Allergy 2003: 58: 893–899
`Printed in UK. All rights reserved
`
`Original article
`
`Copyright Ó Blackwell Munksgaard 2003
`ALLERGY
`ISSN 0105-4538
`
`Levocetirizine is effective for symptom relief including nasal
`congestion in adolescent and adult (PAR) sensitized to house dust
`mites
`
`Background: Antihistamines are the most commonly prescribed class of medi-
`cation for perennial allergic rhinitis (PAR). The primary objective of this study
`was to determine whether levocetirizine (XyzalÒ), the active enantiomer of
`cetirizine, could achieve at least a 50% improvement in PAR symptoms
`compared to the placebo over the first week of treatment.
`Methods: A total of 294 patients with PAR due to house dust mites were
`randomized in this 8-week double-blind, placebo-controlled, multicentre trial to
`receive either levocetirizine 5 mg/day or placebo. Mean Total Four-Symptom
`Scores (T4SS) (nasal pruritus, ocular pruritus, rhinorrhoea and sneezing) were
`compared between treatment groups over weeks 1, 4 and 6. All individual
`symptom scores, including nasal congestion, were also studied.
`Results: Levocetirizine showed an 86% improvement in T4SS over the first week
`of treatment and a 47% improvement over the entire treatment period compared
`with placebo. Absolute changes from baseline were 3.64 and 2.47 for levocetir-
`izine and placebo, respectively. Individual symptom scores showed statistically
`significant (P £ 0.01) differences in favour of levocetirizine for all study time-
`points. Nasal congestion was unexpectedly significantly improved (P < 0.001).
`The incidence of reported adverse events was comparable between treatment and
`placebo group.
`Conclusions: Levocetirizine 5 mg/day is an effective and well-tolerated treatment
`of PAR. In addition, levocetirizine is effective for the relief of nasal congestio.
`
`P. C. Potter, on behalf of the Study
`Group*
`Allergology Unit, Groote Schuur Hospital, Cape
`Town, South Africa
`
`Key words: allergic rhinitis; antihistamine;
`levocetirizine; nasal congestion.
`
`Prof. P. C. Potter, MD
`Allergy Diagnosis and Clinical Research Unit
`UCT Lung Institute, PO Box 34560
`Groote Schuur 7937, South Africa
`
`Accepted for publication 12 February 2003
`
`Perennial allergic rhinitis (PAR) is a chronic condition
`that affects up to 20% of the population in the USA (1, 2)
`and in Europe (3), and the prevalence is increasing. The
`patients display a variety of symptoms that usually
`include nasal pruritus, ocular pruritus,
`rhinorrhoea
`sneezing and nasal congestion. The condition causes a
`significant reduction in the quality of life of sufferers
`including impaired sleep, concentration and social inter-
`action (4). Moreover, the economic impact in terms of
`loss of work time and decreased employee activity is also
`evident (5).
`Antihistamines are the most commonly prescribed class
`of medication for allergic rhinitis (6). They are effective in
`preventing and relieving sneezing, rhinorrhoea, nasal and
`ocular pruritus but unlike corticosteroids and decongest-
`ants they are less effective in treating nasal congestion
`(7–9). Recently however, desloratadine demonstrated an
`activity on the symptoms of nasal congestion (10).
`
`*The names of the investigators are given in the ÔAcknowledgmentsÕ
`section.
`
`Cetirizine, an effective H1-receptor antagonist,
`is a
`levocetirizine (R-enantio-
`mixture of two enantiomers:
`mer) and dextrocetirizine (S-enantiomer). Cetirizine has
`been shown to be effective in relieving the symptoms of
`allergic rhinitis and also significantly reduces the hista-
`mine-induced weal and flare reaction (11, 12). Further
`studies have revealed that
`it
`is
`levocetirizine,
`the
`R-enantiomer, that accounts for cetirizine’s affinity to
`the H1 receptors (13, 14).
`The objective of this study was to investigate the
`efficacy and safety of levocetirizine (XyzalÒ) 5 mg in
`adolescent and adult patients with PAR.
`
`Methods
`
`This was an 8-week randomized, double-blind, placebo-controlled,
`multicentre study that took place in South Africa. Patients with
`PAR ‡12 years of age, who had been sensitized to house dust mites
`as determined by a positive skin prick test or a radioallergosorbent
`test (RAST), were recruited from 26 centres during the winter
`months of 2000.
