Randomized, placebo-controlled study of cetirizine and loratadine in children with seasonal allergic rhinitis DO NOT COPY

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1 Randomized, placebo-controlled study of cetirizine and loratadine in children with seasonal allergic rhinitis Anjuli S. Nayak, M.D., William E. Berger, M.D., 1 Craig F. LaForce, M.D., 2 Eduardo R. Urdaneta, M.D., 3 Mitesh K. Patel, Pharm.D., 3 Kathleen B. Franklin, R.N., 4 and Mei-Miau Wu, Dr.P.H. 5 ABSTRACT Background: Pharmacologic treatment is a mainstay of allergy therapy and many caregivers use over-the-counter antihistamines for the treatment of seasonal allergic rhinitis (SAR) symptoms in children. Objective: To assess the efficacy and safety of cetirizine 10 mg syrup versus loratadine 10 mg syrup versus placebo syrup in a randomized double-blind study of children, ages 6 11 years, with SAR. Methods: This randomized, double-blind, parallel-group, placebo-controlled study was conducted at 71 U.S. centers during the spring tree and grass pollen season. After a 1-week placebo run-in period, qualified subjects were randomized to once-daily cetirizine 10 mg (n 231), loratadine 10 mg (n 221), and placebo (n 231) for 2 weeks. The primary efficacy end point was change from baseline in the subject s mean reflective total symptom severity complex (TSSC) score over 14 days. Results: Children treated with cetirizine experienced significantly greater TSSC score reductions versus children treated with placebo over 14 days (least square mean change, 2.1 versus 1.6; p 0.006). The differences in TSSC score improvement over 14 days between the cetirizine versus loratadine groups ( 2.1 versus 1.8; p 0.124) and between the loratadine versus placebo groups ( 1.8 versus 1.6; p 0.230) were not statistically significant. Predominant adverse events in the cetirizine, loratadine, and placebo groups were headache (3.5, 3.6, and 3.1%, respectively) and pharyngitis (3.5, 2.7, and 3.5%, respectively). Somnolence was reported in three subjects (1.3%) treated with cetirizine and in none of the other subjects. Conclusion: Cetirizine 10 mg was statistically significantly more efficacious than placebo in the treatment of SAR symptoms in children ages 6 11 years. Symptom improvement was not significantly different between the loratadine 10 mg and placebo groups. (Allergy Asthma Proc 38: , 2017; doi: /aap ) Allergic rhinitis, with its associated rhinorrhea, sneezing, congestion, and/or nasoocular pruritus, is one of the most common chronic diseases that affect children. 1 A global survey of 1.2 million children in 98 countries determined that the prevalence of rhinoconjunctivitis in children ages 6 7 years and years was 8.5 and 14.6%, respectively. 2 The onset From the 1 Allergy and Asthma Associates of Southern California, Mission Viejo, California, 2 Medical Director, North Carolina Clinical Research, Raleigh, North Carolina, 3 Medical Affairs, Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division, Fort Washington, Pennsylvania, 4 Franklin Consultants, Phoenixville, Pennsylvania, and 5 Quantitative Sciences, Johnson & Johnson Consumer Inc., Morris Plains, New Jersey Deceased The original clinical study was supported by Pfizer, Inc. Publication of the study results was supported by Johnson Consumer Inc., McNeil Consumer Healthcare Division E. Urdaneta was an employee of Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division, while authoring this publication. M. Patel is an employee of Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division. M. Wu is an employee of Johnson & Johnson Consumer Inc. K. Franklin is a consultant to McNeil Consumer Healthcare. The remaining authors have no conflicts of interest pertaining to this article Address correspondence to Kathleen B. Franklin, R.N., Franklin Consultants, 180 East Beacon Drive, Phoenixville, PA address: kfrankl1@its.jnj.com Copyright 2017, OceanSide Publications, Inc., U.S.A. of allergic rhinitis symptoms commonly occurs after 3 years of age; however, food and airborne allergen sensitizations may be discernible at an earlier age. 3,4 There is evidence to indicate that, in some children, allergic rhinitis represents a stage in the progression of the atopic march. 3,5,6 In childhood, allergic rhinitis may present as recurrent sore throats and upper respiratory tract infections. These symptoms may mistakenly be attributed to colds or other disorders, and allergic rhinitis may remain untreated. 