Levocetirizine improves quality of life and

reduces costs in long-term management of

persistent allergic rhinitis
Claus Bachert, MD, PhD,a Jean Bousquet, MD, PhD,b G. Walter Canonica, MD,c Stephen
R. Durham, MA, MD, FRCP,d Ludger Klimek, MD, PhD,e Joaquim Mullol, MD, PhD,f Paul
B. Van Cauwenberge, MD, PhD,g Geneviève Van Hammée, PhD,h and the XPERT Study
Group Ghent and Braine L’Alleud, Belgium, Montpellier, France, Genoa, Italy, London, United
Kingdom, Wiesbaden and Heidelberg, Germany, and Barcelona, Spain

Background: Allergic Rhinitis and its Impact on Asthma in congestion, and nasal and ocular pruritus) over a period of 4
collaboration with the World Health Organization initiative weeks between levocetirizine 5 mg and placebo. Secondary
reclassified allergic rhinitis, like asthma, by duration and endpoints included similar evaluations at 1 week and 3, 4.5, and
severity. The Xyzal in Persistent Rhinitis Trial is the first large, 6 months, summary scores for a general health status
long-term clinical trial studying patients with persistent rhinitis questionnaire (Medical Outcomes Survey Short Form 36),
Rhinitis, sinusitis, and

as defined by Allergic Rhinitis and its Impact on Asthma. a pharmacoeconomic assessment, comorbidities, and a safety
ocular diseases

Objectives: Two primary objectives were defined: comparison evaluation.

of the Rhinoconjunctivitis Quality of Life Questionnaire overall Methods: The Xyzal in Persistent Rhinitis Trial was a 6-month
score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal double-blind, placebo-controlled, multicenter, multinational
trial in 551 patients. Adults with persistent rhinitis sensitized to
both grass pollen and house dust mite were randomized to
a receive levocetirizine 5 mg/d or placebo.
Member of the Allergic Rhinitis and its Impact on Asthma (ARIA) project,
Results: A total of 421 patients completed the full study.
chairman of the Ear, Nose, and Throat section and member of the executive
committee of the Deutsche Gesellschaft für Allergologie und Klinische Levocetirizine significantly improved both the
Immunologie, and Head of the Department of Oto-Rhino-Laryngology, Rhinoconjunctivitis Quality of Life Questionnaire overall score
University Hospital, Ghent; bARIA Chairman, Director of the Allergy and the Total 5 Symptoms Score from week 1 to 6 months (all
Clinic at the Pasteur Institute, Department of Allergy and Respiratory P values <.001). Medical Outcomes Survey Short Form 36
Diseases, University Hospital, and Director, Institut National de la Santé et summary scores were also improved in the levocetirizine group
de la Recherche Médicale Unit 454, Montpellier; cMember of ARIA, compared with the placebo group. Treatment cessation because
General Secretary of the World Allergy Organization, Chairman of the of lack of effect, comorbidities, and overall costs of disease, and
European Academy of Allergology and Clinical Immunology Continuing
comorbidities per working patient per month (V160.27 vs
Medical Education Council, Full Professor and Director of Allergy and
V108.18) were lower in the levocetirizine group.
Respiratory Diseases Clinic, Department of Internal Medicine, Genoa
University; dMember of ARIA, Professor of Allergy and Respiratory Conclusion: Levocetirizine was shown to improve quality of life
Medicine, Imperial College School of Medicine and Royal Brompton and and symptoms and to decrease the overall costs of the disease
Harefield Hospital NHS Trust, Faculty of Medicine, National Heart and over the 6-month treatment period. (J Allergy Clin Immunol
Lung Institute, London; eDirector of the Center for Rhinologie and 2004;114:838-44.)
Allergologie, Wiesbaden, and Professor of Special Rhinology,
Allergology, and Environmental Medicine at Ruprecht Karl University,
Key words: ARIA, persistent allergic rhinitis, health-related quality
Heidelberg; fHead of the Rhinology Unit, Ear, Nose, and Throat Department,
Unitat de Rinologia, Servei d’Otorhinolaryngology, Hospital Clinic, of life, levocetirizine, long-term therapy, pharmacoeconomics
Barcelona; gCochairman of Global Resources in Allergy (WAO) and ARIA
(WHO), President of the World Allergy Forum, and Full Professor of
Allergic rhinitis is a global health problem of increasing
Otorhinolaryngology, Speech Pathology, and Audiology, Ghent University
Hospital, Department of Oto-Rhino-Laryngology; and hSenior Specialist, prevalence, affecting between 10% and 40% of the world’s
Patient Reported Outcomes, Outcomes Research Department, UCB Pharma population.1,2 In some countries it is now approaching
Research and Development, Braine L’Alleud. epidemic proportions and is becoming a significant public
Supported by UCB Farchim, Chemin de Croix Blanche, Bulle, Switzerland. health concern.3 The cumulative symptoms of allergic
Disclosure of potential conflict of interest: Claus Bachert, Jean Bousquet, G.
Walter Canonica, Stephen R. Durham, Ludger Klimek, Joaquim Mullol, and
rhinitis can be troubling4 and may impair daily activities
Paul B. Van Cauwenberge are XPERT board members. Geneviève Van and sleep patterns, resulting in a significant effect on
Hammée is a UCB Pharma employee. patients’ health-related quality of life (HRQoL),5-7 learn-
UCB Pharma provided all trial medication (active and placebo) but had no ing, and psychomotor performance,8 and thereby in an
conclusive role in study design, data collection, and data presentation.
economic effect on society in terms of both direct and
Received for publication February 24, 2004; revised May 21, 2004; accepted
for publication May 24, 2004. indirect costs.9 Rhinitis is also associated with other
Available online August 9, 2004. conditions such as asthma, sinusitis, and otitis media.10-14
Reprint requests: Claus Bachert, MD, PhD, Department of Oto-Rhino- The Allergic Rhinitis and its Impact on Asthma (ARIA)
Laryngology, Ghent University Hospital, De Pintelaan 185, B-9000 project has developed the rhinitis disease classification and
Ghent, Belgium. E-mail: [email protected].
0091-6749/$30.00
management guidelines to supersede the previous impre-
Ó 2004 American Academy of Allergy, Asthma and Immunology cise seasonal and perennial categories. Persistent allergic
doi:10.1016/j.jaci.2004.05.070 rhinitis is defined by the presence of symptoms for more
838
J ALLERGY CLIN IMMUNOL Bachert et al 839
VOLUME 114, NUMBER 4

