RESEARCH ARTICLE Rupatadine 10 and 20 mg are effective and safe in the treatment of perennial allergic rhinitis after 4 weeks of treatment: a randomized, double-blind, controlled trial with loratadine and placebo Background and objectives: Allergic rhinitis is a global health concern of increasing prevalence that can impact quality of life and work and school performance of affected individuals. Antihistamines are recommended as the first-line treatment. This randomized, controlled trial aimed to investigate the effects of rupatadine in adult subjects with perennial allergic rhinitis. Methods: We randomly assigned 283 patients to receive placebo (n = 69), loratadine 10 mg (n = 70), rupatadine 10 mg (n = 73) or rupatadine 20 mg (n = 71). The study design was double blind and treatment was continued for 4 weeks. Subjective assessment of symptoms (reflective evaluation) was recorded by patients in a diary card. The primary end point was the percentage of days where the score of the most severe symptom was less than or equal to one (Pdmax1). Furthermore, the change from baseline in the severity of total symptom score and nasal symptom score were recorded, and the investigator and patient global assessments were evaluated. Results: All 283 patients were included in analyses (intention to treat); 265 (94%) patients completed the follow-up. Rupatadine 20 mg significantly improved the Pdmax1 in comparison with placebo. Significant reductions from baseline in total symptom score were achieved with rupatadine 10 mg (-4.00), rupatadine 20 mg (-3.96) and loratadine (-3.94) compared with placebo (p < 0.01). Similarly, all three active treatments significantly reduced the nasal symptom score compared with placebo. No significant differences among groups in the incidence of overall adverse events were observed and no clinically significant QTc enlargements were detected. More patients receiving rupatadine complained of somnolence compared with loratadine. Conclusion: Once-daily rupatadine (10 and 20 mg) is an efficacious and safe treatment for the management of patients with perennial allergic rhinitis. KEYWORDS: clinical trial n histamine H1 antagonists n perennial allergic rhinitis Marek L Kowalski, n platelet-activating factor n rupatadine Dariusz Jurkiewicz, Jerzy Kruszewski, Dariusz Nowak, Ziemowit Allergic rhinitis (AR) is an inflammatory early-phase response to allergens, histamine is Zietkowski, Marie chronic disease of the upper airways character- the most important mediator and symptoms Špičaková, Eva ized by anterior or posterior rhinorrhea, sneez- such as rhinorrhea, sneezing and itching are Vernerová, Ester ing, nasal obstruction and/or itching of the nose. largely mediated through histamine recep- Seberová, Kamil Klenha In most cases it is also associated with ocular tors [8]. Lipid mediators, such as leukotrienes, & Iñaki Izquierdo† symptoms [1,2]. AR prevalence has been increas- prosta glandins, and platelet-activating factor †Author for correspondence: ing steadily during the past 40 years. It is esti- (PAF) are also involved. PAF specifically induces J Uriach y Compañía, S.A, mated to affect up to 40% of the population, vasodilatation and an increase in vascular per- Polígono Industrial Riera de depending on the geographical area and age meability, which may contribute to rhinorrhea Caldes, Avinguda Cami Reial, of patients [3]. Lifetime prevalence throughout and nasal congestion [9]. 51–57, 08184 Palau-Solità i European countries ranges between 17 and 29% Both histamine and PAF have complementary Plegamans, Barcelona, Spain [4,5]. Despite these figures, allergic symptoms activities in vivo, and each mediator is able to Tel.: +34 93 863 0272; are often underdiagnosed [5]. AR is considered promote the release of the other [10]. Dual block- Fax: +34 93 864 6606; a global health problem that affects social life, ade of these mediators is likely to be an effective [email protected] sleep, education and work, and accounts for an treatment for AR. *For full affiliation list see end increasing economic burden [1]. Rupatadine is a selective long-acting hista- of article. Symptoms are mainly induced after allergen mine (H1) and PAF receptor antagonist that has exposure due to IgE-mediated inflammation and been approved for marketing in most European complex interactions between effector cells, such Community countries and Brazil for the treat- as mast cells and basophils. Immunologic acti- ment of AR and chronic urticaria in adults vation of these effector cells induces the secre- and adolescents at a once-daily dose of 10 mg tion of proinflammatory mediators [6,7]. In the [11]. In a study involving patients with seasonal 10.2217/THY.09.1 © 2009 Future Medicine Ltd Therapy (2009) 6(3), 417–425 ISSN 14750708 417 RESEARCH ARTICLE Kowalski, Jurkiewicz, Kruszewski et al. Treatment of allergic rhinitis with rupatadine RESEARCH ARTICLE AR exposed to allergens, rupatadine showed a n Patients inclusion & fast onset of action and significantly decreased exclusion criteria allergen-induced nasal and non-nasal symptoms Male and female subjects aged 18–65 years, with [12]. Several randomized, controlled trials dem- a documented history of perennial AR symptoms onstrated that rupatadine 10 and 20 mg, given for at least 1 year were recruited. This study was once daily, are highly efficacious in attenuating undertaken before the release of the updated AR the symptoms of seasonal, perennial and persist- and its impact on asthma (ARIA) document and ent AR in adult and adolescent patients with broad use of new AR classification [17]. Women moderate-to-severe symptoms [13–16]. of child-bearing potential were required to have The present study was conducted to evaluate a negative pregnancy test at inclusion and use the efficacy and safety of rupatadine (10 and contraceptive methods during the study. Patients 20 mg) given once daily in comparison with with an electrocardiogram showing QTc inter- loratadine 10 mg and placebo as oral therapy in val values (according to Bazzet’s formula) of less the treatment of perennial AR. than 430 ms for males or 450 ms for females were permitted to enter the study. A sum of Study design & methods nasal symptoms score equal to or greater than n Study design five, based on the patients’ subjective assessment This was a randomized, double-blind, placebo- of their symptoms during the previous day, was controlled, parallel-group study, conducted in required on inclusion. 22 centers in Poland and the Czech Republic. Patients suffering from non-allergic rhinitis The study was conducted between October and (e.g., vasomotor, infectious or drug-induced rhini- March, to ensure that patients did not have sea- tis) or with a negative prick test were excluded. sonal symptoms. Patients suffering from per- Patients receiving systemic or topical medication, ennial AR were randomized to receive rupat- such as oral H1 or H2-receptor antagonists for at adine (10 mg or 20 mg), loratadine (10 mg) least 1 month, topical antihistamines for 48 h, or placebo once daily for a period of 4 weeks. nasal vasoconstrictors for 24 h, and/or corticos- Patients took a single dose of the study medi- teroids, ketotifen or any immuno suppressant for cation or placebo during the morning. All the 2 weeks prior to the inclusion of the study, were medications were of identical external appear- also excluded. Other exclusion criteria were treat- ance to maintain the blinding conditions of ment with hyposensitization therapy, or abnormal the study. A computer-generated randomized laboratory or electrocardiogram values of clinical scheme was used to provide balanced blocks relevance. Patients who satisfied all the inclusion of patients numbers for each of the three treat- criteria and none of the exclusion criteria started ment groups and the patients were assigned a the study treatment. sequential randomization number. During a screening visit, performed 1 week n Evaluation of efficacy before treatment initiation, the investigator Assessments of efficacy were based on the assessed the patients’ eligibility through a physi- patients’ subjective assessment of their symp- cal exam, symptom assessment, blood laboratory toms. Before taking the medication, patients tests and electrocardiogram. Prick tests were per- were asked to record the severity of symptoms formed if they had not been done within 1 year experienced during the previous day (reflective of the visit. A positive prick test was defined as a 24 h evaluation). Symptoms of rhinitis included wheal diameter exceeding 3 mm for a given non- four nasal symptoms (sneezing, nasal obstruc- seasonal allergen, compared with that of saline tion, nasal itching and rhinorrhea) and one non- solution injection or greater than that obtained nasal symptom (ocular itching). The severity of with histamine 10 mg injection. Participants symptoms was assessed by scoring on a four- were provided with a diary card and admitted to point scale (0 = absence of symptoms; 1 = some the 4-week study, attending a total of three visits but not troublesome; 2 = frequent and annoying (baseline, 2 and 4 weeks of treatment). symptoms; 3 = continuous symptoms, interfering All patients gave written informed consent with sleep or daily activities). to participate in the study, which was approved After 4 weeks of treatment, the investiga- by local ethics review boards and the regula- tor and the patient made a global assessment tory agencies for health in each country. The of efficacy on the basis of change in symptom study was performed in accordance with severity, scored on a five-point scale (0 = worse, the Declaration of Helsinki and subsequent 1 = no change, 2 = slight improvement, 3 = good amendments. improvement, 4 = excellent improvement). 418 Therapy (2009) 6(3) future science group RESEARCH ARTICLE Kowalski, Jurkiewicz, Kruszewski et al. Treatment of allergic rhinitis with rupatadine RESEARCH ARTICLE The primary efficacy outcome was the per- For quantitative (efficacy and safety) variables, centage of days during the study period where mean, median, standard deviation, maximum the score of the most severe symptom on each day and minimum values were calculated. Qualitative was less than or equal to 1 (Pdmax1).