Bepotastine besilate ophthalmic solution 1.5% for alleviating nasal symptoms in patients with allergic conjunctivitis

Figures & data

Figure 1 Phase III conjunctival allergen challenge (CAC) study design.

Notes: CACs were administered 15 minutes (onset of action), 16 hours and 8 hours (duration of action) after treatment instillation and nasal symptoms were measured at 7, 15, and 20 minutes post-CAC. The study also included a BBOS 1% arm, the results of which are not reported here.
Abbreviations: BBOS, bepotastine besilate ophthalmic solution; TAI, test-agent instillation.

Figure 2 Phase IV environmental allergen study design.

Notes: During the study period, subjects instilled BBOS 1.5% (n=123) or placebo (n=122) and recorded their nasal symptoms twice-daily. At visit 3 (day 7±1), subjects were contacted by phone for compliance and adverse-event assessments. Safety assessments were also conducted at visit 4 (day 14±2).
Abbreviation: BBOS, bepotastine besilate ophthalmic solution.

Table 1 Mean rhinorrhea, nasal congestion, nasal pruritus, and nasal ocular symptom scores post-CAC conducted at 15 minutes, 8 hours, and 16 hours after dosing

Time post-CACa		Rhinorrhea		Nasal congestion		Nasal pruritus		NOCSb
		Placebo (n=79)	BBOS 1.5% (n=78)	Placebo (n=79)	BBOS 1.5% (n=78)	Placebo (n=79)	BBOS 1.5% (n=78)	Placebo (n=79)	BBOS 1.5% (n=78)
Screening visit 1
Baseline	Mean (SD)	0.09 (0.29)	0.12 (0.32)	0.14 (0.45)	0.21 (0.52)	0.03 (0.16)	0.01 (0.11)	0.27 (0.69)	0.35 (0.72)
10 minutes	Mean (SD)	1.82 (1.26)	1.58 (1.10)	1.46 (1.35)	1.38 (1.10)	1.15 (1.36)	0.82 (1.03)	5.38 (4.35)	4.46 (2.83)
15 minutes (onset of action)
7 minutes	Mean (SD)	0.94 (1.017)	0.28 (0.682)	0.72 (0.973)	0.31 (0.726)	0.52 (0.814)	0.18 (0.528)	2.63 (2.905)	0.95 (1.765)
	Difference	0.7 (<0.0001*)		0.4 (0.003*)		0.3 (0.0023*)		1.7 (<0.0003*)
	(P-value)
15 minutes	Mean (SD)	1.06 (1.078)	0.38 (0.793)	0.86 (1.071)	0.35 (0.77)	0.66 (0.846)	0.19 (0.604)	3.3 (3.236)	1.33 (2.062)
	Difference	0.7 (<0.0001*)		0.5 (0.0007*)		0.5 (0.0001*)		2.0 (<0.0002*)
	(P-value)
20 minutes	Mean (SD)	0.81 (0.935)	0.35 (0.735)	0.87 (1.017)	0.37 (0.74)	0.52 (0.86)	0.21 (0.543)	2.94 (3.18)	1.31 (1.995)
	Difference	0.5 (0.0007*)		0.5 (0.0006*)		0.3 (0.0071*)		1.6 (0.0002*)
	(P-value)
8 hours (duration of action)
7 minutes	Mean (SD)	0.91 (1.052)	0.23 (0.601)	0.72 (0.973)	0.27 (0.638)	0.53 (0.83)	0.13 (0.466)	2.61 (2.866)	0.73 (1.535)
	Difference	0.7 (<0.0001*)		0.5 (0.0007*)		0.4 (0.0002*)		1.9 (<0.0003*)
	(P-value)
15 minutes	Mean (SD)	1.33 (1.217)	0.24 (0.563)	0.97 (1.097)	0.40 (0.762)	0.75 (1.056)	0.21 (0.589)	3.95 (3.655)	1.1 (1.945)
	Difference	1.1 (<0.0001*)		0.6 (0.0002*)		0.5 (0.0001*)		2.9 (<0.0002*)
	(P-value)
20 minutes	Mean (SD)	1.05 (1.131)	0.31 (0.588)	0.95 (1.097)	0.40 (0.795)	0.67 (1.059)	0.26 (0.673)	3.46 (3.658)	1.32 (2.141)
	Difference	0.7 (<0.0001*)		0.6 (0.0004*)		0.4 (0.004*)		2.1 (<0.0001*)
	(P-value)
16 hours (duration of action)
7 minutes	Mean (SD)	1.00 (1.098)	0.58 (0.83)	0.81 (0.962)	0.51 (0.785)	0.36 (0.683)	0.67 (1.009)	2.89 (3.084)	1.76 (2.084)
	Difference	0.4 (0.0072)		0.3 (0.0356)		0.3 (0.0249)		1.1 (0.0120*)
	(P-value)
15 minutes	Mean (SD)	1.30 (1.191)	0.60 (0.827)	1.00 (1.086)	0.69 (0.944)	0.38 (0.743)	0.8 (1.005)	3.97 (3.826)	2.22 (2.567)
	Difference	0.7 (<0.0001*)		0.3 (0.0601)		0.4 (0.004*)		1.8 (0.0027*)
	(P-value)
20 minutes	Mean (SD)	1.13 (1.202)	0.64 (0.897)	0.94 (1.066)	0.67 (0.949)	0.37 (0.791)	0.73 (1.071)	3.57 (3.865)	2.22 (2.705)
	Difference	0.5 (0.0047*)		0.3 (0.0958)		0.4 (0.0172)		1.4 (0.0122*)
	(P-value)