TABLE I. Study objectives*

Abbreviations used Visit 3 Visit 4 Visit 5 Visit 6 Visit 7
ARIA: Allergic Rhinitis and its Impact on Asthma
1 wk 4 wk 3 mo 4.5 mo 6 mo
HRQoL: Health-related quality of life
ITT: Intention to treat RQLQ overall score 2 1 2 2 2
RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire Mean T5SS 2 1 2 2 2
PER: Persistent rhinitis Individual rhinitis E E E E E
SF-36: Medical Outcomes Survey Short Form 36 symptoms
T5SS: Total 5 Symptom Score SF-36 physical and 2 2 2 2
XPERT: Xyzal in Persistent Rhinitis Trial mental summary scores
Rescue medication use (E) Measured over the whole duration of
the study
Safety of levocetirizine (2) Measured over the whole duration of
the study
than 4 days per week and for more than 4 weeks per year. Pharmacoeconomics (E) Measured over the whole duration of
Corollary, intermittent allergic rhinitis is defined by the the study
presence of symptoms lasting less than 4 days per week or
less than 4 weeks per year. 1, Primary objective; 2, secondary objective; E, exploratory objective.
*Visit 1, selection; visit 2, randomization (baseline); visit 8, follow-up visit.
Levocetirizine (XYZAL; UCB Pharma, Brussels,
Belgium) is a new oral, nonsedating H1-antihistamine

