Faster onset of action with topical levocabastine than with oral cetirizine

This international multicentre, open-label, parallel-group trial was undertaken to compare the therapeutic efficacy and tolerability of topical levocabastine and oral cetirizine in patients with perennial allergic rhinoconjunctivitis, with particular reference to the comparative onset of action of the two drugs. A total of 207 patients were randomized to receive either levocabastine nasal spray (0.5 mg/ml, two sprays in each nostril twice daily) plus levocabastine eye drops as required (0.5 mg/ml, one drop in each eye twice daily p.r.n.) or cetirizine orally (10 mg once daily) with a treatment duration of 2 weeks. Onset of action was found to be significantly more rapid with levocabastine than with cetirizine for both nasal and ocular symptoms (p < 0.001). Within 15 min of study drug administration, 36% of levocabastine-treated patients reported relief from nasal symptoms and 32% relief from ocular symptoms compared with 10% and 17% of patients on cetirizine, respectively. At 1 h, the percentages of patients reporting relief were 76% and 38% for nasal symptoms, and 81% and 48% for ocular symptoms in the levocabastine and cetirizine treatment groups, respectively. At 8 h there were no differences between the two treatments. Overall therapeutic efficacy was found to be comparable in the two treatment groups over the 2-week study period with no significant intergroup differences in symptom severity or global therapeutic efficacy. Both drugs were well tolerated with no significant differences in the incidence or type of adverse reactions between the two groups. In conclusion, levocabastine eye drops and nasal spray are as effective and well tolerated as oral cetirizine for the treatment of perennial allergic rhinoconjunctivitis with the advantage of a significantly faster onset of action for both nasal and ocular symptoms.


Introduction
Levocabastine is a new Hi-receptor antagonist which has been specifically developed for topical ocular and nasal administration.Preliminary placebo-controlled studies have shown that levo- cabastine has an extremely rapid onset of action with effects reported within minutes of applica- tion.2-4 Furthermore, levocabastine has a suffi- ciently long duration of action to permit a twice- daily dosing regimen. 5Comparative clinical trials have shown that topical levocabastine is well tol- erated and at least as effective as the oral anti- histamines terfenadine and loratadine for the treatment of seasonal allergic rhinoconjunctivitis. [6][7][8][9][10] This study was undertaken to assess the ther- apeutic efficacy and tolerability of levocabastine nasal spray and eye drops with those of the second generation oral antihistamine cetirizine in patients with perennial allergic rhinoconjunctivitis with particular reference to the comparative onset of action of the two drugs.While it is to be expected that a topical agent will have a more rapid onset of action than an orally administered drug, no direct comparison of the onset of action of topical levocabastine and an oral anti- histamine has been undertaken to date.The present study was set up as an open, randomized comparative trial.The decision to perform this study in an open fashion was deliberate.Experi- ence in previous studies has shown that the placebo effect with a topical formulation is sub-adequate contraception and patients with con- stantial, and considerably higher than that seen current serious cardiovascular, pulmonary, neuro- with oral study medication.This can be logical, renal, hepatic or malignant disease were explained by the fact that the instillation of fluid also ineligible for participation in this study.in the nose or (in particular) the eyes might dilute or wash away the allergen.Results of a Study design: This was an international (Austria, recent international, double-blind study under-Belgium, Canada, Denmark and The Nether- taken to compare levocabastine nasal spray and lands), multicentre, open-label, parallel-group eye drops with oral terfenadine (using topical trial.Patients were randomized to receive either placebo dummies in the terfenadine treatment levocabastine nasal spray (0.5 mg/ml two puffs in group and oral dummies in the levocabastine each nostril twice daily)plus levocabastine eye treatment group) demonstrate the two ap-drops as required (0.5 mg/ml one drop in each proaches to be equally effective, with an overall eye twice daily p.r.n.) or cetirizine orally (10 mg response for nasal symptoms of 60% on levoca-once daily) with a treatment duration of 2 weeks.bastine and 63% on terfenadine and for ocular The study was conducted in accordance with the symptoms of 80% with levocabastine and 72% Declaration of Helsinki and subsequent revisions.with terfenadine. 6Therefore, in order to assess The study protocol was approved by the local the 'real-life' difference in efficacy between ethics committee and all patients gave their topical and oral antihistamine treatment more written informed consent, with informed parental accurately, in view of the important topical consent required for subjects aged less than 18 placebo effect, an open, randomized study years.design was considered appropriate for this trial.
Assessments and evaluations.. To permit evalua- tion of onset of action, patients were requested Material and Methods to record the overall severity of both nasal and ocular symptoms on a diary card using a 100 mm Patients.. Patients between the age of 12 and 70 visual analogue scale (VAS; extremes: 0 years with at least a 1-year history of perennial absent, 100 very severe) immediately before allergic rhinoconjunctivitis severe enough to taking the first dose of study medication and warrant anti-allergy therapy and a positive skin then at 5, 10, 20, 30 and 40 min, and 1, 2, 3, 4, 6, prick test and/or radioallergosorbent (RAST) for and 8 h after administration.In addition, patients a non-seasonal allergen such as house dust mite were requested to indicate how soon they felt were eligible for inclusion into this trial.In addi- significant improvement in nasal and ocular tion, patients were required to have at least two symptom severity following administration of the typical symptoms of perennial allergic rhino- first dose of study medication, rating onset of conjunctivitis of moderate severity at the time of action as occurring at < 5 min, 5 to 15 min, 15 entry into the trial.The trial was performed out to 30 min or 30 to 60 min following study drug of the hay fever season (October 1 1992 to April administration.30 1993).
To permit assessment of therapeutic efficacy, Exclusion criteria included: concurrent disease the severity of rhinorrhoea, sneezing, nasal which might complicate evaluation of the study itching, nasal congestion and ocular symptoms drugs such as vasomotor rhinitis, rhinitis rnedica-were assessed by the investigator at the start of rnentosa, active infective sinusitis, upper respira-the trial and at the end of the 2-week treatment tory tract infections and large, obstructive nasal period using a 4-point scale (0 none, 1 polyps; use of an investigational drug within 30 mild [noticeable on occasion but not bother- days prior to entry into the trial; concomitant some], 2 moderate [noticeable from time to therapy with any medication which might inter-time and tends to be bothersomeJ; 3 severe fere with the assessment of the study drugs with [frequently noticeable and bothersome]).In a washout period of 1 month for systemic corti- addition, the same symptoms were assessed by costeroids, 2 weeks for topical corticosteroids the patients on a daily basis using the same scale and sodium cromoglycate, 1 week for all anti-and recorded in their diaries.Patients also pro- histamines with the exception of astemizole for vided a VAS rating of the overall severity of which a wash-out period of 6 weeks was rhinoconjunctivitis each day.At the end of the required, and 3 days for decongestants and all trial, both the investigator and the patient proother ocular and nasal medication; hyposensitiza-vided a global evaluation of treatment efficacy tion therapy which had varied within 6 months rating therapy as excellent, good, fair or poor.
of randomization; and use of soft contact lenses.
Statistical analysis: An intention-to-treat analysis was performed.Onset of action for both nasal and ocular symptoms was derived from the patients' diary data generated following adminis- tration of the first dose of study medication.In addition to the individual symptoms listed above, the sum of all nasal symptoms and the sum of all symptoms were analysed at the start of the trial and at the end of the 2-week treatment period.
The area under the curve (AUC) was expressed as a percentage of the maximal AUC and calculated using the trapezoidal rule, the percentage of days with severe symptoms and the percentage of symptom-free days were also determined for all parameters recorded in the patients' diaries.All intergroup differences were subjected to analysis of variance testing (ANOVA).

Results
A total of 207 patients participated in this trial, 105 in the levocabastine group and 102 in the group which received cetirizine.The two treat- ment groups were well matched for the major demographic characteristics and symptom sever- ity at baseline as indicated in Tables 1 and 2. Compliance with the study regimen was found to be comparable in the two treatment groups.The frequency of use of levocabastine eye drops by Nasal symptoms  patients in the levocabastine treatment group was found to be relatively high.In all, 56 levocabas- tine-treated patients used the eye drops on 83.7% of study days.Three patients in each group failed to com- plete the study.Three due to adverse experiences, one cetirizine-treated patient was lost to follow-up and another with- drawn due to a treatment deviation.Adverse events resulting in withdrawal were headache, sore throat, fatigue and nasal irritation in the levocabastine treatment group and eyelid oedema in the cetirizine group.
Onset of action for both nasal and ocular symptoms was found to be significantly more rapid in levocabastine-treated patients than in those who received cetirizine (p < 0.001).In all, 8% of levocabastine-treated patients reported relief from nasal symptoms within less than 5 min of application of the first dose compared with 3% of cetirizine recipients, with onset of action within 15 min reported in 36% of patients in the levocabastine treatment group and 10% of those treated with cetirizine.At 30 min, the cor- responding values were 57% and 19% in the two groups, respectively, with onset of action reported within 1 h for 76% of levocabastine-treated patients and 38% of those on cetirizine.The cor- responding values for relief of ocular symptoms were 9% and 12% at 5 min, 32% and 17% at 15 min, 57% and 24% at 30 min, and 81% and 48% at 1 h, in the levocabastine and cetirizine groups respectively (Fig. 1).

