Azelastine Hydrochloride and Fluticasone Propionate (Page 7 of 9)

Fluticasone Propionate

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 25 and 10 times the MRHDID in adults and children, respectively, on a mcg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 3 and 1 times the MRHDID in adults and children, respectively, on a mcg/m² basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.

Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID for adults on a mcg/m² basis).

14 CLINICAL STUDIES

Adults and Adolescents 12 Years of Age and Older: The efficacy and safety of azelastine hydrochloride and fluticasone propionate nasal spray in adults and adolescents 12 years of age and older with seasonal allergic rhinitis was evaluated in 3 randomized, multicenter, double-blind, placebo-controlled clinical trials in 853 patients. The population of the trials was 12 to 78 years of age (64% female, 36% male; 80% white, 16% black, 2% Asian, 1% other).

Patients were randomized to one of four treatment groups: one spray per nostril twice daily of azelastine hydrochloride and fluticasone propionate nasal spray, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, and vehicle placebo. The azelastine hydrochloride and fluticasone propionate comparators use the same device and vehicle as azelastine hydrochloride and fluticasone propionate nasal spray and are not commercially marketed. Assessment of efficacy was based on the reflective total nasal symptom score (rTNSS), in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients’ scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Patients were required to record symptom severity daily reflecting over the previous 12 hours (morning, AM, and evening, PM). For the primary efficacy endpoint, the combined AM+PM rTNSS (maximum score of 24) was assessed as a change from baseline for each day and then averaged over a 2-week treatment period. The primary efficacy endpoint was the mean change from baseline in combined AM+PM rTNSS over 2 weeks. The iTNSS was recorded immediately prior to the next dose.

In these trials, azelastine hydrochloride and fluticasone propionate nasal spray demonstrated statistically significant greater decreases in rTNSS as compared to azelastine hydrochloride and to fluticasone propionate, as well as to placebo. The differences between the monotherapies and placebo also were statistically significant. Representative results from one of the trials are shown below (Table 3).

Table 3. Mean Change from Baseline in Reflective Total Nasal Symptom Scores over 2 Weeks * in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.
* Sum of AM and PM rTNSS for each day (Maximum Score = 24) and averaged over the 14 day treatment period † Not commercially marketed
		Baseline	Change from Baseline	Difference from Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray
Treatment (one spray/nostril twice daily)	N	LS Mean	LS Mean	LS Mean	95% Cl	P-value
Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray	207	18.3	-5.6	—	—	—
Azelastine HCl Nasal Spray †	208	18.3	-4.3	-1.4	(-2.2, -0.5)	0.002
Fluticasone Propionate Nasal Spray †	207	18.2	-4.7	-1.0	(-1.8, -0.2)	0.022
Placebo	209	18.6	-2.9	-2.7	(-3.5, -1.9)	< 0.001

In these trials, azelastine hydrochloride and fluticasone propionate nasal spray also demonstrated statistically significant, greater decreases in iTNSS as compared to placebo, as did the azelastine hydrochloride and fluticasone propionate comparators. Representative results from one of the trials are shown below (Table 4).

Table 4. Mean Change from Baseline in Instantaneous Total Nasal Symptom Scores over 2 Weeks * in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.
* * Sum of AM and PM rTNSS for each day (Maximum Score = 24) and averaged over the 14 day treatment period † † Not commercially marketed
		Baseline	Change from Baseline	Difference from Placebo
Treatment (one spray/nostril twice daily)	N	LS Mean	LS Mean	LS Mean	95% Cl	P-value
Azelastine Hydrochloride and Fluticasone Propionate Nasal Spray	207	17.2	-5.6	—	—	—
Azelastine HCl Nasal Spray †	208	16.8	-4.3	-1.4	(-2.2, -0.5)	0.002
Fluticasone Propionate Nasal Spray †	207	16.8	-4.7	-1.0	(-1.8, -0.2)	0.022
Placebo	209	17.3	-2.9	-2.7	(-3.5, -1.9)	< 0.001

Onset of action, defined as the first timepoint at which azelastine hydrochloride and fluticasone propionate nasal spray was statistically superior to placebo in the mean change from baseline in iTNSS and which was sustained thereafter, was assessed in each of the three trials. Onset of action was observed as early as 30 minutes following the initial dose of azelastine hydrochloride and fluticasone propionate nasal spray.

The subjective impact of seasonal allergic rhinitis on patient’s health-related quality of life was evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) evaluated on a 7-point scale where 0 = no impairment and 6 = maximum impairment), which was administered to patients 18 years of age and older. An overall RQLQ score is calculated from the mean of all items in the instrument. A change from baseline of at least 0.5 points is considered a clinically meaningful improvement. In each of these trials, azelastine hydrochloride and fluticasone propionate nasal spray demonstrated a statistically significant greater decrease from baseline in the overall RQLQ than placebo, which ranged from -0.55 (95% CI -0.72, -0.39) to -0.80 (95% CI -1.05, -0.55). In these trials, the treatment differences between azelastine hydrochloride and fluticasone propionate nasal spray and the monotherapies were less than the minimum important difference of 0.5 points.

Pediatric Patients 6-11 Years of Age: The efficacy and safety of azelastine hydrochloride and fluticasone propionate nasal spray was evaluated in one randomized, multi-center, double-blind, placebo-controlled trial in 304 children 6 to 11 years of age with seasonal allergic rhinitis. Patients were randomized 1:1 to receive either one spray per nostril twice daily of azelastine hydrochloride and fluticasone propionate nasal spray or placebo (vehicle control) for 14 days. The design of this trial was similar to that of the adult trials.

The primary efficacy endpoint was the mean change from baseline in combined AM+PM reflective total nasal symptom score (rTNSS) over 2 weeks. Azelastine hydrochloride and fluticasone propionate nasal spray was not statistically significantly different than placebo, but the results were numerically supportive (Table 5).

Table 5: Mean Change from Baseline in Reflective Total Nasal Symptom Scores over 2 weeks in Children age 6 to 11 years

CI = confidence intervalLS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data
Treatment	Baseline	LS Mean Change from baseline	LS Mean Difference (95% CI)	P-value
Azelastine Hydrochloride and Fluticasone Propionate Nasal SprayN = 152	18.4	-3.7	-0.8(-1.8, 0.2)	0.099
Placebo N = 152	18.0	-2.9