Rhinitis, sinusitis, and

that has been shown to be effective against allergic performed in 5 European countries (Belgium, France, Germany,

ocular diseases
symptoms while offering good tolerability,15-20 and was Italy, and Spain) as a multicenter, randomized, placebo-controlled,
therefore selected as the active treatment in this persistent double-blind, parallel group trial, designed to investigate several
rhinitis (PER) trial designed by an expert board, which related aspects of PER.
consists largely of ARIA members. The Xyzal in
Persistent Rhinitis Trial (XPERT) used a comprehensive Schedule and inclusion criteria
battery of clinical, HRQoL, and pharmacoeconomic At an initial assessment visit, male or female patients were
assessments, applied over the long term and using considered for inclusion if they were older than 18 years, with
electronic diary cards, where appropriate, to enhance data symptoms of rhinitis present during the pollen season and on house
capture. dust exposure (PER defined as rhinitis lasting 4 days or more per
There were 2 primary objectives for this study. The first week for 4 consecutive weeks or more per year). They also had to
was to compare the effects of levocetirizine and placebo show a positive skin test (wheal >3 mm larger than the diluent
on HRQoL, as measured by the change from baseline of control) or, if a skin test was not possible for a medical reason,
the Rhinoconjunctivitis Quality of Life Questionnaire specific serum IgE (CAP System, Pharmacia Diagnostic, Uppsala,
Sweden) for at least house dust mite and 1 pollen allergen (grass or
(RQLQ) overall score after 4 weeks of treatment. The
Parietaria, IgE level >3.5 U/mL).
second primary objective was to compare the mean Total Treatments were allocated to subjects by means of a randomization
5 Symptoms Score (T5SS; sum of rhinorrhea, sneezing, list prepared by UCB Pharma (blocks of 4).
nasal congestion, and nasal and ocular pruritus; score, Patients were enrolled at a randomization visit 1 week later if their
0-15), evaluated for 24 hours over a period of 4 weeks symptoms were sufficient—that is, showing a combined symptom
of treatment. T5SS >6 of 15 for at least 4 days during the run-in period. Subjects
Secondary objectives were to compare RQLQ overall were randomized to receive either levocetirizine 5 mg or placebo
score and symptom scores over periods of 1 week and 3, orally each evening, starting on the evening of the second visit and
4.5, and 6 months of treatment. Additional secondary continuing for 6 months thereafter. Additional criteria for enrollment
objectives were to compare the effects on health status as into this 6-month study were the ability to understand and complete
electronic diaries and questionnaires. All randomized patients were
measured by means of the Medical Outcomes Survey
assessed at the end of the first treatment week and again at weeks 4,
Short Form 36 (SF-36) questionnaire (physical and mental 12, 18, and 26 before leaving the study at week 27 after an additional
summary scores) over periods of 4 weeks, 3 months, 4.5 week’s follow-up (Table I).
months, and 6 months, and to compare the rescue
medication use over the 6-month treatment period and to Exclusion criteria
assess the overall safety of levocetirizine over the 6-month
Pregnant patients, nursing mothers, and women of childbearing
study period. age not using a medically accepted method of contraception were
The study also provided pharmacoeconomic data on the excluded, as were patients with an ear, nose, or throat or eye infection
treatment of PER. It is the first long-term (6-month) trial during the 2 weeks preceding the initial visit, and patients with
performed with an H1-antihistamine in PER and following asthma requiring daily treatment with other than an inhaled b-agonist
a large multicenter design involving more than 500 as needed. Patients were also excluded if, among other diseases, they
patients throughout 5 European countries. had atopic dermatitis or urticaria requiring antihistamine or cortico-
steroid treatment; an associated ear, nose, or throat disease such as
vasomotor rhinitis or nasal polyps; other clinically significant
METHODS diseases such as glaucoma or cardiovascular or hepatic diseases; or
This study was conducted according to an exacting protocol, any condition likely to disturb absorption, distribution, metabolism,
based largely on ARIA guidelines for rhinitis. The study was or excretion of the investigational drug.
 840 Bachert et al J ALLERGY CLIN IMMUNOL
OCTOBER 2004

