Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial

ARTICLE

Auteur(s) : Annik Pons-Guiraud¹, Kristof Nekam², J Lahovsky³, Angela Costa⁴, Andrea Piacentini⁴

¹Service de Dermatologie, Hôpital St-Louis, Paris
²Országos Reumatológiai és Fizioterápiás Intézet, Allergológiai és Klinikai Immunológiai Osztály, Budapest, Hungary
³Ordinace pro alergologii, Poliklinika Mazurská, Praha, Czech Republic
⁴Innopharma S.r.l. via Genova 5/A 20039 Varedo (MI) Italy

accepté le 27 Juin 2006

Materials and methods

After the screening visit, patients were asked to discontinue all existing anti-allergic medication and start a 1-week placebo run-in period.

At the end of this period eligibility was to be determined. Patients were included if they were Caucasians aged 18-64 years with a diagnosis of idiopathic chronic urticaria formulated at least 3 months earlier and experienced hives associated with at least moderate itching for at least 3 days during the 7-day placebo run-in, provided they had given their informed consent in writing. The main exclusion criteria were: other skin or systemic diseases that could interfere with the evaluation of efficacy, concomitant treatment with other anti-allergic therapy (antihistamines, corticosteroids) or with drugs depressing the central nervous system, such as hypnotics or sedatives, antihistamines in the last 72 hours, topical corticosteroids in the last 7 days, oral corticosteroids in the last 8 weeks or parenteral corticosteroids in the last 3 months, history of failure to respond to antihistamines, hypersensitivity to loratadine, emedastine or study drug excipients, pregnancy or lactation, childbearing age in women if they failed to use effective contraceptives, profession involving driving and/or usage of dangerous machinery, increases in transaminases by more than twice the upper limit of normal, increase in serum creatinine above 1.5 mg/dL, history of drug and/or alcohol abuse, less than 75% compliance during the placebo run-in, lack of co-operation, previous enrollment into the trial.

A total of 220 patients (110 per treatment group) were to be entered into the study. Qualified patients were to be randomized, according to a computer list prepared by the sponsor, either to emedastine or loratadine by oral route for 4 weeks.

Patients always took two identical capsules daily, one in the morning and one in the evening: during the placebo run-in period the capsules contained placebo; during the active treatment period they contained emedastine in the group allocated to emedastine, and placebo in the morning and loratadine in the evening in the group allocated to loratadine.

The study drug was manufactured and packaged by the sponsor¹. A set of code-breaks in sealed envelopes was given to each participating centre.

The following concomitant treatments were not allowed: H₁ and H₂ antagonists; corticosteroids, non-steroidal anti-inflammatory drugs, antibiotics, beta-agonists, beta-agonists, anticholinergics or other drugs that could influence urticaria symptoms, hypnotics, sedatives or other drugs that could induce central nervous system depression.

Patients returned to the centre after 1, 2 (optional) and 4 weeks of treatment and then for an optional follow-up visit 2 weeks after discontinuation of treatment.

At each visit study medication was dispensed and/or returned as appropriate, as well as a study diary on which the patient was to write down daily symptoms as a basis for efficacy assessment.

The efficacy parameters were the following:

Total urticaria symptom score (sum of itching intensity score + hive number score measured twice daily) (primary end-point), erythema intensity score, largest hive score, extension of involved skin score, final overall effectiveness scores (evaluations both by patient and investigator). The semiquantitative rating scales used for the assessments are shown in table 1( Table 1 ).

The assessment of safety included the following investigations: physical examination, electrocardiogram, vital signs, hematological and biochemical laboratory tests (CBC + differential, platelet count, ESR, transaminases, GGT, alkaline phosphatase, total bilirubin, total protein, serum creatinine, urea, uric acid, fasting glucose), urinalyses and adverse event reporting, collecting information on concomitant diseases and treatment.

All assessments and investigations were performed at entry and at the end of the placebo run-in, except laboratory tests. Efficacy assessments were repeated after 1, 2 and 4 weeks of treatment, except for the final overall efficacy assessment, which was provided at week 4 (end of treatment). Safety assessments were repeated at the end of treatment. Only adverse events were evaluated at the follow-up visit, at which vital signs and concomitant medication were also noted.

The primary and secondary efficacy analyses were carried out both in the per protocol (PP) and intention-to-treat (ITT) populations. The ITT sample included all randomised patients who had the baseline evaluation of each symptom and received at least one dose of treatment. In the ITT analysis of the primary variable, the LOCF (Last Observation Carried Forward) method was applied for managing missing data.