a CACs administered at 8 and 16 hours (duration of action) or 15 minutes (onset of action) after treatment instillation;

b sum of four scores – three nasal symptoms (rhinorrhea, nasal congestion, and nasal pruritus) and ear or palate pruritus – each scored on a scale of 0–4;

* P≤0.0125 for 15-minute CAC and P≤0.00625 for 8-hour and 16-hour CAC, except NOCS (P≤0.05). P-values calculated using two-sample t-tests comparing BBOS 1.5% to placebo.

Abbreviations: CAC, conjunctival allergen challenge; BBOS, bepotastine besilate ophthalmic solution; NOCS, nonocular composite-symptom score.

Table 2 Mean change from baseline for twice-daily averaged nasal symptom scores over the treatment period (ITT population)

Nasal symptoma	Baseline mean (SD) score		Mean (SD) change from baseline		P-value
	Placebo (n=122)	BBOS 1.5% (n=123)	Placebo (n=122)	BBOS 1.5% (n=123)
Reflectiveb
Nasal pruritus	2.34 (0.62)	2.44 (0.59)	−0.49 (0.55)	−0.67 (0.60)	0.037*
Sneezing	1.92 (0.79)	1.98 (0.77)	−0.40 (0.61)	0.63 (0.72)	0.010*
Rhinorrhead	2.31 (0.59)	2.35 (0.55)	−0.40 (0.56)	−0.38 (0.58)	0.545
Congestiond	2.50 (0.53)	2.57 (0.53)	−0.41 (0.55)	−0.46 (0.57)	0.772
rTNSS	9.06 (2.03)	9.28 (1.85)	−1.68 (1.93)	−2.14 (2.11)	0.125
Instantaneousc
Nasal pruritus	2.20 (0.65)	2.32 (0.66)	−0.44 (0.56)	−0.64 (0.62)	0.018*
Sneezing	1.56 (0.90)	1.61 (0.89)	−0.40 (0.61)	−0.52 (0.68)	0.142
Rhinorrhead	2.18 (0.64)	2.18 (0.60)	−0.38 (0.55)	−0.34 (0.56)	0.619
Congestiond	2.44 (0.54)	2.48 (0.57)	−0.38 (0.52)	−0.44 (0.52)	0.527
iTNSS	8.33 (2.23)	8.54 (2.04)	−1.53 (1.95)	−1.95 (1.98)	0.125

Notes:

a Individual nasal symptoms were measured on a 0-3 scale; iTNSS and rTNSS were the sum of the four individual symptom scores.

b Denotes the 12-hour period since last instillation of test agent.

c Denotes the 15-minute period prior to instillation of test agent.

d Scores for both placebo (n=107) and BBOS 1.5% (n=109) were for the per patient population.