Rescue medication TABLE II. Patient demographics

In cases of insufficient therapeutic response after at least 1 week of Placebo Levocetirizine Total
randomization and treatment, patients were permitted nasal or ocular (N = 273) 5 mg (N = 278) (N = 551)*
cromoglycate in amounts limited to the least needed. In addition, in
Age at randomization, y
case of unbearable worsening of the symptoms linked to allergic
Mean (SD) 30.8 (8.8) 29.8 (8.9) 30.3(8.9)
rhinitis, after a minimum of 4 weeks of treatment (ie, after visit 4),
Median 29.0 28.0 28.2
patients were permitted a maximum of 20 mg oral prednisolone once
Minimum-maximum 18.1-70.3 18.0-66.2 18.0-70.3
daily for 5 days, for a maximum of 2 prednisolone courses during the
Duration of PER 12.8 (8.2) 11.9 (7.8) 12.3 (8.0)
study. All rescue medication use was carefully recorded, and
before randomization,
compliance for both study and rescue medications was calculated at
y, mean (SD)
each visit, before dispensing new drug.
Sex, female 158 (57.9%) 152 (54.7%) 310 (56.3%)
Working status
Ethical aspects Working 196 (72%) 186 (67%) 382 (69%)
Informed consent was obtained from all participants, and the study Nonworking 77 (28%) 92 (33%) 169 (31%)
was conducted in accordance with good clinical practice (Committee *ITT population.
for Proprietary Medicinal Products/International Conference on
Harmonization/135/95) and the revised Helsinki Declaration of
1996, and with the permission of the respective institutional review tion, physician visits, and concomitant medications for investigated
boards. conditions. By using the World Health Organization adverse reaction
Rhinitis, sinusitis, and

terminology, the verbatims of the study were allocated to specific

ocular diseases

Assessment parameters conditions, before unblinding, to categorize PER and comorbidities

resources and events. Estimates for indirect cost parameters related to
Health-related quality of life is a significant parameter because it
PER or comorbidities—measured through a weekly questionnaire on
considers the effect of both illness and treatment on a patient’s life as
Minidoc—included absenteeism and presenteeism—that is, lost
perceived by the patient. Besides generic HRQoL questionnaires,
productivity while present at work. Because the greatest number of
disease-specific instruments can be used, which are often more
patients was recruited in France, a societal French costing model
sensitive.21,22
based on medication costs, additional physician visit costs, and costs
The RQLQ is a disease-specific, validated, and reproducible
of productivity loss at work was thereafter applied to determine PER
instrument for evaluating HRQoL on the basis of how symptoms and
and comorbidity-related costs in each treatment group for working
treatments affect each patient’s physical, social, and emotional well-
patients. All cost figures used were drawn from national official tariff
being.23 It includes 28 items related to 7 domains. All of the items are
and statistical sources.
averaged in an overall score ranging from 0 (no trouble) to 6 (major
impairment). The RQLQ was completed by each subject at the start of Statistical methods
visit 2 (randomization), and then at visits 3 to 7, or at the end of the
study treatment in case of withdrawal (Table I). Patients were recruited in a total of 63 centers, with each center
The second instrument (SF-36) is a well-validated questionnaire to designed to provide 8 to 16 randomized subjects for a total sample
measure health status. The SF-36 is a generic measure—that is, it size of 500-plus. The primary efficacy analyses were based on the
does not target a specific age, disease, or treatment group. As such, the intention to treat (ITT) population by using the analysis of covariance
SF-36 has been widely used to assess the relative burden of various method, with treatment and countries as factors and baseline values as
diseases, including allergic rhinitis,24 and to compare the effects of the covariate. Treatment effects were tested on an a level of 5%. No
different treatments. Across 36 questions, it measures 8 health adjustment of the significance level was necessary because a signif-
dimensions domains condensed into 2 physical and mental icant result on both primary endpoints was required to have a positive
health summary measures, with scores ranging from 0 (worst reported study. RQLQ data were interpreted on the basis of a within-group
health status) to 100 (best reported health status).25 At each visit, minimal important difference figure of 0.5.26 There are various
except visit 3 (week 1), the SF-36 was completed by patients suggestions for between-group minimal important difference figures.
immediately after the RQLQ. In this study, the XPERT board agreed on a 30% difference to placebo
Rhinitis symptoms were assessed by using the T5SS. This total as clinically meaningful before unblinding. The sample size of 500
symptom score measures not only the typical symptoms normally patients allowed the detection of a treatment difference of 1.0 for the
responding to antihistamines, such as rhinorrhea, sneezing, and nasal T5SS and of 0.36 in the change from baseline for the RQLQ overall
and ocular pruritus, but also nasal congestion, which is, in practice, 1 score (corresponding to a 40% improvement over placebo, assuming
of the most bothersome symptoms for patients with allergic rhinitis. an improvement from baseline for placebo of 0.9) with a 2-sided
Rhinitis symptoms were evaluated each day of the study by means of significance level of 5% and a power of 85%. The bootstrap analysis
the electronic diary by using a 4-point scale from 0 (absent) to 3 was used for cost data.27
(severe) for each symptom (Minidoc; Arracel, Sittingbourne, United UCB Pharma clinical trials operations monitored the trial and
Kingdom). The use of electronic diaries promotes and monitors the helped in conducting the statistical analyses.
daily recording of symptoms, thanks to alarm clock reminders for
completion and prompts for missing data, thus avoiding the parking RESULTS
lot retrospective guesswork that is often involved in completion of
a backlog of paper forms just before a clinic visit.
Pharmacoeconomic investigations included estimates for direct The study randomization started in April 2001 and
medical cost and indirect cost parameters in the working population ended in October 2001. A total of 724 patients were
(69%) related to PER and to comorbidities including asthma, screened at the initial visit, of whom 551 patients were
sinusitis, otitis media, and upper respiratory infections. The direct randomized and received 1 or other study medication. This
costs consisted of the use of medical resources such as hospitaliza- yielded an ITT population of 551 study subjects, 273 of
J ALLERGY CLIN IMMUNOL Bachert et al 841
VOLUME 114, NUMBER 4