7,8 In cases in which the young child is unable to articulate and describe his or her symptoms, allergic rhinitis may remain undiagnosed. 9 Treatment of allergic rhinitis in children is primarily focused on allergen avoidance and pharmacologic therapy. Cetirizine, a H1 receptor antagonist that is available over-the-counter (OTC), has been shown to be well tolerated and effective in children with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis In addition to its antihistaminic properties, cetirizine is considered to have broad anti-inflammatory effects, including the inhibition of leukocyte influx, 18 the reduction of intercellular adhesion molecule 1 expression, 19 and the augmentation of interleukin 10 and interferon gamma production. 20 Survey 222 May June 2017, Vol. 38, No. 3

2 data indicate a high prevalence rate of OTC medicine use in children 18 years of age. In a study of 8145 children in the United States, 70% of respondents stated that they used OTC medications to treat their child s recent illness. 21 Therefore, the objective of this study was to add to the current knowledge regarding the efficacy and safety of cetirizine treatment in children with SAR symptoms. METHODS Subject Characteristics The study participants were 6 11 years of age with a SAR diagnosis to grass or tree pollen of such severity that it required pharmacologic therapy each year for the past 2 consecutive years. SAR was confirmed by a recognized skin test (prick, intradermal, or Multitest, Lincoln Diagnostics, Inc., Decatur, IL) within the previous 15 months (prick and/or puncture wheal of 3 mm larger than the negative control; intradermal [up to a concentration of 1:1000 w/v or 1000 protein nitrogen units wheal of 5 mm larger than the negative control]). Girls who reached menarche, either before or during the study, had to agree to use acceptable methods of birth control if they became sexually active. Clinically significant nasal anatomic deformities, a history of chronic sinusitis, or a major systemic disease were criteria for exclusion. Individuals who were receiving intranasal, ocular, or systemic corticosteroids; oral leukotriene modifiers; immunotherapy; or oral or topical antihistamines were not eligible for the study. Study Design The randomized, double-blind, parallel-group, placebo-controlled study consisted of a 7-day placebo run-in period and a 2-week treatment period, and was conducted at 77 centers in the midwestern, western, and southern United States during the spring season from April 29 to July 25, The study complied with Good Clinical Practices and was conducted in full compliance with the World Medical Assembly Declaration of Helsinki (ClinicalTrials ID NCT ). The Copernicus Central Institutional Review Board (IRB) approved the protocol, protocol amendments, and subject informed consent for most investigative sites. The remaining sites obtained approval from local IRBs, including Creighton University, University of Chicago, St. Vincent Hospital, Vanderbilt, and University of Iowa. Written informed consent and subject assent were obtained before study entry. The subjects were evaluated at the clinic at screening (visit 1), at the baseline visit performed after the 1-week placebo run-in period (visit 2), and at weekly intervals during the 14-day double-blind treatment period (visits 3 and 4). At screening (visit 1), the investigator performed a physical examination, collected vital signs, and reviewed the child s medical history. The subject or the parent or guardian (guardian) was given placebo syrup and diaries in which the subject s self-assessed symptom severity scores were recorded daily before 10:00 AM and before taking the study medication. Symptom severity was based on the subject s assessment of symptoms in an instantaneous (at that moment of evaluation) and a reflective (over the past 24 hours since the last dose) manner. Instantaneous and reflective severity scores for sneezing, runny nose, itchy eyes, and watery eyes were recorded on a four-point scale (0 [none, complete absence of symptoms] to 3 [severe, symptoms present day and night, impact on daily activities, as well as on ability to sleep]). The total symptom severity complex (TSSC) score was the sum of the four individual symptom scores. Nasal congestion was graded separately in the daily diaries in the same instantaneous and reflective manner