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Keywords:

  • bilastine;
  • chronic idiopathic urticaria;
  • Dermatology Life Quality Index;
  • H1antihistamine;
  • total symptoms score

Abstract

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

To cite this article: Zuberbier T, Oanta A, Bogacka E, Medina I, Wesel F, Uhl P, Antépara I, Jáuregui I, Valiente R, the Bilastine International Working Group. Comparison of the efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: a multi-centre, double-blind, randomized, placebo-controlled study. Allergy 2010; 65: 516–528.

Abstract

Background:  Bilastine is a novel nonsedative H1-receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). The aim of this study was to compare the clinical efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg and placebo in CU patients with moderate-to-severe symptoms.

Methods:  Overall 525 male and female subjects aged 18–70 years were randomized to receive bilastine 20 mg, levocetirizine 5 mg or placebo, once daily for 28 days, in double-blind manner, in 46 centres across Europe and Argentina. Patients rated symptoms of pruritus, number of wheals, and maximum size of wheals (on predefined scales) as reflective (over past 12 h) symptoms twice daily, for assessment of change from baseline in the total symptoms scores (TSS) over 28 days as the primary efficacy measure. Changes in reflective and instantaneous symptoms scores, Dermatology Life Quality Index (DLQI), and CU-associated discomfort and sleep disturbance were assessed as secondary outcomes. Safety was assessed according to adverse events, laboratory tests and electrocardiograms.

Results:  Bilastine reduced patients’ mean reflective and instantaneous TSS from baseline to a significantly greater degree than placebo (P < 0.001); from day 2 onwards of treatment. The DLQI, general discomfort, and sleep disruption were also improved significantly in bilastine-treated patients as compared with placebo-treated patients (P < 0.001 for all parameters). Comparison with levocetirizine indicated both treatments to be equally efficacious as well as equally safe and well tolerated as compared with placebo.

Conclusions:  Bilastine 20 mg is a novel effective and safe treatment option for the management of CU.

Chronic urticaria is a common skin condition, characterized by recurrent itchy wheals, which when severe can be highly debilitating (1). In many cases of chronic urticaria, the disease may be regarded as idiopathic (2), primarily as a result of an unknown or only infrequently identified aetiology (1, 3). Chronic idiopathic urticaria (CU) in particular has a world-wide prevalence of approximately 0.5% to 1.0% across the different populations (3, 4) and is defined as the daily or almost daily occurrence of wheals and pruritus for a minimum of 6 weeks, which can cause severe disability and adversely impact the quality of life (QoL) of affected individuals (1, 5). Indeed, it has been suggested that the impact of symptoms of CU on the QoL of affected individuals may be likened to that noted in some elderly patients with ischaemic heart disease (6).

Despite the lack of information regarding the trigger/s involved in the aetiology of CU, evidence suggests that in about 30–50% of CU patients, IgG autoantibody-mediated activation of high affinity IgE receptors (FcεRI) on basophils and dermal mast cells may lead to the release of pro-inflammatory mediators such as histamine, eicosanoids, cytokines, and proteases; which are involved in the manifestation of urticaria and angio-oedema (1, 3). As dermal mast cell-derived histamine is generally associated with the development of the symptoms of pruritus, oedema and erythema, this has traditionally resulted in the use of the modern nonsedating H1-antihistamines as first-line therapy for CU (7), a practice recently endorsed and recommended by an International Consensus guideline on the management of urticaria (8).

Bilastine is a novel H1-antihistamine developed for the symptomatic treatment of CU, seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (9). Pharmacological studies have demonstrated that bilastine is a highly selective and potent H1-antihistamine, with both anti-histaminic and anti-allergic properties in vitro and in vivo (10, 11). Moreover, bilastine has a rapid onset of action (60 min) and a long duration (24 h) of effect (12), undergoes minimal hepatic metabolism (13), and is eliminated mainly in the faeces (9, 14). Similarly, investigations in healthy volunteers (12, 15–17) and patients with allergic rhinitis (18, 19) have indicated that bilastine is a highly efficacious and safe treatment option in the symptomatic relief of these conditions, at a therapeutic dose of bilastine 20 mg. Indeed, two phase III studies in patients with SAR have recently demonstrated a daily dose of bilastine 20 mg to be significantly more efficacious than placebo and equally efficacious as desloratadine 5 mg (18) and cetirizine 10 mg (19) in the treatment of symptoms in these individuals. While studies in healthy volunteers have demonstrated doses four- to fivefold the therapeutic dose of bilastine to be devoid of both sedative (15, 16) and cardiotoxic effects (17), studies in SAR patients have demonstrated that bilastine has an adverse events (AEs) profile similar to that compared with placebo and desloratadine (18), and significantly better than that compared with cetirizine (19); particularly with regard to incidence of drug-related AEs, somnolence, and fatigue.

The aim of this study was therefore to assess the clinical efficacy and safety of bilastine 20 mg in patients with CU and to compare these with the efficacy and safety of levocetirizine, an established second generation H1-antihistamine.

Methods and materials

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

Patients

Male and female subjects, aged 18–70 years, with a documented history of CU; characterized by erythematous skin wheals accompanied by itching attributable to no identifiable cause and occurring regularly at least three times per week for 6 weeks prior to entry in the study; were recruited. Eligible patients were additionally required to demonstrate a symptoms score of ≥2 (i.e. moderate-to-severe intensity scores) for any two of the three features of pruritus, number of wheals, or maximum size of wheals (rated on predefined scales of 0–3) for at least 3 days during the screening period (day −7) and at randomization visit (day 0).

Patients with a history of any dermatological condition (including isolated hereditary angio-oedema, dermographism, physical urticaria, urticaria caused by a medicine or food allergy, infectious urticaria, contact urticaria, urticaria caused by vasculitis and/or collagenosis, paraneoplasic urticaria, parasitary urticaria, urticaria related with thyroid pathology, eczema or atopic dermatitis), which could interfere in the evaluation of the chronic idiopathic urticaria were excluded from the study. Similarly, patients with a history of autoimmune disorders, Hodgkin’s disease and any clinically significant condition (cardiovascular, neurological, hepatic, renal or malignant diseases) were excluded. Patients who had taken systemic or topical corticosteroids within 4 weeks, astemizole within 6 weeks, ketotifen within 2 weeks, any other systemic antihistamine (including loratadine, desloratadine, ebastine, rupatadine, mizolastine, cetirizine or levocetirizine) within 3 days, anti-leukotrienes within 3 days, sodium cromoglycate or nedocromil within 2 weeks, and tricyclic antidepressants within 1 week of randomization were also excluded, as were pregnant or breast-feeding women and patients with hypersensitivity to H1-antihistamines, benzimidazoles or lactose.