TABLE III. T5SS and RQLQ overall score at 4 weeks

Baseline After 4 weeks of treatment Difference vs placebo (95% CI)
Treatment group N* Mean (SD) Adjusted mean (SE)  Adjusted mean P value

RQLQ overall score

Placebo 252 3.06 (0.94) 21.01 (0.07)
Levocetirizine 5 mg 257 3.04 (0.92) 21.49 (0.07) 0.48 (0.29-0.67) <.001
T5SS
Placebo 271 8.90 (2.26) 22.40 (0.15)
Levocetirizine 5 mg 276 9.02 (2.28) 23.54 (0.15) 1.14 (0.75-1.52) <.001

*Number of ITT patients with nonmissing values at baseline and under treatment.
 Mean change from baseline, adjusted for baseline score and country.

whom were randomized to receive placebo and 278 to group. Statistically significant differences were observed
receive the study drug. All patients were sensitized to between levocetirizine and placebo mean changes after 3
house dust mite and pollen. Further demographic details and 4.5 months for the mental component summary score
are shown in Table II. (both P values <.01) and after 4 weeks and 3, 4.5, and 6
Overall, 76.4% of patients completed the 6-month months for the physical component summary score (all

Rhinitis, sinusitis, and

study treatment (80.9% levocetirizine and 71.8% placebo, P values <.01). Similar to the RQLQ overall score,

