratadine), it is possible that the comparatively
faster onset of action (within one week) noted for rupatadine may
actually be a consequence of a potentially greater
anti-inflammatory effect resulting from its dual activity as a
H1- and PAF-receptor antagonist [19]. This is
particularly so in view of evidence that histamine and PAF have
complementary activities in vivo and each mediator may promote the
release of the other from different tissues and cells [20, 21].
While animal studies have suggested that PAF may possibly the most
potent mediator inducing cutaneous vascular leakage [22], studies
investigating the effects of intradermal injections of PAF in human
skin have shown that this mediator causes vasodilatation and
increased vascular permeability, producing a wheal and flare
response with accompanying pruritus [23, 24]. A comparison of the
wheal and flare response induced by PAF and histamine has shown
that PAF leads to opening of endothelial gaps and extravasation of
predominantly neutrophils, suggesting that the inflammatory
response to these agents is different [24]. Despite the
availability of information from mechanistic studies, and the large
body of evidence for the role of PAF in allergic airway diseases,
there is a marked paucity of information regarding the effect of
this mediator in chronic urticaria. One early study documented that
cold-induced urticaria was associated with the release of
histamine, PAF and neutrophilic chemotactic activity (NCA) in
patients with cold-urticaria, and that suppression of urticaria
with doxepin in these patients correlated only with inhibition of
PAF release [25]. The data from these studies collectively suggest
that blockade by rupatadine of the complementary activities of
histamine and PAF, is likely to lead to an overall greater
inhibitory effect of these mediators than that of the individual
mediators. This in turn would manifest clinically as fast and long
lasting improvements in symptoms of CIU that are of greater
magnitude with rupatadine, compared with H1
antihistamines that do not demonstrate such additional anti-PAF
activity. This hypothesis, however, needs to be confirmed in
well-controlled trials directly comparing the effects of rupatadine
with other antihistamines in CIU patients.
It is important to mention that in this study we found a high
treatment response in the placebo group and this efficacy increased
over time, leading to a progressive decrease in the difference
between the active treatments and the placebo group. In the same
way, other studies with second generation anti-histamines have
reported similar placebo response rate [14, 17]. Psychological
factors seem to be frequently associated with CIU and assuming that
MPS is a subjective variable evaluated from the patient’s
perspective, a relative high response in the placebo group should
be expected.
Despite the accordance of our findings for rupatadine and other
H1 antihistamines in reducing symptoms and interference
with daily activities and sleep in patients with moderate-to-severe
CIU, our study is somewhat limited in that the effect of rupatadine
was evaluated on a weekly basis, rather than on a daily basis in
the first week of treatment, and therefore does not allow a more
accurate evaluation of the onset of effect of rupatadine in this
study population cohort. Although measurement of interference with
daily activities and sleep were not the primary outcome measures,
our study is also slightly limited in this respect, because it does
not provide more details of the impact of CIU on the quality of
life of patients. However, the Dermatology Life Quality Index
(DLQI) [26, 27] was used in a recently completed phase III study
investigating the effect of rupatadine in moderate-to-severe CIU
patients. This study demonstrated that rupatadine 10 mg and
20 mg significantly decreased the DLQI scores in these
patients, compared with placebo, with greatest improvements noted
for daily activities and symptoms/feelings [28].
Conclusion
The current dose-finding study provides important information with
respect to use of rupatadine as a novel treatment option for CIU.
The study clearly shows that rupatadine 10 mg and 20 mg
provides rapid and long-lasting relief from pruritus, possibly the
most bothersome symptom of CIU, in affected individuals.
Importantly, from the patient’s perspective, rupatadine appears to
be a highly efficacious therapy that alleviates the symptoms of
their disease and the interference in daily activities and sleep,
associated with these symptoms. In particular, the information on
the effect of rupatadine on interference with sleep is important
because sleep problems have been shown to be associated with
impaired QoL in chronic illnesses such as clinical depression,
congestive heart failure, diabetes, asthma, hypertension, back
problems and arthritis [29]. In view of the dual antagonism of the
H1 and PAF receptors, rupatadine 10 mg is likely to
be equally, or possibly more, effective than some of the currently
available treatments and therefore indicated for the management of
patients with CIU.
Acknowledgements
The authors thank J.Uriach y Compañía (Barcelona, Spain) for
financial support for this study. This study was partially
supported by the National Scientific Research Program of the
Spanish Minister of Science and Technology.
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