Study design

This was an international, double-blind, randomized, placebo and active treatment-controlled, parallel-group study conducted in 46 centres across Argentina, Belgium, France, Germany, Poland, Romania and Spain; between October 2006 to August 2007. The study involved a 1-week screening period, at the end of which (day −7; visit 1) the patients were assessed for eligibility, based on medical history and severity of symptoms. Patients providing written informed consent were subjected to physical examination and the signs and severity of symptoms of urticaria were assessed as described above. The patients were provided with diary cards to record the incidence and severity of symptoms and asked to return to the clinic after 3–10 days (visit 2), during which their diary cards were reviewed for symptom severity and medications used. Patients fulfilling the inclusion and exclusion criteria and having scores of ≥2 for at least two of the symptoms assessed for a minimum of 3 days underwent a physical examination, as well as an assessment of electrocardiogram (ECG), vital signs and blood tests. Patients additionally completed the Dermatology Life Quality Index (DLQI) questionnaire to assess their QoL, performed a global evaluation of discomfort caused by urticaria (using a visual analogue scale, VAS), assessed the impact of urticaria on sleep (using a 5-point scale), and assessed the signs and severity of symptoms of urticaria. The investigators also assessed the severity of urticaria symptoms according to the number and size of wheals, as well as a thorough assessment of the impact of pruritus on the patient, as indicated by anxiety, itching injuries, etc. Patients with scores of ≥2 for at least two of the symptoms assessed for a minimum of 3 days were randomized to receive either bilastine 20 mg, levocetirizine 5 mg or matched placebo once daily for 28 days. Randomization to treatment was achieved according to a computer-generated randomization code provided by the study sponsor (FAES FARMA, SA, Spain) and treatments were allocated to each patient in their chronological order of entry into the study. The study medications were supplied as identical over-encapsulated tablets in individually coded aluminium blister packs to ensure blinding of both the investigators and the patients to treatment, and the patients were instructed to take one tablet an hour before or two hours after breakfast. New diary cards were also provided to record the incidence and severity of symptoms, concomitant medications, and AEs.

The patients returned to the clinic after 14 (visit 3) and 28 days (visit 4), during which physical examinations, global evaluation of urticaria, assessment of impact of urticaria on sleep, and the subjects’ and investigators’ assessment of symptoms severity were repeated as above. Adherence to treatment was also assessed at both these visits, whereas at visit 4 the patients additionally completed the DLQI and the investigators evaluated their global clinical impression (GCI) of treatment.

Adherence to treatment was assessed by drug accountability and by asking the patient. Compliance was calculated using the formula:

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The study was conducted in strict accordance with the ethical principles of the modified Declaration of Helsinki 1964, the International Conference on Harmonization (ICH) principles of Good Clinical Practice, and the applicable regulations of the countries where the study was conducted. The Independent Ethics Committees of each participating centre reviewed and approved the protocol, informed consent document signed by each individual patient, and all patient-related information disseminated prior to recruitment of the patients.

Efficacy measures

The primary efficacy assessment was the change from baseline in the patient’s reflective daily total symptoms score (TSS) over the 28-day treatment period, with baseline defined as the mean of the 3 days with maximum symptoms before randomization. The effect of 2–4 weeks’ treatment on (i) the mean change from randomization visit (day 0) in the patients’ and investigators’ area under the curve for TSS (AUCTSS); (ii) the change from randomization visit (day 0) in the patients’ and investigators mean instantaneous total and individual symptoms scores; (iii) the change from randomization visit (day 0) in the patients’ DLQI scores; (iv) the patients’ VAS scores; (v) the patients’ impact of urticaria on sleep scores; and (vi) the investigator’s GCI of treatment were evaluated as secondary efficacy measures.

Evaluation of symptoms scores  The severity of pruritus, the number of wheals and the maximum size of wheals were assessed daily in the morning and in the evening over the last 12-h period (reflective) and at the time of clinic visit (instantaneous), using 4-point scales of 0–3, modified from Mlynek et al. (20).

Pruritus severity was scored as 0 = absent, 1 = mild (not annoying), 2 = moderate (causing little disruption of activity) and 3 = severe (intense itching causing disruption of activity), whereas the number of wheals were scored as 0 = absent, 1 = some (≤10), 2 = numerous (>10) and 3 = extensive areas of the body covered. Similarly, the size of wheals (diameter of the greatest wheal) was scored as 0 = absent, 1 = ≤1.5 cm, 2 = >1.5 to <2.5 cm and 3 = >2.5 cm.

The TSS was calculated as the sum of scores for pruritus, number of wheals and the maximum wheal size recorded in the patients’ diaries each day.

Assessment of quality of life  The DLQI questionnaire (21, 22), a self-administered QoL instrument comprising 10 questions (each of which is rated on a 4-point scale; 0 = ‘not at all’, 1 = ‘a little’, 2 = ‘a lot’ and 3 = ‘very much’; as well as a ‘not relevant’ response scored as 0), was used to assess the QoL. Patients completed the DLQI at randomization visit (day 0) and at the end of treatment visit (day 28), or in case of withdrawal from the study at the early discontinuation visit. The DLQI was calculated by summing the score of each question to possible maximum score of 30; with a higher score indicating greater impairment in the QoL of the patient.

Global evaluation of discomfort caused by urticaria  Overall discomfort caused by urticaria was assessed at days 0, 14 and 28 (or at the early discontinuation visit in case of withdrawal from the study), using a 0–100 mm VAS; with 0 mm indicating ‘no discomfort’ and 100 mm indicating ‘extreme discomfort’.