ocular diseases
which is commendable considering the size and duration improvement in the self-perceived health condition ap-
of this allergy trial). Forty-five patients in the placebo peared linked to symptom relief.
group (16.5%) dropped out because of lack of efficacy,
compared with 21 (7.6%) in the levocetirizine group Symptom relief
(P = .0007 for the Wilcoxon test on the time to discontin- As with the overall RQLQ score, there was a statistically
uation for lack of efficacy). Further explanations included significant difference in the change from baseline of the
withdrawal of consent for personal reasons (15, 5.5% mean T5SS over a period of 4 weeks in favor of
placebo; 17, 6.1% levocetirizine), adverse events (8, 2.9% levocetirizine versus placebo (–3.54 vs –2.40), which
placebo; 11, 4.0% levocetirizine) and other justifications equates to an adjusted mean difference of 1.14 (P < .001;
(8, 2.9% placebo; 4, 1.4% levocetirizine). One placebo Fig 1). The difference between the 2 arms of the study was
patient was lost to follow-up. itself larger than the minimum clinically relevant differ-
ence versus placebo of 1 that was prespecified by the board
HRQoL of experts. There was a statistically significant difference
The results for HRQoL as measured by the disease- for the individual symptoms rhinorrhea, sneezing, and
specific RQLQ overall score at 4 weeks are shown in nasal and ocular pruritus over a period of 4 weeks of
Table III. There was a larger decrease in RQLQ overall treatment (all P values <.001; Fig 1).
score for levocetirizine compared with placebo (indicating Improvements for overall and individual scores were all
a more important improvement in HRQoL). The adjusted maintained steady for the entire duration of the 6-month
mean reduction for levocetirizine was 1.49 over a period treatment period, and with the exception of nasal conges-
of 4 weeks (P < .001), giving an adjusted mean difference tion, which did not improve significantly before 3 months
versus placebo of 0.48 (95% CI, 0.29-0.67). This differ- of treatment, the difference was apparent and statistically
ence (47.5% improvement over placebo), which exceeded significant as early as 1 week after the start of the
the predefined minimum clinically meaningful percentage treatment. Over the period of the first 4 weeks, cromogly-
for between-group comparison, is consistent with a signif- cates (both nasal and ocular) were more frequently used in
icant reduction in symptom severity. In addition, the the placebo group (62.6% of the placebo patients vs 49.3%
difference in mean reductions remained statistically of the levocetirizine patients; P = .002). Over the period of
significant in favor of levocetirizine for the entire 6 the entire 6 months, a trend for more rescue medication use
months of the study period, and was also apparent as in the placebo group was observed for prednisolone
early as week 1 (P < .001). Improvement of the overall (13.6% vs 10.8%; P = .362) and for cromoglycates
score in favor of levocetirizine compared with placebo (75.8% vs 69.4%; P = .104).
was confirmed for each RQLQ domain (all P values
<.001 at 4 weeks; Table IV). The physical and mental Pharmacoeconomic assessments
component summary scores of the SF-36 followed The incidence of all comorbidity events combined over
a similar course, with a larger improvement for levocetir- the evaluation period was lower in the levocetirizine group
izine group than for placebo at each time point. In the than in the placebo group (54 vs 71 events per 100
levocetirizine group, mean changes from baseline of the patients). The most frequent comorbidities were upper
physical and mental summary scores ranged from 3.65 to respiratory infections (116 events in the levocetirizine
5 and from 3.83 to 5.97, respectively, whereas they ranged group and 143 events in the placebo group) and asthma
from 1.61 to 3.37 and from 2.79 to 3.99 in the placebo (respectively, 20 and 35 events). The absenteeism and
 842 Bachert et al J ALLERGY CLIN IMMUNOL
OCTOBER 2004
Rhinitis, sinusitis, and
ocular diseases

FIG 1. Change in individual symptom scores over a period of 6 months (ITT population).

TABLE IV. Change from baseline of the RQLQ domains at 4 weeks

Placebo change Levocetirizine 5 mg change Difference vs placebo (95% CI)
Domain N* Adjusted mean  (SE) N* Adjusted mean  (SE) Adjusted mean P value

Activities 241 21.36 (0.10) 248 22.08 (0.10) 0.73 (0.47-0.99) <.001
Emotions 252 20.81 (0.07) 257 21.16 (0.07) 0.35 (0.17-0.54) <.001
Eye symptoms 252 20.91 (0.09) 257 21.40 (0.09) 0.48 (0.26-0.70) <.001
Non–hay fever symptoms 252 20.83 (0.08) 257 21.21 (0.08) 0.38 (0.18-0.57) <.001
Nasal symptoms 252 21.10 (0.09) 257 21.64 (0.09) 0.54 (0.31-0.77) <.001
Practical problems 252 21.50 (0.10) 257 22.06 (0.10) 0.56 (0.30-0.82) <.001
Sleep 252 20.86 (0.09) 257 21.35 (0.09) 0.50 (0.27-0.73) <.001

*Number of ITT patients with nonmissing values at baseline and under treatment.
 Mean change from baseline, adjusted for baseline score and country.