and on the same four-point scale. Subject diaries were collected and reviewed at every visit; concomitant medications and adverse events (AEs) were recorded. At baseline (visit 2), subjects qualified for randomization if, on 4 days of the placebo run-in period, they had scores of moderate or more intensity ( 2 on scale of 0 3) for at least two of the four symptoms that comprise the TSSC score. In addition, the subjects had to have a TSSC score of 5 on any 4 days of the placebo run-in period. Qualified subjects were randomly assigned to receive cetirizine syrup 10 mg (1 mg/ml), loratadine syrup 10 mg (1 mg/ml), or placebo syrup in a double-blind fashion (1:1:1 ratio) for 2 weeks. The subjects continued to record daily symptom assessments in their diaries during the treatment period. At visits 2, 3, and 4, the investigators evaluated the subjects symptoms since the last visit by using a scale from 0 (none, complete absence of symptoms) to 3 (severe, symptoms present day and night, impact on daily activities, as well as on ability to sleep). At visits 2, 3, and 4, the guardians assessed the subject s symptoms since the last visit by answering the following questions: (1) how often did your child sneeze, (2) how often did your child have a runny nose, (3) how often did your child have itchy eyes, (4) how often did your child have watery eyes, and (5) how often did your child have a stuffy nose? The guardian used a fourpoint scale to answer the questions, from 0 (not at all) to 3 (very often). The guardians also evaluated the social and emotional impact of caring for a child with SAR by answering the following questions on a Parental Burden Questionnaire at visits 2, 3, and 4, or at early termination: Over the past week, how much did your child s allergies (1) interfere with your normal social activities with family, friends, or groups; (2) interfere Allergy and Asthma Proceedings 223

3 with your ability to conduct routine daily activities (other than your job and/or volunteer work); (3) cause you to worry about his or her health; (4) interfere with your ability to work; and (5) interfere with your ability to be productive at work? The impact of caring for a child with SAR was recorded by using a scale from 1 (not at all) to 5 (extremely). At visit 4 or at early termination, the subject, with or without his or her guardian, provided a global treatment evaluation by answering the following question: Overall, how would you evaluate your response to the treatment you received for your allergy? The subject assessed his or her overall treatment responses by using a scale from 1 (a lot better) to 5 (a lot worse). At visit 4 or at early termination, the guardian completed an appraisal of personal satisfaction with the treatment by answering the following question: overall, how satisfied are you with the medication that your child received during the study? The guardian used a fivepoint scale to rate overall personal satisfaction, from 1 (very satisfied) to 5 (very dissatisfied). At visit 4 or early termination, the investigator used a seven-point scale to assess the treatment s effect, from 1 (major improvement; all signs and/or symptoms improved) to 7 (severe worsening; all signs and/or symptoms worsened). The investigator recorded a global assessment at visit 4 or early termination to assess the treatment effect: 1 (major improvement; all signs and/or symptoms improved) to 7 (severe worsening; all signs and/or symptoms worsened). Final assessments, including a physical examination, were performed at the last visit or at early study termination. Efficacy End Points The primary efficacy end point was the change from baseline in the subject s mean 24-hour reflective TSSC score over 14 days. Changes from baseline in the subject s mean reflective TSSC score over week 1 and week 2 of treatment were secondary end points. Additional secondary end points included the following: the subject s mean reflective TSSC score plus stuffy nose score, subject s instantaneous TSSC score, subject s instantaneous TSSC score plus stuffy nose score, subject s individual symptom scores (reflective and instantaneous), guardian s evaluation of the subject s symptoms, investigator s evaluation of subject s symptoms, and guardian s response on the Parental Burden Questionnaire. The guardian s overall personal satisfaction assessment, subject global evaluation of treatment, and investigator global