Impact of urticaria on sleep  The effect of urticaria on sleep was assessed at days 0, 14 and 28 (or at the early discontinuation visit in case of withdrawal from the study) by rating the question ‘During the last week, how much has your sleep been affected by your urticaria?’ on a 5-point scale; with indications of 0 = not at all, 1 = somewhat, 2 = moderately, 3 = a lot and 4 = very much.

Investigator’s global clinical impression  The investigators’ GCI of each patient was recorded at the end of treatment, or at the early discontinuation visit in case of withdrawal from the study, using an efficacy index. The efficacy index was based on the degree of therapeutic effect and the intensity of adverse effects ranging from a scale of 1–16, with 1 representing ‘vast improvement and no adverse effects’, and 16 representing ‘unchanged or worse therapeutic effect and adverse effects outweighing the therapeutic effect’.

Evaluation of safety

Safety and tolerability to treatment were evaluated according to routine laboratory tests (haematology and biochemistry), 12-lead ECGs, clinical examinations, and the incidence, severity and type of AEs reported by the patients over the course of treatment. All AEs were coded using the Medical Directory for Regulatory Activities (MedDRA; MSSO, Reston, VA, USA) and grouped by treatment.

Statistical analysis

It was estimated that in order to detect a mean treatment difference of 1.0 in the TSS with 80% power at the 5% level of significance and an assumed standard deviation (SD) of 3.0, at least 142 patients would be required for each treatment group. Considering approximately 20% drop-out rate, the overall sample size was calculated to be 540 patients (180 patients per treatment group).

All clinical and other relevant data were entered separately by two individuals into a database specifically created for the study and managed by an independent consultancy (AAI Pharma, Spain). Analyses of all efficacy measures were performed on the intent-to-treat (ITT) population, which consisted of all randomized patients who had received at least one treatment dose and had a baseline assessment and at least one assessment of the primary efficacy variable after the baseline visit. Similarly, analyses of all safety measures were conducted on the ‘safety population’, which consisted of all patients who had received at least one dose of study treatment. The Last Observation Carried Forward approach was used for missing values.

Qualitative variables were summarized as the frequency distribution and quantitative variables as mean, SD or standard error with 95% confidence interval. The change from baseline in the patient’s reflective mean daily TSS over the 28 days treatment period, the primary efficacy measure, was analysed using an analysis of covariance (ancova) model, with change from baseline in mean TSS (mean TSS over the 28 days − TSSbaseline) as the dependent variable, baseline TSS as the covariable and treatment as the main factor. Pair-wise comparisons to test for significance of any differences in the means among the treatment groups were performed using the Tukey’s multiple comparison test. All secondary efficacy variables related to changes in symptoms were also subjected to a similar analysis, as for the primary variable. For secondary variables measuring the AUC, an anova model was performed, with the AUC of symptoms (TSS) as the dependent variable and the treatment group as the main factor. The assessment of the impact of urticaria on sleep scale at each study visit was described and analysed either by means of Chi-square test or Fisher exact test as appropriate. The GCI was summarized with the percentage of patients in each category, and the significance of any treatment differences was assessed using the Kruskal–Wallis test.

Results

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

Patient disposition

Figure 1 shows the disposition of patients involved in this study. A total of 587 patients were screened and 525 (89.4%) were randomized to treatment. Overall, 516 (98.3%) were included in the ITT population of whom 457 (88.6%) completed the study. The safety population comprised 522 (99.4%) patients. Of the 65 patients withdrawing, over half the patients [36 (55.4%) patients; 24 in placebo group, five in bilastine group and seven in levocetirizine group] withdrew because of lack of efficacy, whereas only four (6.2%) patients (one in placebo group and three in bilastine group) withdrew because of an AE (Fig. 1). The overall rate of withdrawal because of lack of efficacy was significantly greater in the placebo-treated group (13%) compared with bilastine 20 mg (2.9%; P < 0.05) and levocetirizine 5 mg (4.2%; P < 0.05) treated groups.

image

Figure 1.  Patient disposition.

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Patient demographics and baseline clinical characteristics

The demographic and baseline clinical characteristics of the patients comprising the ITT population are shown in Table 1. There were twice as many females as males, in both the bilastine 20 mg and levocetirizine 5 mg treated groups and nearly four times as many females as males in the placebo-treated group. The differences in gender were statistically significant for both bilastine and levocetirizine groups compared with placebo group (P < 0.01 vs bilastine and P < 0.05 vs levocetirizine). The treatment groups were otherwise similar with respect to demographics, the duration of disease and TSS at baseline (Table 1).

Table 1.   Demographic and baseline clinical characteristics of patients comprising the intent-to-treat population
VariableBilastine 20 mg (n = 172)Levocetirizine 5 mg (n = 163) Placebo (n = 181) Test P-values
  1. TSS, total symptoms score.

  2. *Mean (SD).

Gender (male), n (%) 63 (36.6)54 (33.1)40 (22.1)Chi-square 0.008
Age (years)*  41.7 (13.8)39.8 (13.5)39.4 (13.9)anova 0.257
Race (Caucasian), n (%)170 (98.8)162 (99.4)179 (98.9)Fisher test 1.000
Height (cm)*167.5 (9.1)166.6 (9.4)165.9 (8.3)anova 0.269
Weight (kg)* 71.5 (15.7) 71.1 (16.2)69.3 (14.8)anova 0.361
Months since diagnosis* 36.7 (51.3) 28.2 (39.6)34.8 (63.6)anova 0.300
TSS* anova
 Patient  6.74 (1.37)  6.44 (1.15)6.46 (1.29)0.051
 Investigator  6.72 (1.25)  6.43 (1.14)6.50 (1.21)0.069
Pruritus severity* anova
 Patient  2.29 (0.64)  2.16 (0.53)2.18 (0.62)0.090
 Investigator  2.26 (0.61)  2.13 (0.55)2.18 (0.57)0.148
Number of wheals* anova
 Patient  2.17 (0.62)  2.04 (0.59)2.06 (0.59)0.073
 Investigator  2.19 (0.58)  2.03 (0.58)2.08 (0.56)0.031
Maximum wheal size* anova
 Patient  2.27 (0.66)  2.24 (0.60)2.24 (0.64)0.776
 Investigator  2.27 (0.65)  2.26 (0.60)2.24 (0.66)0.901

Assessment of the patient cohorts in each country further demonstrated that these were not significantly different with respect to the mean age of the patients, although there were generally more females than males in each country [Argentina (n = 127): age 38.1 ± 13.1, 33M/94F; Belgium (n = 7): age 33.9 ± 8.0, 1M/6F; France (n = 19): age 43.5 ± 13.3, 9M/10F; Germany (n = 16): age 42.1 ± 14.7, 6M/10F; Poland (n = 81): age 43.7 ± 12.9, 25M/56F; Romania (n = 242): age 40.4 ± 14.4, 77M/165F; Spain (n = 24): age 38.2 ± 11.4, 6M/18F].