presenteeism, expressed in days per month per patient, (69.1%) in the levocetirizine group reported at least 1
were lower in the levocetirizine group (0.18 vs 0.45 days adverse event at some point during the 6-month study. The
in absenteeism and 0.70 vs 1.1 days in presenteeism). No most common adverse events were headache (23.2%
hospitalization was reported. placebo vs 24.5% levocetirizine), pharyngitis (20.5%
After applying a French societal costing model to levo- and 19.8%, respectively), influenza-like symptoms
cetirizine and placebo group outcomes, the combined (13.9% vs 14.0%), fatigue (7.0% vs 8.6%), somnolence
direct cost (including levocetirizine costs) and indirect (1.8% vs 6.8%), and gastroenteritis (5.1% vs 2.9%).
cost categories for PER and comorbidity were 160.27V
per working patient per month for the placebo group and DISCUSSION
33% lower for the levocetirizine group at 108.18V per
working patient per month (P = .008). Table V shows Following the recent ARIA initiative, this study
detailed costs by treatment group. attempts to provide a benchmark for future rhinitis trials,
both in terms of definition of allergic rhinitis, its size (over
Adverse events 550 patients), its comprehensive study design (validated
Levocetirizine appeared to be safe and well tolerated, HRQoL and health status measures, symptom scores,
particularly considering the length of the treatment. In the electronic diary capture), and its exceptional duration (26-
placebo group, 193 (70.7%) patients, compared with 192 week treatment phase). Under the formerly used rhinitis
J ALLERGY CLIN IMMUNOL Bachert et al 843
VOLUME 114, NUMBER 4

TABLE V. Mean direct and indirect costs per month per working patient
Placebo mean V Levocetirizine 5 mg Difference
(95% CI) (N = 196) mean V (95% CI)(N = 186) vs placebo P value

Direct costs
Total direct medical 5.32V (4.43, 6.42) 16.81V (15.94, 18.13) 11.50V (10.06, 13.03) <.001
costs for PER
Total direct medical 2.72V (1.82, 4.20) 1.77V (1.14, 3.04) 20.96V (22.60, 0.40) .18
costs for comorbidities
Indirect costs
Absenteeism 45.70V (32.02, 75.00) 18.57V (13.75, 26.00) 227.14V (255.78, 212.10) <.001
Presenteeism 106.54V (86.97, 132.86) 71.04V (56.16, 92.43) 235.50V (265.21, 27.01) .02
Total costs 160.27V (129.93, 204.54) 108.18V (91.55, 131.78) 252.09V (298.18, 213.26) .01

classification system, seasonal rhinitis studies typically of treatment in the placebo group vs 3.72 days per 100
lasted 2 weeks and perennial rhinitis trials normally days of treatment in the levocetirizine group). The mean
4 weeks. Because it was large and lasted 6 months, the duration of sedating events per subject was longer in the
XPERT study clearly offers more meaningful and in- placebo group (42.26 days per 100 days of treatment)
herently more credible insights into the management of than in the levocetirizine group (25.31 days per 100 days

Rhinitis, sinusitis, and

PER and its frequently debilitating symptoms. The of treatment).