evaluation of treatment were also secondary efficacy end points. Safety Safety was evaluated by summarizing observed or subject-reported AEs, vital sign measurements, physical examination findings, and concomitant medication use. AEs were categorized as treatment-related if, in the investigator s judgment, they were most likely caused by the study drug or if the causality was unknown. Clinical laboratory evaluations were not required. Statistical Methods Treatment group comparisons were made on the change from baseline values in efficacy end points that involved rhinoconjunctivitis symptoms and Parental Burden Questionnaire scores treated as a continuous variable by using a two-way analysis of covariance model with terms for treatment and investigator site, with the baseline value as a covariate. Least square means based on this main effect model were used to estimate treatment effect. Pairwise comparisons were made only if the overall treatment effect was significant (Fisher protected least significant difference). Treatment group differences for all categorical efficacy end points (i.e., Parental Burden Questionnaire in its original categorical scale, global evaluations, and parent or guardian overall satisfaction assessment) were analyzed by using Cochran Mantel Haenszel row mean test scores stratified by investigator site. All statistical tests related to treatment effect were two-sided, and statistical significance was declared at the 0.05 probability level. By using a two-sided test, a sample size of 330 subjects per treatment group would assure 81% power to detect a difference of 1.0 point in the mean change from baseline in the primary efficacy variable of TSSC scores between the cetirizine and loratadine treatment groups at the 0.05 significance level with assuming a pooled standard deviation of 4.5. The primary efficacy analysis was based on intention-to-treat subjects, defined as subjects who were randomized, received at least one dose of study medication and had at least one efficacy end point at baseline and at any subsequent visit. Safety was evaluated for all randomized subjects who received at least one dose of study medication. RESULTS Patient Characteristics Of 683 subjects randomized to treatment, safety was evaluated for 677 subjects who received at least one dose of cetirizine (n 228), loratadine (n 220), or placebo (n 229). These 677 subjects in the safety population were comparable at baseline with respect to sex, race, and age (p 0.05) (Table 1). Efficacy was evaluated in 677 intention-to-treat subjects in the cetirizine (n 210), loratadine (n 201), and placebo (n 214) groups; 52 subjects discontinued the study: 18 in the cetirizine group (7.9%), 19 in the loratadine group (8.6%), and 15 in the placebo group (6.6%). One subject 224 May June 2017, Vol. 38, No. 3

4 Table 1 Demographic and baseline characteristics of 677 in safety population* Characteristic taking cetirizine, three subjects taking loratadine, and two subjects taking placebo discontinued the study due to drug-related events. Five subjects in the cetirizine group, nine subjects in the loratadine group, and seven subjects in the placebo group discontinued the study due to AEs not related to the study drug (Table 2). Efficacy Results Primary Efficacy End Point. At baseline, there were no significant differences in the reflective TSSC scores among the cetirizine, loratadine, and placebo groups: 7.5, 7.6, 7.7, respectively; p Over the 14-day treatment period, the subjects treated with cetirizine experienced a significantly greater improvement in the reflective TSSC score compared with subjects taking placebo: 2.1 and 1.6, respectively; p (Fig. 1). Cetirizine (n 228) Loratadine (n 220) Placebo (n 229) Age, mean SD, y Sex, no. (%) Boys 131 (57.5) 125 (56.8) 123 (53.7) Girls 97 (42.5) 95 (42.2) 106 (46.3) Race, no. (%) White 173 (75.8) 170 (77.2) 167 (72.9) Black 31 (13.5) 26 (11.8) 39 (17.0) Other 24 (10.5) 24 (10.9) 23 (10.0) Weight, mean SD, kg Boys Girls Duration since first PAR diagnosis, mean 5.4 ( ) 5.6 ( ) 5.6 ( ) (range), y Drugs used to treat allergic disorders required 159 (69.7) 155 (70.5) 155 (67.7) in 3 mo before study, no. (%) Baseline TSSC score, mean SE# SD Standard deviation; PAR perennial allergic rhinitis; TSSC total symptom severity complex; SE standard error. *The p values for the three treatment groups were 0.094, 0.754, and 0.302, for age, sex, and