* P≤0.05 (analysis of covariance).

Abbreviations: ITT, intent to treat; BBOS, bepotastine besilate ophthalmic solution; iTNSS, instantaneous total nasal symptom score; rTNSS, reflective TNSS.

Figure 3 Mean reflective sneezing scores by day and time (ITT population).

Notes: Reflective assessment of sneezing was recorded on a 4-point scale twice daily (morning and evening) during baseline assessment and the 2-week treatment period. Baseline value represents averaged responses of the last seven predose sneezing assessments collected at visit 2 (day 0) and twice daily during the 7-day screening period (ie, during the last 3 days of the screening period). *P≤0.05 vs placebo (analysis of covariance).
Abbreviations: ITT, intent to treat; BBOS, bepotastine besilate ophthalmic solution.

Table 3 Median days to improvement of nasal symptoms (ITT population)

Nasal symptom	Placebo		BBOS 1.5%		P-value
	Days (95% CI)a	Subjects (n)	Days (95% CI)a	Subjects (n)
Reflectiveb
Pruritus	NA (10.0–NA)	115	7.0 (5.5–9.0)	117	0.004*
Sneezing	13.3 (10.0–NA)	104	7.5 (5.0–13.0)	107	0.055
rTNSS	3.0 (1.5–5.0)	118	2.0 (1.5–3.0)	122	0.031*
Instantaneousc
Pruritus	NA (13.5–NA)	114	7.5 (6.0–10.5)	118	0.001*
Sneezing	8.5 (5.0–NA)	83	7.0 (4.5–11.0)	93	0.184
iTNSS	4.0 (3.0–6.5)	119	2.5 (1.5–3.5)	122	0.010*

Notes:

a Median days to improvement was the first time point out of ≥3 consecutive time points for which there was a greater decrease in mean averaged scores for BBOS 1.5% vs placebo;

b 12-hour period since last instillation of test agent;

c 15-minute period prior to instillation of test agent. NA indicates that median time to response for a treatment group was not achieved by the end of the 14 days of dosing during the treatment period. Data analysis was not performed for rhinorrhea or nasal congestion.

* P≤0.05 (log-rank statistics).

Abbreviations: ITT, intent to treat; BBOS, bepotastine besilate ophthalmic solution; iTNSS, instantaneous total nasal symptom score; rTNSS, reflective TNSS.

Table 4 Global therapeutic response ratings by subjects and investigators (proportions)

Endpoint	Proportion of subjects (%) with each global therapeutic response ratinga		P-value
	Placebo (n=122)	BBOS 1.5% (n=123)
Subject evaluation
No change	43.4	34.1	0.183
Slight improvement	36.9		41.5
Improved	13.9		22.0
Marked improvement	5.7		2.4
Improved or marked improvement	19.7	24.4	0.441
Any improvement	56.6	65.9	0.150
Investigator evaluation
No change	48.4	34.1	0.006*
Slight improvement	37.7		39.0
Improved	9.8		19.5
Marked improvement	4.1		7.3
Improved or marked improvement	13.9	26.8	0.017*
Any improvement	51.6	65.9	0.028*

Notes:

a Global therapeutic response (overall assessment of nasal and ocular symptoms) for the 2-week treatment period was graded by subjects at day 13 and investigators at visit 4 (day 14±2), both on a scale of 0–3.

* P≤0.05. Differences between BBOS 1.5% and placebo for the four response categories across treatment groups were analyzed using a Wilcoxon rank-sum test. Differences between BBOS 1.5% and placebo for the proportion of subjects with a rating of improved or marked improvement and proportion of subjects with any improvement were based on Fisher’s exact test.

Abbreviation: BBOS, bepotastine besilate ophthalmic solution.