Symptom scores were analysed quantitatively i.e. assessing mean changes in symptom scores from baseline and qualitatively i.e. calculating the proportion of patients showing no symptoms or mild, moderate or severe symptoms after 4 weeks of treatment. The Shapiro and Wilk’s W test was used to assess the normality of quantitative parameter distributions. Among quantitative parameters, only the mean change from baseline of the total urticaria symptom score expressed by patients was normally distributed (both in the ITT and the PP sample); Bartlett’s test was used to assess homogeneity of variances, while t-test for independent samples was employed for between group comparisons. All the other quantitative variables required the non-parametric Mann-Whitney U test for the between group comparisons; in all cases, within group tests for significance were carried out using the t-test for paired samples.

The qualitative parameters were described by absolute and relative frequencies; chi-square test or likelihood ratio chi-square test was used for between group comparisons, the latter being preferred in the presence of low frequencies of the study parameters; within group tests were carried out by applying the McNemar’s test to the shift tables obtained for the study parameters. Significance tests were one tailed, with α error fixed at the 5% level.

The safety data were analyzed descriptively.

The statistical analysis was performed using SAS statistical software (8.1 version).

The study was carried out according to the principles of the Declaration of Helsinki and subsequent amendments, and to the GCP regulations in force.
Table 1 Semiquantitative rating scales used for the assessment of therapeutic efficacy

Results

Patients

After data verification 12 patients were excluded because they had taken prohibited antihistamine treatment and 19 because they did not report the required scores related to hives and itching during the placebo run-in phase.

Thus, the ITT efficacy analysis included 161 patients; their main characteristics at baseline are shown in table 2( Table 2 ).

The PP analysis included 153 patients, because a further 8 patients had major protocol violations or dropped out; their baseline characteristics were similar to those of the ITT population.
Table 2 Main baseline characteristics of the ITT population

Efficacy

Also the proportion of patients with no symptoms at the end of treatment was similar (emedastine 52.4% vs. loratadine 54.5% – p = 0.41) and so was the proportion of patients with mild symptoms (total score ≤ 8) (emedastine 92.9% vs. loratadine 96.1% – p = 0.37).

After 28 days of treatment mean symptom scores recorded in patients improved significantly versus baseline both with emedastine and loratadine (both p < 0.00005, t test for paired samples; table 3( Table 3 )). No significant difference between groups was found (p = 0.48 for intensity of erythema, p = 0.30 for number of hives, p = 0.39 for size of the largest hive, p = 0.45 for the extent of the skin area involved and p = 0.19 for the overall assessment of urticaria symptoms).

As far as overall effectiveness scores at the end of treatment are concerned, no statistically significant differences were observed between investigator and patient mean scores or between the two treatment groups, the mean values expressed by the investigator and by patients being 2.69 ± 1.34 and 2.63 ± 1.34, respectively, for patients receiving emedastine, while the corresponding values in the loratadine group were 2.76 ± 1.31 and 2.78 ± 1.26.

The proportions of patients with no or mild symptoms at the end of treatment were similar in the two treatment groups: no or mild erythema with emedastine 83.1% vs. 89.5% with loratadine; no or less than 7 hives with emedastine 80.7% vs. 89.5% with loratadine; no hives or hives smaller than 1.5 cm with emedastine 80.7% vs. 82.9% with loratadine; involvement of no more than 10% of body skin with emedastine 92.8% vs. 89.5% with loratadine; complete disappearance of symptoms or marked improvement with emedastine in 81.9% vs. 89.5% with loratadine. However, significant differences were recorded after only one week of treatment: in the emedastine group the proportion of patients in whom the extent of body skin involvement diminished from ≥ 11% to 0-10% after one week was 57.1% vs. 38.2% with loratadine (p = 0.0019); also the proportion of patients with a total urticaria symptom score of 0 or 1 was significantly superior with emedastine after 1 week of treatment (83.3% vs. 64.5% for loratadine p = 0.0134). The superiority in reducing extension in skin involvement was still present at week 2 (p = 0.0074).

At the end of treatment there was no significant difference between treatments in the overall effectiveness scores provided by both investigators and patients: according to the opinion of the investigator 65.1% of patients were asymptomatic or markedly improved with emedastine vs. 65.8% with loratadine, 22.9% were slightly or moderately improved with emedastine vs. 25.0% with loratadine and 10.8% did not improve at all with emedastine vs. 9.2% with loratadine; the corresponding values according to patients were: asymptomatic or markedly improved 61.4% vs. 64.5%, slightly or moderately improved 27.7% vs. 28.9% and not at all improved 10.8% vs. 6.6%.

The results of the PP efficacy analysis were similar.

The safety analysis included 192 patients, 96 treated with emedastine and 96 with loratadine.

Forty patients, 23 (23.95%) in the emedastine group and 17 (17.70%) in the loratadine group experienced a total of 69 adverse events (41 with emedastine and 28 with loratadine). Twenty-eight events were related to study treatment: 19 in 15 patients in the emedastine group and 9 in 9 patients in the loratadine group (chi square test, p = 0.0294).