race, respectively. #The baseline TSSC score is defined as the mean of the last three non-missing scores at and before visit 2. Table 2 Discontinuations from the study Cetirizine, no. (%) Loratadine, no. (%) Placebo, no. (%) Related to the study drug Adverse event 1 (0.4) 1 (0.5) 0 Lack of efficacy 0 2 (0.9) 2 (0.9) Not related to the study drug Adverse event 5 (2.2) 9 (4.1) 7 (3.1) Other 10 (4.4) 5 (2.3) 5 (2.2) Lack of efficacy 2 (0.9) 2 (0.9) 1 (0.4) Total 18 (7.9) 19 (8.6) 15 (6.6) The difference in the reflective TSSC score improvement between the cetirizine ( 2.1) and loratadine ( 1.8) groups did not reach statistical significance (p 0.124). The loratadine group ( 1.8) and placebo ( 1.6) group scores did not show a statistical difference either (p 0.230) (Table 3 and Fig. 1). Secondary Efficacy End Points. Baseline values were not statistically different among the treatment groups for the secondary efficacy end points, with the exception of the score for one individual item on the Parental Burden Questionnaire, How much did your child s allergies interfere with your ability to be productive at work? Over week 1, children treated with cetirizine experienced significantly greater improvements in the reflective TSSC score compared with children treated with placebo ( 1.6 and 1.1, respectively; p 0.010). Allergy and Asthma Proceedings 225

5 Table 3 period* Figure 1. Mean change from baseline in reflective total symptom severity complex (TSSC) score. Primary end point: Change from baseline in the mean reflective TSSC scores during a 14-day Cetirizine (n 228) The week 1 differences between the cetirizine and loratadine groups ( 1.6 and 1.2, respectively) and the loratadine and placebo groups ( 1.2 and 1.1, respectively) were not statistically significant (Table 4 and Fig. 1). Over week 2, children who were treated with cetirizine experienced significant improvement in the reflective TSSC score compared with the placebo group ( 2.8 and 2.3, respectively; p 0.027). The differences over week 2 between the cetirizine and loratadine groups ( 2.8 and 2.5, respectively) and loratadine and placebo groups ( 2.5 and 2.3, respectively) were not statistically significant (Table 4 and Fig. 1). Loratadine (n 219) Placebo (n 229) p Value Baseline, mean SE Day period, mean SE Change from baseline, LS mean SE Overall treatment effect Cetirizine vs placebo Cetirizine vs loratadine Loratadine vs placebo TSSC Total symptom severity complex; SE standard error; LS least square. *The baseline TSSC score is defined as the mean of the last three non-missing scores at and before visit 2. Over 2 weeks, improvement in the reflective TSSC score plus the stuffy nose score was significantly greater for subjects treated with cetirizine compared with subjects treated with placebo (p 0.011). Over the same period, the differences between cetirizine and loratadine and between loratadine and placebo were not statistically significant. For the reflective individual symptoms scores, improvements in sneezing scores over 14 days were significantly greater in the cetirizine group compared with placebo (p 0.007). For reflective runny nose, itchy eyes, watery eyes, and stuffy nose scores, the differences were not statistically sig- 226 May June 2017, Vol. 38, No. 3

6 Table 4 Secondary end point: Change from baseline in the mean reflective TSSC scores during the first and second weeks of treatment nificant among the groups (Fig. 2). The reduction in mean instantaneous TSSC scores over 14 days was significantly greater for the cetirizine group compared with placebo (p 0.014). The differences between cetirizine and loratadine, and between loratadine and placebo were not statistically significant. Over 2 weeks, improvement in the instantaneous TSSC plus stuffy nose scores were not significantly different among the groups. For the 14-day instantaneous itchy eye score, cetirizine and loratadine showed a significant reduction versus placebo (p and p versus placebo, respectively). The difference between the two active treatment groups was not statistically different. For the remaining four instantaneous individual symptom scores, the improvements from baseline were not significant among the groups. The cetirizine and loratadine groups had statistically greater reductions over 2 weeks in the investigatorassessed TSSC scores compared with placebo (p and p compared with placebo, respectively) and the guardian-assessed