Treatment compliance

The total mean compliance was 99.8% for bilastine 20 mg, 99.9% for levocetirizine 5 mg and 99.7% for placebo, with no statistically significant differences among the treatment groups (anova, P = 0.436).

Effect of treatment on the patients’ symptom scores

Total symptoms score  The TSS was reduced progressively by all treatments from baseline over a period of 28 days treatment (Fig. 2); with significant differences noted between bilastine 20 mg and levocetirizine 5 mg-treated groups vs placebo-treated group from day 2 onward over the entire treatment period (Fig. 2). The mean change from baseline in the patients’ reflective daily TSS over the 28-day treatment period, the primary efficacy measure, was significantly greater for bilastine 20 mg and levocetirizine 5 mg treated groups compared with placebo-treated group (P < 0.001 for bilastine and levocetirizine vs placebo), but not significantly different between the active treatment groups (Table 2). Overall, the efficacy of bilastine was not dependent on ethnicity (nationality), age or gender of the patient.

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Figure 2.  Effect of treatment with bilastine 20 mg, levocetirizine 5 mg, or placebo on mean total symptoms score recorded as reflective 12 hourly scores in the morning (m) and evening (e); over a period of 28 days.

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Table 2.   Effect of treatment on patients’ reflective total and individual symptoms scores in the intention-to-treat population
VariableBilastine 20 mg (n = 172)Levocetirizine 5 mg (n = 163) Placebo (n = 181)ancova test (P-values)
  1. Values are given as mean (SD).

  2. TSS, total symptoms score.

  3. *P < 0.001 for bilastine/levocetirizine vs placebo, using Tukey’s multiple comparisons test. †P < 0.05 for levocetirizine vs bilastine, using Tukey’s multiple comparisons test.

TSS
 At baseline6.87 (1.07)6.70 (0.94)6.70 (1.05) 
 Mean change over 14 days−3.99 (2.07)*−4.35 (1.95)*−2.61 (1.98)*<0.001
 Mean change over 28 days−4.23 (2.1)*−4.63 (1.91)*−2.99 (2.16)<0.001
Pruritus
 At baseline2.32 (0.45)2.23 (0.44)2.29 (0.44) 
 Mean change over 28 days−1.48 (0.73)*−1.56 (0.67)*−1.01 (0.78)<0.001
Number of wheals
 At baseline2.24 (0.43)2.15 (0.43)2.17 (0.43) 
 Mean change over 28 days−1.37 (0.73)*−1.47 (0.70)*−1.00 (0.74)<0.001
Maximum wheal size
 At baseline2.30 (0.53)2.32 (0.47)2.25 (0.54) 
 Mean change over 28 days−1.37 (0.83)*−1.60 (0.75)*,†−0.97 (0.80)<0.001

The significant improvements in TSS scores over 28-day treatment with bilastine and levocetirizine were reflected by significantly greater changes from baseline in the AUC of the TSS over 28 days, compared with placebo treatment (Table 3).

Table 3.   Change from baseline in area under the curve for patients’ reflective symptoms scores in the intention-to-treat population
VariableBilastine 20 mg (n = 172)Levocetirizine 5 mg (n = 163)Placebo (n = 181)anova test (P-values)
  1. Values are given as mean (SD) [95% CI].

  2. AUC, area under curve; TSS, total symptoms score.

  3. *P < 0.001 for bilastine/levocetirizine vs placebo, using Tukey’s multiple comparisons test.

  4. P < 0.05 for levocetirizine vs bilastine, using Tukey’s multiple comparisons test.

AUCTSS
 Change over 28 days’ treatment−115.21 (58.05)* [−123.95, −106.47]−126.50 (52.55)* [−134.63, −118.38]−81.50 (59.22) [−90.19, −72.81]<0.001
AUCpruritus
 Change over 28 days’ treatment−40.47 (20.04)* [−43.48, −37.45]−42.75 (18.41)* [−45.60, −39.91]−27.69 (21.39) [−30.82, −24.55]<0.001
AUCnumber of wheals
 Change over 28 days’ treatment−37.32 (20.15)* [−40.36, −34.29]−40.08 (19.26)* [−43.06, −37.10]−27.26 (20.34) [−30.24, −24.27]<0.001
AUCmaximum wheal size
 Change over 28 days’ treatment−37.42 (22.63)* [−40.82, −34.01]−43.67 (20.60)*,† [−46.86, −40.48]−26.56 (21.73) [−29.75, −23.37]<0.001

The change from baseline in the patients’ instantaneous TSS was also similar and significantly greater for bilastine 20 mg and levocetirizine 5 mg treated groups compared with placebo-treated group at 14 days and 28 days (P < 0.001 for bilastine/levocetirizine vs placebo) (Table 4).

Table 4.   Effect of treatment on patients’ instantaneous symptoms scores in the intention-to-treat population
VariableBilastine 20 mg (n = 172)Levocetirizine 5 mg (n = 163)Placebo (n = 181)Test, P-values
  1. Values are given as mean (SD).

  2. TSS, total symptoms score.

  3. *P < 0.001 for bilastine/levocetirizine vs placebo, using Tukey’s multiple comparisons test.

