Randomized, Double Blind, Parallel Group, Placebo Controlled, Multi-Center Study of the Efficacy and Safety of Cetirizine HCl Syrup vs. Loratadine Syrup vs. Placebo in Treatment of Children With Seasonal Allergic Rhinitis (SAR)

The objective of this clinical trial was to assess the efficacy and safety of cetirizine HCl syrup vs. loratadine syrup vs. placebo syrup in the treatment of SAR in children 6 to 11 years old.

This was a multi-center, randomized, double-blind, parallel-group, placebo-controlled, double dummy study of children with SAR conducted during the Spring tree and grass allergy season. Subjects qualified for randomization if the diary cards included (1) symptom scores of ≥2 for at least 2 of the following 4 rhinoconjunctivitis symptoms on 4 or more days: sneezing, runny nose, itchy eyes, and watery eyes; and (2) a total rhinoconjunctivitis (or Total Symptom Severity Complex \[TSSC\]) score of ≥5 on any 4 days. The TSSC score was expressed as the sum of the 4 individual symptoms scores recorded in the daily diary cards for the following symptoms: sneezing, runny nose, itchy eyes, and watery eyes.

Subjects were randomized to receive 1 of 3 treatments in a double-blind fashion using a 1:1:1 allocation ratio: cetirizine HCl syrup and placebo loratadine syrup; loratadine syrup and placebo cetirizine HCl syrup; or cetirizine placebo syrup and loratadine placebo syrup.

Number of Subjects (Planned and Analyzed): 1100 planned; 1536 screened; 683 randomized: 231 (33.8%) randomized to the cetirizine HCl treatment group, 221 (32.4%) to the loratadine treatment group, and 231 (33.8%) to the placebo treatment group.

Test Product and Reference Therapy: Subjects randomized to receive cetirizine HCl syrup also received placebo syrup; subjects randomized to receive loratadine syrup also received placebo syrup; and both placebo syrups were received by subjects randomized to receive placebo.

Duration of Double-Blind Treatment: 2 weeks.

Safety measures included the incidence and severity of treatment-emergent adverse events (AEs), vital signs, concomitant medications, and physical examination findings. Clinical laboratory evaluation was not required for this study.

Statistical Methods: All statistical tests related to treatment effect were 2-sided, and statistical significance was declared at the 0.05 probability level. Least squares means (LSMeans) were used to estimate treatment effect. Populations analyzed included the Full Analysis (intent-to-treat \[ITT\]) Set (FAS), Per-Protocol Set (PPS), Safety-Analyzable Set, and All-Screened Analysis Set. Demographic and baseline data for all subjects in the Safety-Analyzable Set were summarized and listed. The effects of treatment at the Overall and all other analysis Time Points were assessed using ANCOVA models. The main effects model contained terms for treatment and Investigator site, with baseline TSSC value as a covariate. The LSMeans and standard errors were based on the main effects model. Methods of analysis of secondary efficacy data included analysis of covariance (ANCOVA) models and Cochran-Mantel-Haenszel (CMH) row mean scores tests. Analysis of drug safety included the incidence of treatment-emergent AEs (TEAE), concomitant medications, vital signs, and physical examination findings for the Safety-Analyzable Set.

Eligibility Criteria:
Inclusion Criteria:

* Male or female 6 to 11 years of age.
* Females who reached menarche either before or during the study, agreed to use acceptable methods of birth control if they became sexually active. Acceptable birth control was defined as oral contraceptives or Norplant®.
* Outpatient.
* History and diagnosis of seasonal allergic rhinitis (SAR) to a prevalent allergen (grass or tree).
* SAR to a prevalent allergen (grass or tree) of such severity that it required pharmacologic therapy each year for the last 2 consecutive years (including the present year).
* Documented SAR to a prevalent allergen (grass or tree) as confirmed by a recognized skin test (prick, intradermal \[ID\], or Multitest®) within the previous 15 months (Prick/Puncture wheal® ≥3 mm over the negative control; ID \[up to concentration of 1:1000 w/v or 1000 protein nitrogen units (PNU)\] wheal® ≥5 mm over the negative control). Documentation of SAR must have occurred at Visit 1 or within 15 months prior to Visit 1. If not performed at Visit 1, SAR testing must have been performed in the Principal Investigator's office or full documentation must have been available prior to randomization.
* Diary-recorded rhinoconjunctivitis symptom scores (24 hour reflective) that included at least two symptoms (sneezing, runny nose, itchy eyes, or watery eyes) at moderate severity (i.e., symptom score ≥2) on at least 4 days between Visits 1 and 2.
* Diary-recorded TSSC score ≥5 (based on the four symptoms noted in the criteria above) on any 4 days between Visits 1 and 2.
* Someone (subject and parent/legal guardian) from whom the Principal Investigator or study personnel would have expected conscientious cooperation over the duration of the study.
* A written informed assent must have been provided by the subject and a written informed consent must have been provided by the parent/legal guardian at Visit 1.