`
`893
`
`Apotex, Inc. (IPR2019-00400), Ex. 1009, p. 001
`
`

`

`Potter
`
`Selection of patients was based on a positive skin test (2+) or
`RAST (>class 3 or 23.5 IU/ml) to house dust mites, dating less
`than 1 year before inclusion in the study. If these tests were not
`available, a skin prick test was to be performed at visit 1. Based on
`anamnesis, patients with seasonal allergic rhinitis that was likely to
`result in significant changes in the subject’s symptoms during the
`study, were excluded.
`Patients with an ear, nose and throat (ENT) infection during the
`2 weeks preceding the first study visit; asthma requiring daily
`therapy; atopic dermatitis or urticaria treated with antihistamine or
`corticosteroids; vasomotor rhinitis; rhinitis medicamentosa or other
`debilitating conditions, were excluded.
`
`Study sequence
`
`Patients attended the investigator’s site for a total of six visits during
`the total 8-week study period.
`Patients entered a run-in period prior to the randomization visit,
`during which they recorded the frequency of their symptoms of
`nasal pruritus, ocular pruritus, rhinorrhoea, sneezing and nasal
`congestion on diary cards. Patients were provided with a ques-
`tionnaire to evaluate the severity of their symptoms on a scale
`ranging from 0 (absent) to 3 (severe, hampering daytime activities
`and/or sleep). The results obtained from the diary cards and ques-
`tionnaires provided the Total Four-Symptom Score (T4SS). The
`mean T4SS was defined as the sum of scores of nasal pruritus,
`ocular pruritus, rhinorrhoea and sneezing. Only patients with a
`mean T4SS ‡ 5 Units were assigned by randomization into the
`study. The severity of symptom scores for nasal congestion was not
`included in the T4SS scale but was measured separately.
`Prohibited treatments prior to visit 1 and also at any time during
`the study (i.e. from visit 1 to visit 5) included: astemizole, systemic
`or topical corticosteroids, ketotifene, cromoglycate, topical H1
`antihistamines, decongestants (oral, nasal spray or drops), desen-
`sitization in the ascending phase, nasal or ocular topical treatment,
`asthma treatments other than beta 2 agonists.
`Patients were randomized to receive either levocetirizine 5 mg or
`placebo once daily at bedtime. From visits 2–5, patients continued
`to complete the T4SS questionnaire on daily diary cards (Fig. 1).
`Individual scores were recorded prior to taking the medication and
`were to reflect the condition over the previous 24-h period. At visit
`5, patients provided a global evaluation of efficacy on a four-point
`scale: ÔWorsening of SymptomsÕ, ÔNo ChangeÕ, ÔSlight to Moderate
`ImprovementÕ and ÔGood to Excellent ImprovementÕ.
`Patient follow-up was conducted at the final visit (visit 6), 1 week
`after visit 5. This visit was used to assess patientsÕ status after study
`drug discontinuation (Fig. 1). Adverse events (AEs) were collected
`during visits 2–6; blood samples were taken at visits 1 and 5 and
`electrocardiogram (ECG) examinations were performed at visits 1
`and 3.
`
`Primary and secondary objectives
`
`The study was to be considered positive if two criteria were met: first,
`levocetirizine 5 mg had to be statistically superior (alpha error of 5%,
`two-sided) to placebo over the first week and over 4 weeks of treat-
`ment. Second, the point estimate of the treatment difference between
`levocetirizine 5 mg and placebo over the first week of treatment
`had to show a relative improvement from baseline over placebo of
`at least 50%. This relative improvement defined the clinical rele-
`vance of study results knowing that the placebo effect is generally
`important in allergic rhinitis trials, and symptom relief should be
`fast to be perceived as a significant improvement by the patient.
`The secondary efficacy variables were as follows: mean T4SS
`scores over the total 6-week treatment period, over weeks 2–6 of
`study treatment; mean individual symptom scores (nasal pruritus,
`ocular pruritus, rhinorrhoea, and sneezing) during week 1, the first
`4 weeks and over the total treatment period. The diary card and
`questionnaire mean scores for nasal congestion were also measured
`alongside each of the secondary variables.