TSS
 At day 06.74 (1.37)6.44 (1.15)6.46 (1.29)anova, 0.052
 At day 141.98 (2.24)1.58 (2.04)2.82 (2.66) ancova, <0.001 anova, <0.001
 Change from day 0−4.71 (2.47)*−4.86 (2.29)*−3.61 (2.27)
 % Change from day 0−69.91 (33.87)*−74.91 (33.03)*−55.04 (43.68)
 At day 281.95 (2.51)1.38 (2.29)2.63 (2.78) ancova, <0.001 anova, <0.001
 Change from day 0−4.81 (2.64)*−5.07 (2.45)*−3.84 (2.92)
 % Change from day 0−70.93 (37.42)*−78.44 (35.33)*−57.98 (47.52)
Pruritus
 At day 02.29 (0.64)2.16 (0.53)2.18 (0.62)anova, 0.090
 At day 140.64 (0.77)0.47 (0.71)0.94 (0.91) ancova, <0.001 anova, <0.001
 Change from day 0−1.63 (0.97)*−1.69 (0.84)*−1.20 (1.04)
 % Change from day 0−70.39 (38.23)*−78.03 (34.12)*−52.95 (49.36)
 At day 280.59 (0.81)0.41 (0.72)0.87 (0.98) ancova, <0.001 anova, <0.001
 Change from day 0−1.71 (0.94)*−1.75 (0.85)*−1.31 (1.11)
 % Change from day 0−73.95 (36.98)*−80.71 (34.91)*−56.67 (52.98)
Number of wheals
 At day 02.17 (0.62)2.04 (0.59)2.06 (0.59)anova, 0.073
 At day 140.67 (0.82)0.52 (0.73)0.91 (0.91) ancova, <0.001 anova, <0.001
 Change from day 0−1.49 (0.93)*−1.53 (0.83)*−1.15 (1.04)
 % Change from day 0−68.0 (39.93)*−74.24 (37.35)*−52.20 (51.19)
 At day 280.63 (0.88)0.46 (0.79)0.86 (0.96) ancova, <0.001 anova, <0.001
 Change from day 0−1.54 (0.96)*−1.60 (0.95)*−1.20 (1.10)
 % Change from day 0−69.72 (43.63)*−75.89 (44.68)*−55.40 (55.39)
Maximum wheal size
 At day 02.27 (0.66)2.24 (0.60)2.23 (0.64)anova, 0.776
 At day 140.67 (0.86)0.59 (0.85)0.98 (1.00) ancova, <0.001 anova, <0.001
 Change from day 0−1.59 (0.93)*−1.64 (1.00)*−1.26 (1.07)
 % Change from day 0−70.35 (36.67)*−71.86 (40.31)*−55.56 (45.88)
 At day 280.73 (1.01)0.52 (0.89)0.90 (1.00) ancova, <0.001 anova, <0.001
 Change from day 0−1.56 (1.13)−1.72 (0.99)*−1.33 (1.10)
 % Change from day 0−66.37 (49.45)−76.52 (40.66)*−60.04 (47.24)

Individual symptoms scores  Analysis of patients’ reflective daily scores for pruritus severity, the number of wheals, and the maximum size of wheals at the end of treatment demonstrated that the mean change from baseline for each of these parameters was also significantly greater in bilastine 20 mg and levocetirizine 5 mg treated groups compared with the placebo-treated group (P < 0.001 for bilastine/levocetirizine vs placebo) (Table 2). Although bilastine and levocetirizine were not significantly different with respect to their effects on pruritus and the number of wheals, levocetirizine produced a significantly greater change from baseline in the maximum size of wheals compared with bilastine (P < 0.05) (Table 2). The significantly greater improvements in the individual symptoms over 28 days’ treatment with bilastine 20 mg and levocetirizine 5 mg were also reflected as significantly greater changes from baseline in the AUC for the individual symptoms scores in bilastine 20 mg and levocetirizine 5 mg-treated groups compared with placebo treated group (Table 3).

The effect of treatment on the patients’ instantaneous scores for pruritus severity, the number of wheals, and the maximum size of wheals is shown in Table 4. Bilastine 20 mg produced significantly greater changes from baseline at 14 and 28 days of treatment in each of these parameters (P < 0.001), except for the change in the maximum size of the wheals at 28 days, compared with placebo. Similarly, levocetirizine 5 mg also produced significantly greater changes from baseline in each of these parameters at 14 and 28 days, compared with placebo (P < 0.001) (Table 4).

Effect of treatment on the investigators’ symptom scores

Table 5 shows the investigators’ instantaneous assessment of the patients’ symptoms at days 0, 14 and 28, and indicates that overall the investigators’ TSS and individual symptom’s scores closely resembled the patients’ instantaneous scores; with significantly greater improvements demonstrated in patients treated with bilastine 20 mg and levocetirizine 5 mg compared with patients treated with placebo. Neither the TSS nor the individual symptoms scores were significantly different for the active treatments after 14 and 28 days of treatment.

Table 5.   Effect of treatment on investigators’ instantaneous symptoms scores in the intention-to-treat population
Variable Bilastine 20 mg (n = 172)Levocetirizine 5 mg (n = 163) Placebo (n = 181)Test, P-values
  1. Values are given as mean (SD).

  2. TSS, total symptoms score.

  3. *P < 0.001 for bilastine/levocetirizine vs placebo, using Tukey’s multiple comparisons test. †P < 0.05 for bilastine vs levocetirizine, using Tukey’s multiple comparisons test.

