The efficacy and safety of loratadine for perennial allergic rhinitis in a phase III, randomized, double-blind, multi-center comparative study

Abstract

A phase III double-blind comparative study was conducted to examine the superiority of loratadine (SCH 29851), a selective H1-receptor antagonist, to placebo and non-inferiority to ketotifen fumarate (1 mg b.i.d.) in perennial allergic rhinitis when administered at a dose of 10 mg once a day for two weeks following a one-week pretreatment observation period. Of 280 patients enrolled, two were discontinued immediately due to incorrect administration of drug and 278 were included in FAS analysis (loratadine: 102 patients, ketotifen: 107 patients, placebo: 69 patients). Some imbalance in patient background factors was observed between these groups (p<0.15), but there was no effect on the primary efficacy variable, although effect was observed on the baseline score of 5 nasal symptoms. Since the baseline was a covariate in the analysis of all nasal symptom scores, the imbalance was adjusted and was considered not to have affected the interpretation of results. With the score of 5 nasal c symptoms (total of scores for sneezing, rhinorrhea, nasal congestion, nasal itching, and post-nasal drip) as the primary efficacy variable, the superiority of the loratadine group to placebo was examined stepwise at one week after the start of treatment. It was then examined whether there was non-inferiority to ketotifen fumarate at the end of one week and two weeks of treatment. Koch's non-parametric ANCOVA was used to analyse nasal symptom scores. Compared to placebo, there was a significant reduction in the score of 5 nasal symptoms at the end of one week of treatment (p<0.0001), verifying the superiority of loratadine to placebo. In addition, the superiority of loratadine to placebo was also verified by the score after 3 days and at the end of 2 weeks of treatment (p=0.0422, p=0.0226, respectively). Non-inferiority of loratadine to ketotifen fumarate was also verified at the end of one week of treatment (p=0.0062) but not at the end of two weeks of treatment. A significant reduction was observed in the scores of each nasal symptom compared to placebo (p< 0.05 to 0.0001) at one week after the start of treatment. After two weeks of treatment, a significant reduction was observed in the scores for sneezing (p=0.0472) and post-nasal drip (p=0.0011). On comparison between the loratadine and ketotifen groups, a significant reduction was observed with loratadine in the score for nasal congestion at the end of one week of treatment (p=0.0114). Loratadine was superior to placebo in global improvement (marked and moderate improvement) at the end of both one and two weeks of treatment (p<0.0001 at one week and p=0.0174 at two weeks). The 95% two-sided confidence interval of the difference in improvement rates (marked and moderate) between loratadine and ketotifen fumarate was estimated to be -9.39 to 17.62% and -13.73 to 13.25 %, respectively, at the end of one and two weeks of treatment. There were 77 adverse events in 36 patients (51.4%) in the placebo group, 76 adverse events in 51 patients (49.5%) in the loratadine group, and 186 adverse events in 79 patients (73.8%) in the ketotifen fumarate group. Among these adverse events, causality to study drug administration could not be discounted in 43 adverse reactions in 23 patients (32.9%) in the placebo group, 34 in 26 patients (25.2%) in the loratadine group, and 130 in 69 patients (64.5%) in the ketotifen fumarate group. The difference in incidence between groups was significant (p<0.0001) when homogeneity between the three groups was examined. The main adverse reactions (incidence of 5% or more) were sleepiness in 9 patients (12.9%) and malaise in 4 patients (5.7%) receiving placebo, sleepiness in 14 patients (13.6%) receiving loratadine, and sleepiness in 64 patients (59.8%), malaise in 18 patients (16.8%), and thirst in 13 patients (12.1%) receiving ketotifen fumarate. The 95% confidence interval of the incidence of sleepiness for which causality could not be discounted was 7.6 to 21.8% for loratadine which was nearly the same as that for placebo at 6. 1 to 23.0%, whereas it was clearly higher for ketotifen fumarate at 49.9 to 69.2%. It was also clearly higher with ketotifen fumarate in the case of malaise. Based on the above, loratadine is considered to be clinically useful in the treatment of perennial allergic rhinitis.