`
`Statistical analysis
`
`Descriptive statistics were used to summarize baseline character-
`istics by treatment group. The primary and secondary efficacy
`variables were analysed using an analysis of covariance (AN-
`COVA) model that included the mean baseline as covariate with
`treatment and study centre as factors. Global evaluation scores
`were analysed using the Cochrane–Mantel–Haenszel test based on
`ranks. All statistical tests were two-tailed at the 5% level of
`significance.
`It was calculated that a minimum of 125 patients per group was
`required (alpha error ¼ 5%). Statistical analyses were performed on
`both the intention-to-treat (ITT) and per-protocol (PP, i.e. a subset
`of the ITT population consisting of those subjects who did not have
`any major protocol deviation) populations, in order to assess the
`impact of any possible protocol violations on the results of the
`study. The relative difference between the two groups was calculated
`as follows:
`
`100  ð[change from baseline levocetirizine/change
`from baseline placebo) 1Š:
`
`Study supplies were identical in appearance. They were provided
`to investigators together with coded envelopes and clear handling
`instructions in case of emergency.
`The study was performed in accordance with the International
`Conference on Harmonization (ICH) Note for Guidance on Good
`Clinical Practice, the Declaration of Helsinki (Somerset West,
`Republic of South Africa Revision, 1996), and approved by the
`Ethics and Research Committee of the University of Cape Town.
`
`Selection
`
`Treatment
`
`Treatment
`
`Treatment
`
`After
`treatment
`
`1 week
`
`2 weeks
`
`2 weeks
`
`2 weeks
`
`1 week
`
`Results
`
`Levocetirizine 5 mg
`or placebo
`
`➟
`➟
`Visit 1 Visit 2
`Initial
`Randomisation
`visit
`visit
`
`➟
`Visit 3
`Control visit
`
`➟
`Visit 4
`Control
`visit
`
`➟
`Visit 5
`End of
`treatment
`visit
`
`➟
`Visit 6
`Final
`visit
`
`Figure 1. Schematic diagram of the study.
`
`Of the 368 patients enrolled into the study, a total of 294
`were randomized to receive either levocetirizine 5 mg
`once daily at bedtime (n ¼ 150) or placebo (n ¼ 144).
`Eighteen patients prematurely withdrew from the study
`(levocetirizine: 5 [3.3%]; placebo: 13 [9.3%]), and of these
`patients 10 withdrew due to lack of efficacy (levocetiri-
`zine: 2 [1.3%]; placebo: 8 [5.6%]. A patient flow diagram
`is shown in Fig. 2.
`
`894
`
`Apotex, Inc. (IPR2019-00400), Ex. 1009, p. 002
`
`

`

`Screened subjects
`n = 368
`
`Randomized
`subjects
`ITT population
`n = 294
`
`Screening failures
`n = 74
`
`ITT population
`n = 294
`
`PP population
`n = 251
`
`Major protocol
`deviations
`n = 43
`
`Placebo
`n = 120
`
`Levocetirizine
`n = 131
`
`Placebo
`n = 144
`
`Levocetirizine
`n = 150
`
`Completed
`(n = 131)
`Prematurely
`discontinued
`(n = 13)
`
`Completed
`(n = 145)
`Prematurely
`discontinued
`(n = 5)
`
`Figure 2. Patient flow diagram.
`
`A total of 43 patients (14.6%) were excluded from the
`ITT population due to major protocol deviations and
`composed the PP population.
`The main causes of protocol deviations during the
`study were the use of prohibited concomitant medications
`(15.0%); that occurred twice as often in the placebo
`group compared with the levocetirizine group (20.1 vs
`10.0%, respectively).
`Patient demographics at baseline were comparable
`between both treatment groups and are presented in
`Table 1. The mean daily compliance (number of tablets
`effectively taken over number of
`tablets that were
`supposed to be taken) was 98.5% for the overall
`treatment period.