TSS
 At day 06.72 (1.25)6.43 (1.14)6.50 (1.21)anova, 0.069
 At day 141.91 (2.19)1.59 (2.05)2.75 (2.64) ancova, <0.001 anova, <0.001
 Change from day 0−4.79 (2.39)*−4.84 (2.27)*−3.73 (2.73)
 % Change from day 0−71.25 (33.11)*−74.75 (32.69)*−57.16 (41.50)
 At day 281.95 (2.51)1.40 (2.28)2.66 (2.78) ancova, <0.001 anova, <0.001
 Change from day 0−4.79 (2.63)*−5.05 (2.36)*−3.86 (2.98)
 % Change from day 0−71.00 (37.51)*−78.65 (33.66)*−57.62 (46.59)
Prritus
 At day 02.26 (0.61)2.13 (0.55)2.18 (0.57)anova, 0.148
 At day 140.57 (0.73)0.45 (0.68)0.88 (0.90) ancova, <0.001 anova, <0.001
 Change from day 0−1.67 (0.94)*−1.69 (0.84)*−1.28 (1.02)
 % Change from day 0−73.50 (35.38)*−77.81 (34.30)*−55.97 (47.89)
 At day 280.57 (0.81)0.40 (0.72)0.85 (0.97) ancova, <0.001 anova <0.001
 Change from day 0−1.69 (0.94)*−1.74 (0.85)*−1.32 (1.07)
 % Change from day 0−74.15 (36.34)*−81.22 (33.48)*−58.43 (49.92)
Number of wheals
 At day 02.19 (0.58)2.03 (0.58)†2.08 (0.56)anova, 0.031
 At day 140.66 (0.82)0.51 (0.70)0.89 (0.91) ancova, <0.001 anova, <0.001
 Change from day 0−1.52 (0.88)*−1.52 (0.83)*−1.19 (0.98)
 % Change from day 0−69.02 (38.88)*−74.03 (37.00)*−55.77 (46.54)
 At day 280.64 (0.90)0.47 (0.79)0.89 (0.97) ancova, <0.001 anova, <0.001
 Change from day 0−1.56 (0.93)*−1.58 (0.94)*−1.20 (1.13)
 % Change from day 0−70.81 (41.70)*−75.05 (44.25)*−53.88 (55.74)
Maximum wheal size
 At day 02.27 (0.65)2.26 (0.60)2.24 (0.66)anova, 0.901
 At day 140.67 (0.85)0.62 (0.89)0.98 (1.01) ancova, <0.001 anova, <0.001
 Change from day 0−1.60 (0.95)*−1.63 (1.02)*−1.26 (1.00)
 % Change from day 0−69.73 (38.41)*−70.89 (41.07)*−54.82 (47.97)
 At day 280.73 (1.01)0.53 (0.89)0.92 (1.00)ancova, <0.001 anova, 0.001
 Change from day 0−1.55 (1.14)−1.73 (0.97)*−1.34 (1.15)
 % Change from day 0−65.88 (48.65)−76.31 (39.44)*−58.33 (48.40)

Effect of treatment on quality of life

Bilastine 20 mg decreased the mean DLQI Global score of 13.38 ± 5.96 at randomization to a score of 3.98 ± 4.99 at day 28 (mean change of −9.45 ± 6.98), compared with a decrease from 12.71 ± 5.80 at randomization to 6.81 ± 6.26 at day 28 (mean change of −5.93 ± 7.67) after treatment with placebo (P < 0.001 vs bilastine). Similarly, the mean DLQI Global score was also decreased to a significantly greater extent from 12.63 ± 5.61 at randomization to 3.80 ± 5.50 at day 28 (mean change of −8.94± 6.53) after treatment with levocetirizine 5 mg, compared with placebo (P < 0.001). Analyses of changes in the individual DLQI items scores, showed that apart from the ‘Work and School’ item score for bilastine-treated patients, all other DLQI items scores (including Symptoms and feelings; Daily activities; Leisure; Personal relationships; and Treatments) were decreased to significantly greater extent from randomization visit to final visit, compared with placebo-treated patients. In levocetirizine-treated patients, there were no statistically significant differences in ’leisure’, ‘personal relationships’ and ‘treatment’ items scores. Any differences in either the DLQI Global or individual items scores were not statistically significant between the active treatment groups.

Effect of treatment on urticaria-associated discomfort

Bilastine 20 mg and levocetirizine 5 mg significantly reduced the discomfort resulting from CU to a greater extent from the randomization visit to 14- and 28-day visits, compared with placebo, as indicated by greater decrease in VAS scores (Table 6). The active treatments were not significantly different.

Table 6.   Effect of treatment on discomfort and disruption of sleep caused by chronic idiopathic urticaria in the intention-to-treat population
VariableBilastine 20 mg (n = 172)Levocetirizine 5 mg anova (n = 163)Placebo (n = 181)Test, P-values
  1. VAS, visual analogue scale.

  2. *P < 0.001 for bilastine/levocetirizine vs placebo, using Tukey’s multiple comparisons test.

  3. P < 0.001 for bilastine/levocetirizine vs placebo, using Chi-square test.

Discomfort VAS (mm)
 At day 072.49 (20.58)70.28 (18.14)71.33 (19.46) ancova, <0.001 ancova, <0.001
 At day 1427.65 (26.95)21.97 (23.44)39.51 (27.47)
 Change from day 0−44.34 (29.13)*−48.81 (25.39)*−30.36 (29.54)
 At day 2823.22 (28.29)16.6 (23.84)36.94 (33.89)
 Change from day 0−49.71 (32.13)*−53.59 (27.63)*−34.48 (35.18)
Disruption of sleep, n (%)
 At day 0
  Not at all9 (5.2)5 (3.1)5 (2.8)Chi-square, 0.247
  Somewhat34 (19.8)41 (25.2)33 (18.2)
  Moderately51 (29.7)63 (38.7)69 (38.1)
  A lot62 (36.0)40 (24.6)60 (33.1)
  Very much16 (9.3)14 (8.6)14 (7.7)
 At day 14
  Not at all89 (54.6)†103 (66.9)†55 (34.4)Chi-square, <0.001†
  Somewhat51 (31.3)38 (24.7)50 (31.3)
  Moderately15 (9.2)5 (3.2)38 (23.8)
  A lot7 (4.3)7 (4.5)14 (8.8)
  Very much1 (0.6)1 (0.6)3 (1.9)
  Missing9921
 At day 28
  Not at all106 (62.7)†115 (72.5)†76 (42.7)Chi-square, <0.001†
  Somewhat38 (22.5)29 (18.2)46 (25.8)
  Moderately18 (10.7)5 (3.1)26 (14.6)
  A lot4 (2.4)5 (3.1)20 (11.2)
  Very much3 (1.8)5 (3.1)10 (5.6)
  Missing343

Effect of treatment on urticaria-associated disruption of sleep

Significantly larger number of patients experienced improvements in sleep after 14 and 28 days of treatment with bilastine 20 mg and levocetirizine 5 mg compared with treatment with placebo (Table 6). Indeed, 54.6% and 62.7% of patients treated with bilastine 20 mg and 66.9% and 72.3% of patients treated with levocetirizine 5 mg experienced no disturbance at all in sleep associated with CU after 14 and 28 days of treatment respectively, compared to 34.4% and 42.7% of patients treated with placebo. Any differences between the active groups were not statistically significant at either time-point.