Exclusion Criteria:

* Had clinically significant nasal anatomical deformities with \> 50% obstruction (i.e., septal defects, polyps).
* Experienced an episode of acute sinusitis or an upper respiratory tract infection (URTI) including otitis media and the common cold) within 21 days of Visit 1.
* Had a history of chronic sinusitis.
* Initiated or advanced an immunotherapy regimen during the course of the study. Subjects receiving a maintenance dose of immunotherapy were eligible.
* Had a history of attention deficit/hyperactivity disorder (ADHD) that was considered unstable by the Investigator, or if pharmacotherapy (i.e., Ritalin®, Adderall®) was required, subject must have been on pharmacotherapy for at least 1 month prior to Visit 1. The pharmacotherapeutic regimen was to remain stable during the conduct of the study.
* Had a history of learning disabilities or intellectual impairment that, in the opinion of the Investigator, would prevent the subject from participating in the study.
* Had impaired hepatic function (cirrhosis, hepatitis), glaucoma, or any symptomatic infection, any clinically significant hematologic, renal, endocrine, or gastrointestinal disease, and/or current neuropsychiatric condition with or without drug therapy, that was judged by the Investigator to be clinically significant and/or affect the subject's ability to participate in the clinical trial.
* Had a history of malignancy (except basal cell carcinoma), epilepsy or seizures (excluding febrile seizures), excessive alcohol intake or drug addiction, hypertension, or other clinically significant cardiovascular disease.
* Had a physical examination abnormality considered by the Investigator to be clinically significant and limiting to the study's conduct, unless the abnormality was related to underlying allergic rhinitis.
* Had a history of an allergy or hypersensitivity to cetirizine, loratadine, hydroxyzine, or any of their ingredients.
* Had asthma, which required any of the following within the past 30 days: 1) admission to the hospital, 2) emergency room visit, or 3) a change in dosing regimen. Subjects were allowed to continue theophylline, long acting β2 agonists, inhaled cromoglycate no more than 6.4 mg/day, or nedocrimil no more than 14 mg/day. Subjects were allowed to continue inhaled corticosteroids in doses not exceeding those listed in Appendix B of the study protocol, as long as the dose did not change during the study. Subjects were allowed the use of short acting β2 agonists on an as needed (PRN) basis.
* Had used intranasal or intra ophthalmic corticosteroids; oral leukotriene modifiers or leukotriene receptor antagonists within 14 days; or systemic (intramuscular and/or intravenous and/or oral) corticosteroids within 35 days prior to Visit 2. Topical corticosteroids for skin were allowed if covering ≤10% of body surface without occlusion.
* Used intranasal cromolyn (Nasalcrom®), optical cromolyn (Crolom®), ipratropium bromide (Atrovent® Nasal Spray), azelastine hydrochloride (Astelin® Nasal Spray), monamine oxidase (MAO) inhibitors, or beta blockers for the treatment of migraine headaches within 14 days prior to Visit 2.
* Used antiallergic ophthalmic treatments such as Acular®, Patanol®, or Alomide® within 7 days prior to Visit 2.
* Used H1-receptor antagonists (oral and topical), H2-receptor antagonists, or decongestants after Visit 1.
* Used tricyclic antidepressants, tranquilizers, or antiemetics of the phenothiazine class within 14 days prior to Visit 2.
* Used oral macrolide antibiotics or oral antifungals within 7 days prior to Visit 2.
* Used saline nasal spray or ocular drops (unless for contact lens use) within 72 hours prior to Visit 2.
* Participated in any other studies involving investigational or marketed products within 30 days prior to entry into the study or participated in studies which involved norastemizole, or monoclonal anti-immunoglobulin E (IgE) antibody within 90 days prior to entry into the study.
* Donated blood or blood products for transfusion within 30 days prior to initiation of treatment with study drug and at any time during the study.