`
`Efficacy
`
`The mean T4SS at baseline were comparable between the
`two treatment groups (levocetirizine: 7.69 ± 1.82; pla-
`cebo: 7.44 ± 1.80). The results of inferential ANCOVA
`analysis of T4SS by treatment group and treatment
`period are shown in Table 2. The difference between both
`groups at each treatment period showed a statistically
`significant T4SS decrease in favour of the levocetirizine
`group compared with the placebo group (week 1 and first
`4 weeks, P < 0.001; total 6-week period, P < 0.001).
`The relative improvement in the levocetirizine group
`during week 1 of
`treatment was 86%. The relative
`improvements from baseline over placebo in the levoce-
`tirizine group during the first 4 weeks and during the total
`6-week period were 56 and 47%, respectively. Statistical
`analyses were also performed on the PP population for
`the primary endpoints and these revealed similar results
`as shown for the ITT population (57% relative improve-
`ment over 4 weeks).
`The individual symptom scores after the first week of
`study treatment are presented in Table 3. These results
`show significant improvements for levocetirizine com-
`
`Levocetirizine treatment in perennial allergic rhinitis
`
`Table 1. Patient demographic characteristics (ITT population)
`
`Demographic feature
`
`Gender
`Female
`Male
`Ethnic origin
`White/Caucasian:
`Other/mixed race:
`Asian/Pacific Islander
`Black/African-American
`Age (years)
`Mean € SD
`Median
`Min–max
`Baseline T4SS (Units):
`Mean € SD
`Median
`Min–max
`
`Placebo
`(n ¼ 144)
`
`Levocetirizine 5 mg
`(n ¼ 150)
`
`80 (55.6%)
`64 (44.4%)
`
`98 (68.1%)
`24 (16.7%)
`20 (13.9%)
`2 (1.4%)
`
`28.76 € 13.27
`25.3
`12.6–69.6
`
`7.47 € 1.80
`7.3
`2.7–11.6
`
`88 (58.7%)
`62 (41.3%)
`
`102 (68.0%)
`26 (17.3%)
`19 (12.7%)
`3 (2.0%)
`
`29.18 € 12.61
`26.6
`12.3–1.4
`
`7.69 € 1.82
`7.3
`4.5–12.0
`
`individual
`
`symptoms
`
`pared with placebo for all
`(P < 0.01).
`Interestingly, nasal congestion symptom was also
`significantly reduced in the levocetirizine group compared
`with the placebo group over all treatment period (week 1:
`0.17 vs 0.43, P ¼ 0.002; first 4 weeks: 0.27 vs 0.55,
`P < 0.001;
`total 6 weeks: 0.32 vs 0.59, P < 0.001)
`(Fig. 4). Nasal congestion relative improvement over
`the 6 weeks of treatment was 83%.
`The results from the global evaluation, which took
`place at the follow-up visit (Visit 6), showed improve-
`ments in favour of levocetirizine compared with placebo
`(ÔSlight to Moderate ImprovementÕ ¼ 36% (54/150) vs
`41% (59/144); ÔGood to Excellent ImprovementÕ: 41.3%
`(62/150) vs 22.9% (33/144)).
`
`Safety
`
`The mean duration of treatment was 41.9 days in the
`levocetirizine group and 40.0 days in the placebo group.
`Overall, 63.9% (188/294) of patients experienced at least
`one AE (levocetirizine, 60.0% (90/150); placebo, 68.1%
`(98/144)). The most frequently reported AEs for both
`levocetirizine and placebo groups, respectively, included
`headache (34.7 vs 34.7%), influenza-like symptoms (16.7
`vs 13.9%) and upper respiratory tract infections (6.7 vs
`9.0%) (Table 4).
`The most common AEs that were judged related to
`study treatment were headache and somnolence. One
`patient experienced an increase in serum glutamic pyruvic
`transaminase (SGPT) that was considered to be drug-
`related but this resolved spontaneously after 9 days.
`A total of three serious AEs occurred but these were not
`considered to be related to study treatment.
