Efficacy of Loratadine Compared with Fexofenadine or Placebo for the Treatment of Seasonal Allergic Rhinitis

Harold B. Kaiser, Clinical Research Institute, Minneapolis, Minnesota, USA; Anthony Rooklin, Allergy Research Associates, Media, Pennsylvania, USA; Dennis Spangler, Atlanta Allergy & Immunology Research Foundation, Atlanta, Georgia; David Capano, Integrated Therapeutics Group, Inc., New Jersey, USA

Clin Drug Invest. 2001;21(8) 

In This Article

Patients and Methods

This multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group study was conducted at 25 sites in the United States. Eligible patients were randomised according to a computer-generated global randomisation code in a 3:3:1 ratio to loratadine 10mg once daily, fexofenadine 60mg twice daily, or placebo. Clinic visits occurred at screening (3 to 10 days before baseline), baseline (day 1) and on day 8 (fig. 1).

Study design.

Eligible patients were men and women between the ages of 12 and 60 years, inclusive, with at least a 2-year history of spring/summer SAR. All patients had positive skin test responses (skin prick wheal diameter at least 3mm or intradermal wheal diameter at least 5mm greater than diluent control) to allergens (trees, grasses and weeds) and/or seasonal molds as appropriate for the study location and time of year. Skin testing and pollen/mold counts at each site (recorded at least 5 days per week) had to demonstrate that subjects were sensitive and exposed to appropriate seasonal allergen(s) for the duration of enrolment. Patients had to have a total nasal and non-nasal symptom severity score (TSS) of at least 8 (maximum score 15) on 6 of 14 diary time-points (am/pm) recorded during the 7 days before randomisation and on the morning of randomisation (see fig. 1). Baseline symptom scores were the mean symptom scores (am and pm) from visit 1 to visit 2. Patients were free of clinically significant diseases, other than SAR, that would interfere with the study evaluations. Women of childbearing potential had a negative urine pregnancy test at visit 2 and were required to use an acceptable method of birth control. Patients were required to adhere to drug administration regimens and visit schedules, and agree to record accurately and consistently symptom scores, medication times, concomitant medication use, and adverse events twice daily in a diary.

Patients were excluded if they had significant nasal structural abnormalities, or an upper or lower respiratory tract infection within 2 weeks of the screening visit, or if they were dependent upon nasal antihistamines, nasal decongestants, or nasal or ocular anti-inflammatory agents. Also excluded were patients with a history of asthma (unless their symptoms were controlled with only a short-acting inhaled ß2-agonist on an as-needed basis) or those with a history of allergy to multiple drugs, excluding antibiotics, or a hypersensitivity to anti-histamines. Patients who used an investigational medication within 30 days prior to enrolment were ineligible, as were patients who failed to observe the designated washout periods for prohibited medications (primarily medications that could affect SAR symptoms). Patients were also ineligible if they participated in more than two clinical trials involving SAR within the previous 12 months, or more than one such trial within the previous 6 months.

Patients were prohibited from taking certain medications, including corticosteroids, cromolyn, lodoxamide, nedocromil, antihistamines, leukotriene inhibitors, theophylline, oral sympathomimetic bronchodilators, ketotifen, systemic anti-biotics (unless on a stable dose), immunotherapy (unless on a stable dose and none within 24 hours before any study visit), decongestants, nasal saline, eye washes or drops, ophthalmic ketorolac, certain antihypertensives (methyldopa, reserpine, guanethidine), investigational medications, tricyclic and tetracyclic antidepressants, and inhibitors of CYP450 3A4. The dose of chronic medications, other than those previously listed, was to remain stable if possible. Patients were discontinued from the study for failure to adhere to the protocol, for occurrence of adverse event(s) or concurrent condition(s) that required discontinuation of the study medication, or therapeutic failure indicated by intolerable symptoms of SAR.

This study was performed in accordance with Good Clinical Practice guidelines and under the principles of the Declaration of Helsinki, and patients provided written informed consent.

Treatment administration. Treatment was self-administered in a double-blind fashion (using a double-dummy design) orally twice daily for 7 days, once in the morning and again 12 hours later. All patients took 1 tablet and 1 capsule at each dose (loratadine 10mg tablet and matching placebo, fexofenadine 60mg capsule and matching placebo, or placebo; see table I). The first dose was taken on the morning of the baseline visit (visit 2) after completion of all evaluations.

Evaluation criteria. Patients recorded the severity of each of five symptoms of SAR (see table II) twice daily in a diary, assessing the status over the previous 12 hours (reflective score) and at the time of assessment (instantaneous score). The individual symptom scores were summed as the TSS. Symptoms were assessed immediately preceding the morning dose (am) and immediately preceding the evening dose (pm). The investigator also evaluated the patient's SAR symptoms at each visit after screening. Symptom severity was scored on a 4-point scale. Both investigators and patients assessed the overall response to therapy at visit 3 using a 5-point scale (1 = complete relief, 2 = marked relief, 3 = moderate relief, 4 = slight relief, 5 = treatment failure). Patient satisfaction was assessed at visit 3 using a 10-point scale, with 1 as the most negative response and 10 as the most positive. The effect of allergy symptoms on ability to work, attend class and perform regular daily activities was assessed through the Work Productivity and Activity Impairment Questionnaire (WPAIQ), administered at visit 2 (baseline) and visit 3.

Efficacy outcomes. The primary end-point was the change from baseline in patient-assessed TSS based on am and pm reflective and instantaneous scores, using the last available measure after baseline (final assessment). Secondary outcomes included the investigator-and patient-assessed overall response to therapy at visit 3, patient satisfaction with therapy, and changes from baseline in WPAIQ score. The time to maximum reduction and a 25% reduction in patient-assessed am and pm TSS was also calculated. Efficacy outcome measures were analysed using the intent-to-treat (ITT) population (n = 836). Safety outcomes were analysed using all randomised patients who took at least one dose of study medications.

Safety evaluation. Patients were questioned at visits 2 and 3 about the occurrence of adverse events (AEs). Any physical or clinical change or disease experienced by a patient at any time during the course of the study, regardless of its relationship to the study drug(s), was considered an AE, including onset of new illness and exacerbation of pre-existing conditions other than SAR.

TSS was analysed using ANCOVA, with treatment centres, treatment-by-centre interaction, and baseline covariate adjustments. Pairwise comparisons were made using Fisher's Least Significant Difference (LSD). All tests were 2-sided at the 5% significance level. Baseline am evaluations were derived using the average of day -6 to day -1 am diary data, and baseline pm evaluations were derived using the average of day -7 to day -1 pm evaluations. Time-to-event analysis was performed using the Kaplan-Meier method and tested for significance of difference between loratadine and fexofenadine in the distribution of time to TSS reduction using the Wilcoxon test. Analysis of patient-and investigator-rated response to therapy was based on the Cochrane-Mantel-Haenszel test (mean score) stratified by centre. Patient satisfaction was analysed with an ANOVA model.

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