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Mediators of Inflammation Vol 4 (Supplement).1995 Each symptom was scored on a scale of 0-3.The four nasal symptoms have been combined to give a total symptom score.
Analysis of the AUCs for the patients' VAS ratings of nasal and ocular symptom severity over the 8-h period following administration of the first dose of study medication confirms the patients' reports of symptom relief with time.The median change in the VAS scores from base- line was greater in levocabastine-treated patients than in those who received cetirizine with inter- group differences most marked during the first 2 h after study drug administration (Fig. 2).At 8 h there were no differences between the two treat- ments.
Investigator assessments revealed a comparable reduction in symptom severity in the two treat- ment groups over the 2-week study period (Table 2).Similarly, no significant intergroup dif- ferences were observed between levocabastine and cetirizine for the patient assessments of indi- vidual symptom severity (Fig. 3) and VAS ratings of the overall severity of rhinoconjunctivitis.The percentage of symptom-free days and the percentage of days with severe symptoms were also found to be similar in the two treatment groups.
The results of the global evaluations of ther- apeutic efficacy showed no statistically significant differences between the two drugs.At the end of the trial, the investigator rated the effect of therapy to be excellent or good in 62% of levo- cabastine-treated patients and 59% of the cetir- izine group (Fig. 4).The corresponding values for the patient evaluations were 61% and 62% in the two groups, respectively.
Adverse experiences (as noted by either the investigator or the patient) were reported by 25 patients (24%) in the levocabastine group and 20 (20%) of those who received cetirizine.A wide range of adverse reactions was reported (Table 3), the most common being application site reac- tion (usually mild burning or prickling sensation in the eyes or nose; in 6% of levocabastine- treated patients and 1% of cetirizine patients), common cold symptoms (5% of patients in the levocabastine group and 2% of patients in the cetirizine group), headache (5% of patients in each group), fatigue and somnolence (each reported by 4% of cetirizine-treated patients, and by 2% and 1% of levocabastine-treated patients, respectively).No statistically significant inter- group differences in the incidence or type of adverse reactions were observed.

Discussion
Second generation, oral H-receptor antago- nists such as cetirizine are widely considered to be a first-line therapeutic option for the treat- ment of perennial allergic rhinoconjunctivitis. 1 The therapeutic efficacy of cetirizine for the treatment of this common condition is well documented.2' The present study was under- taken to compare the efficacy and tolerability of cetirizine given once daily with those of a recently developed topical H-receptor antago- nist, levocabastine, given twice daily with parti- cular reference to the comparative onset of action of the two drugs.
The reports from subjects of how soon they felt significant improvement in their symptoms demonstrate that onset of action was significantly more rapid in levocabastine-treated patients than in those who received cetirizine for both nasal and ocular symptoms (p < 0.001).Analysis of the AUCs for patient VAS ratings of nasal and ocular symptom severity over the 8-h period fol- lowing administration of the first dose of study medication confirms a faster onset of action for levocabastine.
No significant differences in overall therapeutic efficacy were reported with a comparable reduc- tion in symptom severity observed over the 2- week period in the two treatment groups.Inves- tigator assessments at the end of the study revealed an excellent or good response to therapy in 62% of levocabastine-treated patients compared with 59% for patients treated with cetirizine.In all, 61% of patients in the levocabas- tine group and 62% of those on cetirizine repor- ted the effect of therapy to be excellent or good.
Mediators of Inflammation Vol 4 (Supplement).'8 Both drugs were found to be well tolerated with no statistically significant intergroup differ- ences in the incidence or type of adverse experi- ences reported.Application site reaction was the most common adverse event reported in levoca- bastine-treated patients in this study, with an inci- dence of 6%.Previous studies have shown that the incidence of local irritation following topical administration of levocabastine is comparable with that seen with placebo.In contrast, oral antihistamine administration is associated with a greater potential for systemic adverse effects.Clinical trials have shown that the most frequent adverse event seen in cetirizine-treated patients is sedation, 12 with fatigue and somnolence each reported by 4% of patients who received this oral antihistamine in the present trial.
In conclusion, topical levocabastine appears to be as effective and well tolerated as cetirizine for the treatment of perennial allergic rhino- conjunctivitis with the advantage of a significantly faster onset of action.These findings suggest that levocabastine eye drops and nasal spray may be considered as an alternative to oral antihistamine therapy as a primary treatment option for patients with this condition.

FIG. 1 .FIG. 2 .
FIG.1.Onset of action for nasal and ocular symptoms in the two treatment groups.Mediators of Inflammation Vol 4 (Supplement). 1995S7

FIG. 3 .
FIG.3.Patient evaluations of nasal and ocular symptom severity during the 2-week trial.Each symptom was scored on a scale of 0-3.The four nasal symptoms have been combined to give a total symptom score.

FIG. 4 .
FIG.4.Investigator evaluations of global therapeutic efficacy at the end of the 2-week treatment period (L levocabastine;'C cetirizine).

Table 1 .
Baseline demography in the two treatment groups

Table 2 .
Investigator assessments of symptom severity at baseline and at the end of the trial*

Table 3 .
Adverse experiences* *Adverse experiences occurring in at least two patients per treatment group.