`The frequency distribution of
`the QTc values at
`baseline and after treatment showed normal QTc inter-
`vals in both treatment groups. No cases of borderline or
`
`895
`
`Apotex, Inc. (IPR2019-00400), Ex. 1009, p. 003
`
`

`

`Potter
`
`Table 2. ANCOVA results for mean T4SS by treatment period (ITT population)
`
`Treatment period
`
`Week 1
`
`First 4 weeks
`
`Total 6 weeks
`
`Treatment
`group
`
`Placebo
`LCTZ 5 mg
`Placebo
`LCTZ 5 mg
`Placebo
`LCTZ 5 mg
`
`n
`
`142
`150
`142
`150
`142
`150
`
`Mean*
`(SE)
`
`6.16 (0.193)
`4.94 (0.185)
`5.39 (0.183)
`4.17 (0.176)
`5.10 (0.185)
`3.93 (0.177)
`
`Change from
`baseline adjusted
`mean
`
`Difference vs
`placebo
`(95% CI)
`
`1.41
`2.63
`2.18
`3.40
`2.47
`3.64
`
`1.22 (0.73; 1.71)
`
`1.22 (0.76; 1.69)
`
`1.17 (0.70; 1.64)
`
`P value 
`
`<0.001
`
`<0.001
`
`<0.001
`
`Relative
`improvementà (%)
`
`86
`
`56
`
`47
`
`ANCOVA, analysis of covariance; LCTZ, levocetirizine. * Mean adjusted for baseline score and centre.   P value obtained from an ANCOVA with baseline score as covariate,
`centre and treatment as factors. à Relative improvement with respect to placebo.
`
`Individual symptom scores after the first week of treatment (ITT popula-
`
`Table 3.
`tion)
`
`Table 4. Adverse events with an occurrence of ‡5% in either treatment group (ITT
`population)
`
`Change from
`baseline
`mean
`
`Difference vs
`placebo
`(95% CI)
`
`Mean*
`(SE)
`
`Relative
`improvementà
`(%)
`
`P value 
`
`1.76 (0.060)
`1.46 (0.057)
`
`1.48 (0.058)
`1.16 (0.057)
`
`1.29 (0.062)
`1.08 (0.060)
`
`1.76 (0.066)
`1.50 (0.065)
`
`1.62 (0.060)
`1.25 (0.058)
`
`0.33
`0.63
`
`0.39
`0.71
`
`0.39
`0.60
`
`0.17
`0.43
`
`0.31
`0.68
`
`0.30 (0.15; 0.46) <0.001
`
`0.32 (0.17; 0.47) <0.001
`
`0.21 (0.06; 0.37)
`
`0.008
`
`0.26 (0.10; 0.42)
`
`0.002
`
`0.37 (0.22; 0.53) <0.001
`
`94
`
`82
`
`55
`
`154
`
`120
`
`Treatment group
`
`Rhinorrhoea
`Placebo
`LCTZ 5 mg
`Nasal pruritus
`Placebo
`LCTZ 5 mg
`Ocular pruritus
`Placebo
`LCTZ 5 mg
`Nasal congestion
`Placebo
`LCTZ 5 mg
`Sneezing
`Placebo
`LCTZ 5 mg
`
`ANCOVA, analysis of covariance; LCTZ, levocetirizine. * Mean adjusted for baseline
`score and centre.   P value obtained from an ANCOVA with baseline score as
`covariate, centre and treatment as factors. à Relative improvement with respect to
`placebo.
`
`extended QTc intervals were reported throughout study
`treatment.
`
`Discussion
`
`This multicentre study has shown that levocetirizine was
`effective for the treatment of patients with perennial
`rhinitis due to house dust mite allergy. It is generally
`considered that an improvement above 50% of placebo is
`a significant
`treatment effect. In the study, patients
`receiving levocetirizine showed an overall 86% relative
`improvement of major symptoms of rhinitis from baseline
`above placebo during the first week of treatment (Table
`3). Patients in the levocetirizine group also showed highly
`significant (P < 0.01) improvements in mean T4SS for
`all symptoms for all treatment periods during study
`treatment (Fig. 4).
`
`896
`
`Adverse event
`
`Headache
`Influenza-like symptoms
`Pharyngitis
`Upper respiratory tract infection
`Somnolence
`Sinusitis
`Abdominal pain
`
`Placebo
`(n ¼ 144)
`50 (34.7%)
`20 (13.9%)
`6 (4.2%)
`13 (9.0%)
`4 (2.8%)
`10 (6.9%)
`9 (6.3%)
`
`Levocetirizine 5 mg
`(n ¼ 150)
`52 (34.7%)
`25 (16.7%)
`13 (8.7%)
`10 (6.7%)
`9 (6.0%)
`6 (4.0%)
`3 (2.0%)
`
`The results obtained from this study used a 5 mg dose,
`50% less than the effective dose of cetirizine, as shown by
`patientsÕ daily diary cards, mean T4SS results and
`individual symptom scores were significantly reduced
`within the first 24 h of study treatment. This improve-
`ment was maintained throughout the 6 weeks of study
`treatment (Table 2).