TSSC scores (p and p compared with placebo, respectively). There were no significant differences between the cetirizine and loratadine groups in these end point results. For the individual question how much did your child s allergies interfere with your ability to be productive at work over 2 weeks, improvements in the cetirizine group were statistically superior to the placebo and loratadine groups (p versus Cetirizine Loratadine Placebo p Value Week 1 No. patients Baseline, mean SE Week 1, mean SE Change from baseline, LS mean SE Overall treatment effect Cetirizine versus placebo Cetirizine versus loratadine Loratadine versus placebo Week 2 No. patients Baseline, mean SE Week 2, mean SE Change from baseline, LS mean SE Overall treatment effect Cetirizine vs placebo n/a Cetirizine vs loratadine n/a Loratadine vs placebo n/a TSSC Total symptom severity complex; SE standard error; LS least square; n/a not applicable. Pairwise comparisons were not performed because the overall treatment effect was not significant (p 0.05). placebo and p versus loratadine, respectively). The differences for the remaining Parental Burden Questionnaire individual question scores were not statistically different among the groups. For the global evaluation of treatment, the subjects rated their response to treatment as a lot better in 22.8% of subjects treated with cetirizine, 21.9% of subjects treated with loratadine, and 17.5% of subjects on placebo. The differences in subject-assessed global evaluation scores for the individual response categories, from a lot better to a lot worse, were not significantly different among the treatment groups. Investigators assessed global treatment responses as a major improvement in 12.7% of subjects treated with cetirizine, 8.2% of subjects treated with loratadine, and 10.0% of subjects treated with placebo. The differences in investigator-assessed global evaluation scores for the individual response categories from major improvement to severe worsening were not significantly different among the treatment groups. For the guardian-assessed overall personal satisfaction assessment, 16.7% of the guardians in the cetirizine group, 14.2% of the guardians in the loratadine group, and 11.4% of the guardians in the placebo group were very satisfied with the treatment. There was a significant difference among the three treatment groups for the individual response categories from very satisfied to very dissatisfied (p 0.017). The difference Allergy and Asthma Proceedings 227

7 Figure 2. Mean change from baseline in the reflective individual symptom scores over the 14-day period. in the response category ratings between the cetirizine and loratadine groups was not significant. Safety Evaluation Safety data were evaluable for 677 children. Similar incidences of concomitant medication use were reported in the cetirizine, loratadine, and placebo groups: 39.0, 39.5, and 39.7%, respectively. Drugs used in allergic disorders were required by 23 subjects in the cetirizine group (10.1%), 16 subjects in the loratadine group (7.3%), and 24 subjects in the placebo group (10.5%). Incidences of all-causality AEs were similar in the cetirizine, loratadine, and placebo treatment groups: 19.7, 21.8, and 22.7%, respectively. The predominant all-causality AEs in the cetirizine, loratadine, and placebo groups were headache (3.5, 3.6, and 3.1%, respectively) and pharyngitis (3.5, 2.7, and 3.5%, respectively). Somnolence was reported in three subjects only in the cetirizine group (1.3%) (Table 5). The incidences of treatment-related AEs were 4.8% for cetirizine, 4.5% for loratadine, and 2.6% for placebo (Table 6). All of the treatment-related AEs were mild or moderate in severity. Vomiting was the most frequently reported treatment-related AE, with 0.9% of subjects treated with cetirizine, 1.8% of subjects treated with loratadine, and 0.4% of subjects treated with placebo who reported the event. There were no serious AEs in this study. DISCUSSION In this 14-day study of 677 children ages 6 to 11 years, cetirizine 10 mg produced significantly greater SAR symptom relief compared with placebo as determined by the primary study end point: TSSC score reductions from baseline over 2 weeks. The differences in TSSC score improvement between cetirizine 10 mg and loratadine 10 mg as well as between loratadine 10 mg and placebo were not statistically significant. Over 2 weeks, cetirizine