Effect of treatment on the investigator’s GCI

The investigators’ GCI scores were significantly lower for bilastine 20 mg [5 (range 1–9)] and levocetirizine 5 mg [2 (range 1–6)] treated patients, compared with placebo-treated patients [6 (range 1–13); Kruskal–Wallis test, P < 0.001].

Safety assessment

Overall, 35.8%, 37.0% and 29.9% of patients taking bilastine 20 mg, levocetirizine 5 mg and placebo respectively, experienced at least one AE; of which the most frequently reported (≥3.0%) in each group were headache (13.9%, 15.8% and 12.0% respectively) and somnolence (5.8%, 6.7% and 3.3% respectively). Similarly, the incidences for drug-related AEs were 30.1%, 26.7% and 22.8% respectively, for patients taking bilastine 20 mg, levocetirizine 5 mg and placebo; with headache (12.1%, 12.1% and 9.2% respectively) and somnolence (5.8%, 6.7% and 3.3% respectively) being the most common. Just under 3.0% of the patients in bilastine 20 mg (2.9%) and placebo (2.7%) treated groups also experienced drug-related fatigue, which was not reported by any patient treated with levocetirizine 5 mg. Neither glaucoma nor prostatic hypertrophies, both of which are antimuscarinic effects associated with some antihistamines, were reported by any patient in any treatment group. The differences in the overall and drug-related incidence of AEs were not significant among the treatment groups. No serious AEs or death were reported during the study and there were no clinically significant changes in any laboratory tests, ECGs, heart rate, or systolic and diastolic blood pressure, in any treatment group.

Discussion

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

This study was specifically designed to assess the efficacy and safety of bilastine, a novel H1-antihistamine for the treatment of symptomatic patients with CU, and to compare these with the efficacy and safety of levocetirizine, a more extensively investigated H1-antihistamine. Our study demonstrated that bilastine 20 mg was significantly more effective than placebo in reducing the symptoms of CU; as indicated by induction of greater decreases from baseline in the patients’ mean reflective and instantaneous total (TSS; comprising the sum of scores for pruritus severity, the number of wheals and the maximum size of wheals) and individual symptom scores, over a period of 28 days. Moreover, significant reduction of TSS was marked from day 2 of treatment and maximal from days 6–7 onwards. Bilastine 20 mg was also significantly more effective than placebo in improving the QoL of these patients and in reducing the general discomfort and disruption of sleep associated with CU. Comparison with levocetirizine 5 mg indicated both compounds to be equally effective in reducing symptoms and improving the quality of life, discomfort, and sleep in these patients. The similarities in the incidences of overall and drug-related AEs profiles and the lack of abnormalities in clinical and laboratory assessments of safety reported in the bilastine 20 mg and the placebo-treated groups indicated that the recommended therapeutic dose of bilastine 20 mg was also well tolerated and safe in patients with CU.

Our findings for the efficacy of bilastine 20 mg are in accordance with the preliminary findings of Audicana et al. (23), who investigated the effect of bilastine 10, 20 and 30 mg or placebo once daily for 4 weeks in symptomatic patients with CU. These authors demonstrated that all doses of bilastine led to significantly greater change from baseline in the TSS (for pruritus severity, the number of wheals, and the maximum size of wheals) at the end of treatment, compared with placebo. Indeed, our findings also reflect the findings of studies in healthy volunteers. One randomized, double-blinded, four-period crossover study evaluated the effect of single doses of bilastine 2.5, 5, 10, 20 and 50 mg, and cetirizine 10 mg on histamine-induced wheal and flare responses before and after 1.5–24 h post dosing in 21 healthy male subjects (12). While all the doses of bilastine inhibited histamine-induced wheal and flare reactions equally or more effectively than cetirizine 10 mg during the first 12 h, only doses of bilastine 20 and 50 mg were equally or more effective than cetirizine at 24 h post dosing. Moreover, an open-label study in healthy 18- to 35-year-old and elderly (≥65 years of age) subjects demonstrated that inhibition by bilastine 20 mg of the histamine-induced wheal and flare reaction was not affected by age or gender, suggesting that dose adjustments for bilastine are unlikely to be necessary on this basis (24).

The findings from the present study are also in general accordance with the findings for several other H1-antihistamines, particularly desloratadine (25–27), fexofenadine (28–30) and levocetirizine (31, 32), which have been shown to lead to significantly greater improvements in symptoms and QoL of symptomatic CU patients over a period of 4–6 weeks of treatment. However, unlike these studies, our study was designed to additionally determine the degree of concordance between the patients’ and investigators’ evaluation of the efficacy of treatment, by means of both the patients and investigators assessing instantaneous symptom scores at each clinic visit. Indeed, the close similarity in the TSS and individual symptoms scores noted by both the patients and investigators suggests that the improvements in symptoms noted by the patients following treatment with bilastine and levocetirizine were likely to be an accurate reflection of the beneficial effects of these agents in the treatment of CU. This is further emphasized by the demonstration of significant improvements in the overall QoL of these individuals, measured objectively by a well-established instrument, as well as significant reductions in general discomfort and disruption of sleep associated with CU. The finding that a substantial number of patients treated with placebo experience no sleep disruption after 14 and 28 days’ treatment as compared with baseline, may in the first instance suggest that the effect of active treatment is not much greater than that of placebo in improving sleep. It is likely, however, that this is primarily the classical ‘placebo-effect’ because examination of the number of patients experiencing a ‘lot’/‘very much’ sleep disruption after 2–4 weeks indicates that this increases in the placebo-treated group, where as the number of patients experiencing a ‘lot’/‘very much’ sleep disruption generally decreases in the active-treatment groups.