`While the main criterion for inclusion was a T4SS
`greater than 5 Units, patients in both groups had a
`median of 7.3 Units at baseline. Over 4 weeks,
`the
`levocetirizine group had a median T4SS of 3.7 vs 5.3 for
`the placebo group. The rapid decrease of the levocetir-
`izine group score was striking in this population. House
`dust mites are an important cause of PAR in South Africa
`in the Mediterranean regions and also in tropical envi-
`ronments of Africa, South East Asia, the USA and
`Australia (15). As in other Westernized countries, there
`has been an increase in the prevalence of sensitization to
`mites in recent years. In this winter study in South Africa,
`the allergic stimulus was constant, as demonstrated by the
`relatively low reduction in the T4SS score changes in the
`placebo population (Fig. 3). Constancy of the allergen
`stimulation somewhat increases the ability to demon-
`strate improvement in the study population allowing a
`better appreciation of the active treatment effect.
`PAR due to mites is characterized by nasal congestion
`being a prominent and troublesome symptom and often
`intranasal
`steroids are required for
`relief of nasal
`congestion symptoms in PAR. Despite the fact that
`second generation antihistamines have been reported to
`
`Apotex, Inc. (IPR2019-00400), Ex. 1009, p. 004
`
`

`

`Levocetirizine treatment in perennial allergic rhinitis
`
`In a nasal challenge setting, cetirizine but not lorata-
`dine displayed a dose-response curve of relief of nasal
`obstruction to histamine, that was significantly lower
`after treatment, compared with placebo (P < 0.05) (17).
`A study using acoustic manometry found that nasal
`congestion was less severe after nasal histamine challenge
`in 63.3% of patients treated with cetirizine (18).
`The role of enantiomers in pharmacology is currently
`under debate. Chiral molecules can have different biolo-
`gical activities. For instance, both glucose enantiomers
`taste sweet, but only the right-handed form can be
`metabolized by the body. Knowing that receptors are
`proteins built from asymmetric aminoacids (left handed),
`it is not surprising that receptors show differences in
`affinity for stereoisomers. Levocetirizine has twice the
`affinity for H1 receptors as compared with cetirizine.
`From the dissociation kinetics curves, it is known that
`levocetirizine binding to the human H1 receptor is longer
`than cetirizine (115 vs 95 min) (19). In a study comparing
`levocetirizine to cetirizine in a histamine-induced weal and
`flare model, levocetirizine was found to be more active
`when area under the curve (AUC) were compared (14).
`The mechanisms whereby an antihistamine may relieve
`obstruction are also of great interest. In PAR, nasal
`obstruction may be caused by mediators such as hista-
`mine resulting in increased vascular permeability and
`vasodilation in the early phase and by cellular mucosal
`inflammation in the late phase. Antihistamines may
`relieve obstruction by an inhibitory effect on vascular
`permeability and vasodilation in the early phase of the
`allergic response. However, if the antihistamine has a
`significant Ôantiinflammatory effectÕ, it may also reduce
`Ômucosal inflammationÕ of the late-phase reaction.
`
`* P < 0.001
`
`Placebo
`Levocetirizine 5 mg
`
`Week 1
`
`First 4 weeks
`
`Total treatment period
`
`86%
`
`56%
`
`47%
`
`0
`
`–0.5
`
`–1
`
`–1.5
`
`–2
`
`–2.5
`
`–3
`
`–3.5
`
`–4
`
`Mean T4SS score change from baseline
`
`Figure 3. Mean Treatment Four-Symptom Score
`(T4SS)
`change from baseline for patients
`receiving levocetirizine
`5 mg/day or placebo over the study duration.