was significantly more effective than placebo for the following seven secondary efficacy parameters: reflective TSSC score with stuffy nose, instantaneous TSSC score, reflective sneezing score, instantaneous itchy eye scores, investigator-assessed TSSC score, guardian-assessed TSSC score, and the item how much did your child s allergies interfere with your ability to be productive at work on the Parental Burden Questionnaire. Compared with placebo, loratadine produced significant improvements over 2 weeks in the following three secondary efficacy end points: instantaneous itchy eyes scores, investigator-assessed TSSC scores, and guardian-assessed TSSC 228 May June 2017, Vol. 38, No. 3

8 Table 5 All causality AEs with a >1% incidence, safety-analyzable set AE Cetirizine, no. (%) (n 228) scores. Cetirizine was well tolerated; incidences of allcausality AEs, treatment-related AEs, and AEs that led to discontinuation were similar among the three treatment groups. Somnolence was reported in 1.3% of the subjects in the cetirizine group. These findings strengthened the evidence from earlier randomized, placebo-controlled studies, which also concluded that cetirizine 10 mg is a well-tolerated and effective therapy for the relief of symptoms in children with SAR. 11,12 In a 2-week pediatric study, Masi et al. 11 found that cetirizine 10 mg (n 63) was significantly superior to placebo (n 61) for the primary end point of days with no or mild symptoms. A subject-reported disease severity score (DSS) was used to evaluate the efficacy of cetirizine 5 mg administered twice daily to children ages 6 to 12 years with seasonal allergic rhinoconjunctivitis. The DSS was the maximum score of any of the five symptoms assessed (rhinorrhea, sneezing, blocked nose, or pruritus that involved the nose or eyes). The primary end point of the study was the percentage of days over the 2-week treatment period when the DSS was 1 (absent or mild symptoms). Loratadine, no. (%) (n 220) Placebo, no. (%) (n 229) Headache 8 (3.5) 8 (3.6) 7 (3.1) Pharyngitis 8 (3.5) 6 (2.7) 8 (3.5) Fever 4 (1.8) 2 (0.9) 2 (0.9) Vomiting 3 (1.3) 6 (2.7) 2 (0.9) Sinusitis 3 (1.3) 4 (1.8) 4 (1.7) Somnolence 3 (1.3) 0 (0.0) 0 (0.0) Lymphadenopathy 1 (0.4) 4 (1.8) 0 (0.0) Asthma 1 (0.4) 1 (0.5) 3 (1.3) Nausea 0 (0.0) 4 (1.8) 2 (0.9) Epistaxis 0 (0.0) 3 (1.4) 2 (0.9) Bronchitis 0 (0.0) 0 (0.0) 3 (1.3) AE Adverse event. Table 6 Treatment-related AEs with >1% incidence, safety-analyzable set* AE Cetirizine, no. (%) (n 228) Loratadine, no. (%) (n 220) Placebo, no. (%) (n 229) Somnolence 3 (1.3) 0 (0.0) 0 (0.0) Vomiting 2 (0.9) 4 (1.8) 1 (0.4) Headache 2 (0.9) 3 (1.4) 0 (0.0) Nausea 0 (0.0) 3 (1.4) 2 (0.9) AE Adverse event. *AEs are deemed if, in the investigator s judgment, the study drug was the most likely cause of the AE or if the causality was missing. The subjects treated with cetirizine experienced a significantly greater percentage of days when symptoms were absent or mild (56.2%) than subjects treated with placebo (29.7%) (p 0.05). Investigator-rated DSS also improved more with cetirizine than placebo after 1 week (p 0.007) and 2 treatment weeks (p 0.001). In another study, cetirizine 10 mg syrup administered once daily (n 70) produced significantly greater mean total symptom severity (TSS) score reductions than placebo (n 66) in children ages 6 to 11 years old with SAR (p 0.05). 12 TSS was the sum of sneezing, nasal discharge, itchy oral and/or nasal mucosa, itchy eyes, and conjunctivitis severity scores. The subjects rated symptoms on a four-point scale, from 0 (none) to 3 (severe). Over the entire 4-week period, reductions in the mean TSS scores were 3.19 and 2.09 in the cetirizine and placebo groups, respectively (p 0.05). Cetirizine 10 mg also reduced individual symptoms more effectively than placebo, with a significant difference for ocular itching and oral and/or nasal itching (p 0.05). For children in the present study who were too young to accurately verbalize and record their selfassessment in daily diaries, the guardians evaluated Allergy and Asthma Proceedings 229