As mediators other than histamine are thought to play a role in the manifestation of the symptoms of CU (1, 3), it is possible that the efficacy of bilastine in significantly attenuating the symptoms of CU and improving the QoL of patients in this study may at least be in part resulting from some of the anti-inflammatory properties of bilastine. Although, data on the specific anti-inflammatory effects of bilastine in humans are currently sparse, preliminary findings from in vitro studies nevertheless indicate bilastine to possess demonstrable anti-inflammatory effects. Indeed, the close similarities in the findings for the beneficial effects of bilastine and levocetirizine in this study suggest that bilastine may also possess anti-inflammatory properties and act via mechanisms similar to those demonstrated for levocetirizine (33), as well as its parent compound cetirizine (34), at clinically relevant concentrations. This is particularly likely, as some in vivo anti-inflammatory properties of H1-antihistamines are thought to be related to inhibition of transcriptional factors (NF-kB), whose activation depends on H1-receptor active conformations; thus suggesting a degree of accordance of effect within this drug class (35, 36). Moreover, studies in animals have demonstrated that bilastine possesses anti-allergic activity similar to that noted for cetirizine and fexofenadine (10).

In summary, this study confirms that a therapeutic dose of bilastine 20 mg is a novel effective and safe treatment option for the management of symptomatic patients with CU, which is likely to add substantially to existing treatments in the context of considerable number of unsatisfied and undertreated CU patients (37).

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

We thank the study investigators and assistants at the investigative sites as shown below: MDS Pharma Services Inc. for technical assistance for development of study, data management and statistical analysis; Dr JL Devalia, PhD; and Dr Lourdes Azcárate, MD (FAES FARMA, S.A., Bilbao, Spain) for assistance with preparation and editing of the manuscript.

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  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Methods and materials
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  8. Appendix

Principal Investigators in the Bilastine International Working Group:

Argentina: René Baillieau, MD, Juan Ramos, MD (Mar del Plata); Diego Fernández, MD, Marta La Forgia, MD, María Valeria Dávila, MD (Buenos Aires); Maximiliano Gómez, MD, Federico Gómez (Salta); Tomás Herrero, MD, Ernesto Sánchez, MD (Buenos Aires); Alejandro Malbrán, MD, Mariano Marini, MD (Buenos Aires); Adriana Marcipar, MD, Dario Ardusso, MD, Ernesto Muñoz, MD (Rosario); Jorge Maspero, MD, Cesar Viegas, MD (Buenos Aires); Iris Medina, MD, Lorena Cerutti, MD, Javier Bercovich, MD, Juan Carlos Sendota, MD (Buenos Aires); Anahí Yánez, MD, Maria Sol Reyes, MD, Verónica Adriana Martínez, MD, Norma Esther Arroyo, MD (Buenos Aires).

Belgium: Wim Stevens, MD, Didier Elbo, MD (Antwerpen-Edegem); Anya de Moor, MD (Aalst); Erwin Suys, MD (Kortrijk); Linda Temmerman, MD, Els Van Autryve (Gent).

France: Patrick Combemale, MD, Jean-Louis Estival, MD (Lyon); Louis Dubertret, MD, Hamidou Zhor, MD, Marod Lahfa (Paris); Jean-Paul Ortonne, MD, Abdallah Khemis, MD, Kristel Chammat-Napritson, MD (Nice); Françoise Sanquer, MD (Quimper); François Wessel, MD, Dubreil Yann, MD (Nantes).

Germany: Volker Steinkraus, MD, Andrea Schlöbe, MD, Alexandra Gust, MD (Hamburg); Thomas Wildfeuer, MD (Berlin); Jan Simon, MD, Regina Treudler, MD, Max Simon Schlaak, MD, Anke Süb, MD (Leipzig); Peter Uhl, MD, Sylvia Gercken, MD (Berlin).

Poland: Ewa Bogacka, MD PhD, Marita Marszalska, MD, Dagmara Witkowska, MD, Joanna Bromirska, MD, Marzana Solecka, MD (Wroclaw); Ewa Chlebus, MD PhD, Monika Serafim, MD (Warszawa); Grazyna Chodorowska, MD, Dorota Urasowska, MD (Lublin); Monika Kapinska-Mrowiecka, MD, Beata Juszczynska-Darasz, MD, Fustyna Kostyra-Grabowska, MD, Marzena Czubak-Macugowska, MD (Krakow); Andrzej Kaszuba, MD, Iwonna Michalak, MD, Michal Senesczko, MD, Anna Ograczyk, MD (Lodz); Andrzej Langner, MD, Kristina Zadworna-Welz, MD, Anna Rajchel, MD, Artur Stedien, MD (Iwonicz Zdroj); Mariola Pawlaczyk, MD, Danuta Janicka, MD, Barbara Swatlowska Gorna, MD, Anita Rokowska, MD (Poznan).

Romania: Vasile Benea, MD, Alice Rusus MD, Simona Georgescu, MD (Bucaresti); Tania Cristodulo, MD, Adriana Diconeasa, MD, Kristina Nikulajevic, MD (Bucaresti); Dan Gheorghe Forsea, MD, Catalin Mihai Popescu, MD (Bucaresti); Alexandru Oanta, MD, Madalina Peres, MD (Brasov); Carmen Maria Salavastru, MD, George-Sorin Tiplica, MD (Bucaresti); Gloria Suciu, MD (Bucaresti); Lavinia Zalupca, MD, Dana Petrescu Seceleanu, MD (Bucaresti); Dan Mihail Toma, MD, Simona Laura Ianosi, MD (Craiova); Daniel Boda, MD, Harillaq Kalashi, MD (Bucaresti); Mihaela-Anca Jian, MD, Anca Debu, MD, Corina Mihailescu, MD (Brasov).

Spain: Luis Miguel Olmos, MD (Madrid); Miguel Ángel Gallego, MD, Eva Fernández, MD, Elena Vargas, MD, Mahmoud Houmani, MD, Antonio Aforcar, MD (Leganes, Madrid); Carlos Ferrándiz, MD, Jordi Rex, MD (Badalona, Barcelona); Ignacio Antépara, MD, Ignacio Jáuregui, MD, Iñaki Urrutia, MD, Pedro Gamoa, MD (Bilbao); Maite Audicana, MD, Daniel Muñoz, MD, Eduarda Fernández, MD, Miguel Echenagusia, MD (Vitoria); Mario Lecha, MD, Pilar Iranzu, MD (Barcelona); Ángel Campos Andreu, MD, Ramón Almero, MD (Valencia).