Two patients were withdrawn because of serious adverse events: a suicide attempt not related to study treatment (loratadine) and a bilateral fracture of the calcaneum following a fall, which lead to hospitalization, in the emedastine group. Although the patient who fell was taking a number of medicinal products besides emedastine (paracetamol, hydroxyzine, enoxaparin, ketoprofen and omeprazole), the causal relationship with emedastine was not ruled out and considered possible.

Among the adverse reactions that occurred in the emedastine group, 4 were classified as mild, 13 as moderate and only 2 severe, while in the loratadine group 4 were mild and 5 moderate.

The two severe adverse events were sleepiness probably related to emedastine and the case of bilateral fracture of the calcaneum.

The most common adverse event with emedastine was sleepiness: 11 events (related and not related to drug) were reported by 7 patients, one being severe, 7 moderate and 3 mild; the causal relationship was probable in all moderate to severe cases, except one (classified as remote). Next in order of frequency was headache (3 cases related to treatment, out of which 2 were of moderate intensity and 1 was classified mild). The other events were isolated cases; those of moderate intensity were tiredness probably related to treatment and increase in ALT and AST remote relation to study treatment.

Sleepiness was reported by two patients in the loratadine group; in one case it was moderate and possibly related to treatment. The other events were isolated cases; those of moderate intensity were nausea, constipation and palpitations, all possibly related to treatment, and dry mouth probably related to treatment.

No important changes in vital signs, ECG or laboratory tests were recorded.
Table 3 Mean symptom scores at baseline and end of treatment by treatment ITT secondary efficacy analysis (quantitative approach)

Discussion

The results are consistent with the outcome of 4 randomized, double-blind, parallel-group studies carried out with emedastine (1-2 mg b.i.d.) in Japanese patients suffering from urticaria. The first three studies were comparisons between two dosage regimens (1 and 2 mg b.i.d.) in fairly small groups of patients (total number of patients: 83, 29 and 68 respectively, out of whom 43, 18 and 30 were assigned to the 2 mg b.i.d. regimen for 14 days). A marked reduction/disappearance of itching was obtained in 44-65% of patients with 1 mg b.i.d. and 44-72% with 2 mg b.i.d., whereas hives were well controlled/disappeared entirely in 24-54% of patients with 1 mg b.i.d. and 24-63% with 2 mg b.i.d. None of these differences were statistically significant ([17, 19] Horio, unpublished data]). The fourth study was a much larger comparison versus ketotifen in 400 patients: 133 patients allocated to 1 mg b.i.d. emedastine, 133 to 2 mg b.i.d. emedastine and 134 to ketotifen 2 mg. After 14 days of treatment moderate clinical improvement or better was achieved in 66% of patients treated with 1 mg b.i.d. emedastine, in 72% with 2 mg b.i.d. and 64% treated with ketotifen. None of these differences were statistically significant [18].

The results appear to be reliable, as also the results obtained with loratadine are consistent with those reported in previous trials in chronic idiopathic urticaria [20-22]: 64-75% patients became asymptomatic or experienced marked improvement after 4 weeks of treatment with 10 mg od in previous trials versus 65.8% in this study.

Both drugs were well tolerated. The most common adverse event was sleepiness with 11 events in 7 patients treated with emedastine and 2 events in 2 patients treated with loratadine. No significant difference was found (p = 0.0846). Only one patient in each treatment group was withdrawn because of an adverse event: bilateral fracture of calcaneum for the patient treated with emedastine; this event was judged by the investigator as possibly related to treatment even if, as stated in the result section, the patient was taking a relevant number of medicines besides emedastine. The other adverse event which led to withdrawal was a suicide attempt; this event was not related to treatment.

The adverse reactions to emedastine and loratadine in this study were consistent with the known safety profile of the two drugs. The phase II/III clinical trials with oral emedastine difumarate in 1428 Japanese patients, approximately 450 of whom were suffering from urticaria (Innopharma, Emedastine Investigational brochure), and pharmacovigilance reports since 1996 have shown that the most common adverse reactions to emedastine involve the central nervous system and the gastrointestinal tract, so the only unexpected adverse reaction was the calcaneum fracture. Regarding loratadine, all the adverse reactions were expected, except two isolated cases of insomnia and weight gain.

Thus, this study indicates that emedastine is well tolerated and is at least as effective as loratadine, and suggests that its onset of action may be faster. What is the price to pay for this potential advantage? The cost of one day of therapy with emedastine is approx 1 euro, the same as the cost of one day of therapy with loratadine. Thus, the potential advantage of faster onset of action with emedastine is not associated with additional costs.

In conclusion, emedastine difumarate, given by oral route at the dosage of 2 mg b.i.d., is well tolerated and at least as effective as loratadine 10 mg o.d. in the short-term treatment (4 weeks) of chronic idiopathic urticaria.

Acknowledgements

Financial support: SALUC-PHARMA S.A.

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1 SALUC-PHARMA S.A., Prangins (Switzerland), under licence of Nippon Organon K.K.