9 symptom severity. The substitution of the guardian s symptom severity interpretation, in place of the subject s self-report, may have introduced bias into the study results. Analysis of the research indicated that there may be significant differences between the level of actual interference caused by allergic rhinitis that the child experiences and what is perceived by the guardian or health care provider. 22 The same may be true for symptom severity assessments, with guardians and investigators rating symptom severity less severe than would the pediatric subjects themselves. CONCLUSION Over a 2-week period, cetirizine 10 mg was statistically significantly more effective than placebo for SAR symptom relief in children ages 6 11 years. SAR symptom improvement was not significantly different between the loratadine 10 mg and the placebo group. ACKNOWLEDGMENT The authors dedicate this manuscript to Anjuli Seth Nayak, M.D. Anjuli was a renowned allergist and immunologist who ensured her patients received compassionate care. Additionally, Anjuli advanced cancer research by endowing a professorship for leukemia research at the University of Chicago Medicine. Dr. Nayak chronicled her journey with acute lymphoblastic lymphoma in her inspirational memoir, Plucked from a Mango Tree. REFERENCES 1. Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31: , Mallol J, Crane J, von Mutius E, et al. The International Study of Asthma and Allergies in Childhood (ISAAC) phase three: A global synthesis. Allergol Immunopathol (Madr) 41:73 85, Balatsouras DG, Koukoutsis G, Ganelis P, et al. Study of allergic rhinitis in childhood. Int J Otolaryngol 2011:487532, Gustafsson D, Sjöberg O, and Foucard T. Sensitization to food and airborne allergens in children with atopic dermatitis followed up to 7 years of age. Pediatr Allergy Immunol 14: , Spergel JM, and Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 112(suppl.):S118 S127, Kulig M, Klettke U, Wahn V, et al. Development of seasonal allergic rhinitis during the first 7 years of life. J Allergy Clin Immunol 106: , Lack G. Pediatric allergic rhinitis and comorbid disorders. J Allergy Clin Immunol 108:S9 S15, Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol 108(suppl.):S2 S8, Fireman P. Therapeutic approaches to allergic rhinitis: Treating the child. J Allergy Clin Immunol 105(pt. 2):S616 S621, Segal AT, Meltzer EO, Lockey RF, et al. Once-daily cetirizine is safe and effective for children with allergic rhinitis with and without intermittent asthma. Pediatr Asthma Allergy Immunol 16: , Masi M, Candiani R, and van de Venne H. A placebo-controlled trial of cetirizine in seasonal allergic rhino-conjunctivitis in children aged 6 to 12 years. Pediatr Allergy Immunol 4(suppl.): 47 52, Pearlman DS, Lumry WR, Winder JA, and Noonan MJ. Oncedaily cetirizine effective in the treatment of seasonal allergic rhinitis in children aged 6 to 11 years: A randomized, doubleblind, placebo-controlled study. Clin Pediatr (Phila) 36: , Allegra L, Paupe J, Wieseman HG, and Baelde Y. Cetirizine for seasonal allergic rhinitis in children aged 2 6 years: A doubleblind comparison with placebo. Pediatr Allergy Immunol 4: , Gillman SA, Blatter M, Condemi JJ, et al. The health-related quality of life effects of once-daily cetirizine HCl syrup in children with seasonal allergic rhinitis. Clin Pediatr (Phila) 41: , De Benedictis FM, Forenza N, Armenio L, et al. Efficacy and safety of cetirizine and oxatomide in young children with perennial allergic rhinitis: A 10-day, multicenter, double-blinded, randomized, parallel-group study. Pediatr Asthma Allergy Immunol 11: , Sienra-Monge JJ, Gazca-Aguilar A, and Del Rio-Navarro B. Double-blind comparison of cetirizine and loratadine in children ages 2 to 6 years with perennial allergic rhinitis. Am J Ther 6: , Lai DS, Lue KH, Hsieh JC, et al. The comparison of the efficacy and safety of cetirizine, oxatomide, ketotifen, and a placebo for the treatment of childhood perennial allergic rhinitis. Ann Allergy Asthma Immunol 89: , Townley RG. Antiallergic properties of the second-generation H1 antihistamines during the early and late reactions to antigen. J Allergy Clin Immunol 90(pt. 2): , Ciprandi G, Passalacqua G, Mincarini M, et al. Continuous versus on demand treatment with cetirizine for allergic rhinitis. Ann Allergy Asthma Immunol 79: , Uğuz A, SanlioğluS,Yüzbey S, et al. The effect of cetirizine on IFN-gamma and IL-10 production in children with allergic rhinitis. Turk J Pediatr 47: , Kogan MD, Pappas G, Yu SM, and Kotelchuck M. Over-thecounter medication use among US preschool-age children. JAMA 272: , Mir E, Panjabi C, and Shah A. Impact of allergic rhinitis in school going children. Asia Pac Allergy 2:93 100, e 230 May June 2017, Vol. 38, No. 3