`
`be generally ineffective in nasal congestion (7–9), this
`study showed a statistically significant reduction of nasal
`congestion for levocetirizine across all treatment periods
`compared with placebo (Table 3, Fig. 4). The relief of
`congestion is comparable to that observed in another trial
`which used a similar symptom scoring to the current
`study (16). In this trial, comparing triamcinolone to
`loratadine, triamcinolone achieved a symptom improve-
`ment that is comparable to levocetirizine in the current
`trial. Relief of nasal congestion has also been reported for
`desloratadine using a similar scale, but the effects were
`evaluated on a shorter period of time (10).
`
`** P < 0.001
`*P < 0.01
`
`897
`
`Sneezing
`
`Runny nose
`
`Itchy nose
`
`Itchy eyes
`
`Blocked nose
`
`Placebo
`Levocetirizine 5 mg
`
`1
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`Score improvement
`
`W 1
`
`Total treatm ent**
`First 4 W
`
`W 1
`
`Total treatm ent**
`First 4 W
`
`W 1
`
`Total treatm ent**
`First 4 W
`
`W 1
`
`Total treatm ent*
`First 4 W
`
`W 1
`
`Total treatm ent**
`First 4 W
`
`Figure 4. Individual symptom scores improvement.
`
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`

`

`Potter
`
`Thompson et al. have observed significant anti-inflam-
`matory effects of levocetirizine on eosinophils in vitro
`(20). In vivo studies are required to assess whether this
`effect is also seen in target organs of the allergic response
`(e.g. the nose). Levocetirizine has also been shown to
`reduce levels of sVCAM-1 and proteins during the first
`6 h postchallenge in an in vivo skin chamber study by
`Michel et al. (21). Although previous studies of the
`antiinflammatory effects of second generation antihista-
`mines have focussed on their effect on minimal persistent
`inflammation, with little clinical effect on the congestive
`symptoms induced by chronic nasal inflammation, it is
`possible that the newer generation antihistamines may be
`shown to have a more significant clinical effect on
`congestion particularly if studied over longer periods to
`allow time for a clinical antiinflammatory effect
`to
`become apparent.
`The safety profile of levocetirizine did not reveal any
`prominent safety issues that could be related to the study
`drug. The overall incidence of adverse events was slightly
`higher in the placebo group than in the levocetirizine
`group. However, this may be attributed to the fact that
`influenza-like symptoms, pharyngitis, upper respiratory
`tract infections are common winter season ailments – the
`study took place during the Southern hemisphere winter
`season.
`The results from this study are in part due to a very low
`dropout rate (levocetirizine, 3.3%; placebo, 9.0%) and a
`treatment compliance that was particularly high (98.5%).
`
`Lack of adherence is often a major cause of therapeutic
`failure. It has been estimated that 20–30% of patients fail
`to follow a curative medication regimen (22). However, in
`this study, the severity of symptoms and possibly the
`availability of free treatment for the duration of the study
`may have prompted a higher compliance rate.
`The overall efficacy of levocetirizine in this study is
`promising, especially in the context of a better awareness
`of rhinitis comorbidities (23), associated with nasal
`obstruction in PAR.
`In conclusion,
`levocetirizine 5 mg once daily is an
`effective and well-tolerated treatment for the symptoms of
`PAR caused by house dust mites. In addition, levocetir-
`izine also significantly relieves nasal congestion, which is
`unusual for products of this class.
`
`Acknowledgments
`
`The author would like to thank M. Wajskop and V. Suznjevic for
`their assistance in the realization of this study. The author wishes to
`acknowledge the assistance of the following doctors who partici-
`pated in the study as investigators: Drs M. J. Bailey, M. Bateman,
`W. V. Boyd, C. T. de Villiers, I. Engelbrecht, E. J. Evans,
`A. P. Foden, S. Furman, P. C. Grey, M. Groenwald, D. Hawarden,
`E. L Janari, A. Macleod, H. A. Makan, J.-M. Malan, W. E. Mans,
`W. W. Neethling, P. R. Nel, H. Nell, S. R. Pillay, G. Ras, J. D. Smit,
`H. H. Snyman, Prof. J. J Snyman, Drs J. F. Strauss, C. Tucker,
`B. J. van de Merwe, C. C. J. van Rensburg, F. Vawda and
`J. H. Vermeulen.
`
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