ocular diseases
concept of minimal persistent inflammation implies that Health-related quality of life was not altered by the
although patients with persistent allergic rhinitis have somnolence rate observed in the levocetirizine group, as
varying allergen exposure throughout the year, even indicated by the larger improvement reported in this group
during periods when they might be symptom-free, these at all time points for the RQLQ overall score. More
patients can still have inflammation in the nose.28 For such specifically, the RQLQ domain including items such as
patients, long-term therapy might be desirable if it fatigue or tiredness (ie, the nonhayfever symptoms
successfully improves symptoms that significantly de- domain) also showed a larger improvement in the
grade their perceived HRQoL and their productivity in levocetirizine group than in the placebo group.
society, as investigated in this study. The advantages of This study seems to support the correctness of the
a long-term and continuous therapy with antihistamines ARIA classification and validates the concept of persistent
have been formerly demonstrated in children, in whom disease in a distinct and numerically large subset of rhinitis
a 6-month treatment was able to reduce both rhinitis and patients, who have symptoms sufficiently to impair their
comorbid diseases.29 quality of life both in season and out of season. In such
As far as levocetirizine itself is concerned, it appears to patients, effective long-term treatment results in an
be effective over extended periods, and most of the equally persistent improvement in quality of life and
benefits are maintained for as long as therapy is continued. health status as measured by 2 reliable instruments, 1
Furthermore, statistically significant relief was available specifically tailored to measure the effect of allergic
within a week for almost all of the cardinal symptoms. rhinitis (RQLQ) and 1 generic and allowing comparison
Even nasal congestion—in which reversal of established with other diseases (SF-36). Thus, the symptom scores tie
mucosal inflammation is required and traditional antihist- in with the HRQoL results, insofar as placebo patients
amines are acknowledged to be less effective—was continued to have heavier symptoms and to report poorer
eventually brought under control. It is not clear why this HRQoL compared with patients receiving levocetirizine,
particular aspect of relief took about 3 months to develop, with the benefits of active therapy maintained for as long
but it may be a result of a longer-term anti-inflammatory as the treatment was given.
action of levocetirizine. In terms of adverse events, for the Effective long-term treatment with levocetirizine also
most part, levocetirizine appeared to give rise to a number appears to deliver an overall reduced disease burden in
and type of events similar to placebo with the exception of terms of overall costs (direct and indirect costs) for PER
a higher, though still low, incidence of somnolence. At itself and associated comorbidities. Because most patients
first sight, many adverse events in both arms seemed to in this study were recruited in France, a specific societal
occur in greater absolute percentages of patients than French costing model was used to estimate direct medical
might be anticipated. However, most of this excess can be costs (drug costs, intervention costs) and indirect costs
explained by the exceptionally long duration of the study, (work productivity losses) by using official drug/physi-
with the probability of having an adverse event obviously cian pricing and average earnings statistics. Therefore,
higher in a 6-month study compared with a study of 2 to although the specific cost savings determined may vary
4 weeks. between countries, as may the figure of an overall 33%
Further analyses revealed that the relative duration reduction in disease costs with active treatment, it seems
of sedating events (adverse events reported as being likely that effective therapy of PER will produce monetary
‘‘fatigue,’’ ‘‘asthenia,’’ or ‘‘somnolence’’) in the ITT pop- benefits for the society. As expected from the HRQoL
ulation was similar in the 2 groups (3.26 days per 100 days results, the levocetirizine group scored more favorably in
 844 Bachert et al J ALLERGY CLIN IMMUNOL
OCTOBER 2004

pharmacoeconomic parameters, translating the improved 15. Leynadier F, Mees K, Arendt C, Pinelli ME. Efficacy and safety of
levocetirizine in seasonal allergic rhinitis. Acta Otorhinolarygol Belg
well-being into practical socioeconomic benefits.
2001;55:305-12.
Levocetirizine appears to be a rapidly and sustainably 16. Clough GF, Boutsiouki P, Church MK. Comparison of the effects of
effective antihistamine for the treatment of PER and levocetirizine and loratadine on histamine-induced wheal, flare, and itch
provides statistically significant and clinically meaningful in human skin. Allergy 2001;56:985-8.
improvements of symptom scores, overall HRQoL, and 17. Devalia JL, De Vos C, Hanotte F, Baltes E. A randomized, double-blind,
crossover comparison among cetirizine, levocetirizine, and ucb 28557 on
pharmacoeconomic criteria, which are some of the key histamine-induced cutaneous responses in healthy adult volunteers.
criteria for the successful treatment of a chronic disease. Allergy 2001;56:50-7.
18. Gandon JM, Allain H. Lack of effect of single and repeated doses of
We thank Anne Danniau and Liesbeth Verstreken for their role in
levocetirizine, a new antihistamine drug, on cognitive and psychomotor
statistical analysis and Nadia Demarteau for the pharmacoeconomic
functions in healthy volunteers. Br J Clin Pharmacol 2002;54:51-8.
analysis. Help from the UCB Clinical Operations team in recruiting 19. Grant JA, Riethuisen JM, Moulaert B, DeVos C. A double-blind
the patients in a timely manner was appreciated. randomised single-dose, crossover comparison of levocetrirzine with
ebastine, fexofenadine, loratadine, mizolastine and placebo: suppression
of histamine-induced wheal-and-flare response during 24 hours in
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