Adults and Pediatric Patients 12 Years of Age and Older: 

The efficacy of ZETONNA was evaluated in one randomized, double-blind, parallel-group, multicenter, placebo-controlled dose-ranging trial (74 mcg, 148 mcg, and 282 mcg once daily) and 3 confirmatory trials (74 mcg and 148 mcg once daily) in adult and pediatric patients 12 years and older with allergic rhinitis. Efficacy endpoints were evaluated at 2 weeks for the two seasonal allergic rhinitis trials and at 6 weeks for the perennial allergic rhinitis trial. These trials were all conducted in the United States. A total of 3001 patients were included in these 4 trials. The dose-ranging trial included a total of 513 patients [193 males (37.6%) and 320 females (62.4%)], of whom 65 (12.7%) were pediatric patients 12 years and older. The three confirmatory trials included a total of 2488 patients (905 males and 1583 females) of whom 170 were pediatric patients, ages 12 to 18 years. Patients enrolled in the trials were 12 to 81 years of age with a history of seasonal or perennial allergic rhinitis, a positive skin test to at least one relevant allergen, and active symptoms of allergic rhinitis at study entry. Assessment of efficacy in these trials was based on patient recording of four nasal symptoms (runny nose, nasal itching, sneezing, and nasal congestion) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) as reflective or instantaneous total nasal symptom scores (rTNSS and iTNSS respectively). Reflective scoring required the patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity over the previous 10 minutes. 

Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) in the seasonal allergic rhinitis trials and the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)] in both seasonal and perennial allergic rhinitis trials. TOSS is calculated as the sum of the patients’ scoring of the three individual ocular symptoms (itching, tearing, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous (iTOSS) scores. To assess efficacy, rTOSS and iTOSS were evaluated as described above for the TNSS. Patients perceptions of disease specific quality of life were evaluated through the use of the RQLQ(S), which assesses the impact of allergic rhinitis symptoms and treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = not troubled and 6 = extremely troubled. An overall RQLQ(S) score is calculated from the average of the domain scores. An absolute difference of ≥ 0.5 in mean change from baseline over placebo is considered the minimally clinically important difference (MCID) for the RQLQ(S). 

Dose-Ranging Trial: There was a 2-week placebo-controlled, double-blind, dose-ranging trial that evaluated efficacy of three doses of ZETONNA (74 mcg, 148 mcg, and 282 mcg once daily) in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score (rTNSS) averaged over the 2-week treatment period. The rTNSS showed a statistically significant estimated treatment difference from placebo of 0.81 (95% CI: 0.32, 1.29); 0.90 (95% CI: 0.40, 1.39); and 0.66 (95% CI: 0.16, 1.16) for 282 mcg, 148 mcg and 74 mcg, respectively.

Confirmatory Seasonal Allergic Rhinitis Trials: There were two 2-week placebo-controlled, double-blind confirmatory trials that evaluated efficacy of two doses of ZETONNA (74 mcg and 148 mcg once daily) in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the 2-week treatment period. Table 2 displays the efficacy results from one of these trials in patients with seasonal allergic rhinitis. The other trial showed similar results. In these trials, ZETONNA 74 mcg once daily was statistically significantly different from placebo. Statistically significant differences in the morning pre-dose iTNSS indicate that the effect was maintained over the full 24-hour dosing interval. ZETONNA 74 mcg demonstrated a statistically significant decrease from baseline in the rTOSS compared to placebo. Similarly, a clinically significant decrease (≥ 0.5) from baseline compared to placebo for the RQLQ(S) was also shown. ZETONNA 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Confirmatory Perennial Allergic Rhinitis Trial: There was one 26-week placebo-controlled, double-blind trial that evaluated efficacy of two doses of ZETONNA (74 mcg and 148 mcg once daily) in patients with perennial allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the first 6 weeks of treatment. In this trial, ZETONNA 74 mcg once daily was statistically significantly different from placebo (Table 2) in decreasing nasal symptom scores. Statistically significant differences in the morning pre-dose instantaneous total nasal symptom score indicate that the effect was maintained over the full 24‑hour dosing interval. ZETONNA 74 mcg did not demonstrate a clinically significant change from baseline in the overall RQLQ(S) compared to placebo. TOSS was not evaluated in this trial. ZETONNA 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Onset of Action: Onset of action was evaluated in both 2-week seasonal and one 6-week perennial allergic rhinitis trials by frequent recording of instantaneous symptom score. In these trials, onset of effect was seen after 36 hours following the first dose. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing.