Efficacy and safety of benzalkonium chloride-free fixed-dose combination of latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension

Figures & data

Figure 1 Patient disposition.

Notes: ^aThe 227 randomized patients represented the safety population, which included all patients who received at least one dose of study medication. ^bITT population (efficacy analysis population) included all patients with baseline visit assessment who received at least one dose of study medication and at least one on-therapy efficacy assessment. Missing data were treated by last observation carried forward. ^cPP population included patients with at least one on-therapy efficacy assessment and no major protocol violation.
Abbreviations: ITT, intent to treat; PP, per protocol; N/n, number.

Table 1 Patient demographic and baseline characteristics (ITT population)*

Category	Treatment group												Overall (n=221)
	Latanoprost/timolol fixed-dose combination (n =55)			Latanoprost + timolol (n=56)			Latanoprost (n=54)			Timolol (n=56)
Sex, n (%)
Male	39 (70.9)			38 (67.9)			36 (66.7)			35 (62.5)			148 (67.0)
Female	16 (29.1)			18 (32.1)			18 (33.3)			21 (37.5)			73 (33.0)
Age (years)
Mean	56.3			53.5			56.2			54.0			55.0
SD	14.30			12.59			14.38			12.93			13.53
Range	24–83			22–72			20–78			23–77			20–83
Iris color, n (%)
Brown	55 (100.0)			56 (100.0)			53 (98.1)			56 (100.0)			220 (99.5)
Hazel	0			0			1 (1.9)			0			1 (0.5)
Mean baseline IOP (mmHg)a
	9 am	11 am	5 pm	9 am	11 am	5 pm	9 am	11 am	5 pm	9 am	11 am	5 pm
Mean	26.38	26.48	25.93	26.81	26.22	26.16	26.25	26.59	25.79	26.86	26.43	26.20
SD	2.80	3.13	3.19	2.42	2.67	2.81	2.69	3.11	2.84	3.50	3.61	2.98
Range	20.33–35.00	20.00–37.66	19.33–36.00	19.67–33.33	19.33–32.33	20.00–34.00	20.66–34.00	18.00–36.00	18.33–34.00	19.66–39.00	16.00–37.00	19.33–35.00
P-valueb				0.3942	0.6458	0.6870	0.7983	0.8482	0.8126	0.4318	0.9375	0.6403
Difference				−0.42	0.25	−0.23	0.13	−0.11	0.14	−0.48	0.05	−0.27
95% CI				−1.41 to 0.56	−0.84 to 1.35	−1.36 to 0.90	−0.91 to 1.18	−1.30 to 1.07	−1.01 to 1.28	−1.67 to 0.72	−1.22 to 1.32	−1.43 to 0.89

Notes:

* Data shown are for the efficacy analysis (ITT) population.

a Mean IOP at baseline is for the study eye only.

b P-value was calculated for each group compared with latanoprost/timolol fixed-dose combination at the corresponding time point, using unpaired Student’s t-test.

Abbreviations: CI, confidence interval; IOP, intraocular pressure; ITT, intent to treat; SD, standard deviation.

Figure 2 Mean IOP at each time point by visit.

Notes: Mean IOP is the mean per treatment group at each time point at each visit (day 7±1, 14±2, 28±2, and 42±2) during the 6-week treatment period. Data shown are from the efficacy analysis (ITT) population. P-value was calculated using a paired Student’s t-test for comparing mean value from baseline (day 0) to mean value for week 1 (day 0 to day 7±1), week 2 (day 0 to day 14±2), week 4 (day 0 to day 28±2), and week 6 (day 0 to day 42±2) for each treatment group.
Abbreviations: IOP, intraocular pressure; ITT, intent to treat.

Table 2 IOP change from baseline at each time point during 6 weeks of treatment with a fixed-dose combination of latanoprost/timolol, concomitant latanoprost + timolol, latanoprost alone, and timolol alone

Treatment	Mean change in IOP from baseline (mmHg)
	9 am	11 am	5 pm
Latanoprost/timolol fixed-dose combination	−9.91 to −11.29	−10.34 to −11.38	−9.92 to −10.73
Latanoprost + timolol	−9.94 to −11.64	−9.74 to −11.01	−9.92 to −11.04
Latanoprost	−9.52 to −10.48	−9.76 to −10.27	−8.90 to −9.92
Timolol	−7.82 to −9.08	−7.61 to −8.89	−7.47 to −8.57

Notes: Mean IOP change shown is range from baseline at the time point indicated across treatment visits (day 7±1, 14±2, 28±2, and 42±2) during the 6-week treatment period. Baseline IOP across the four treatment groups ranged from 25.79 mmHg to 26.86 mmHg. Latanoprost/timolol fixed-dose combination was administered once daily at 9 pm, concomitant latanoprost + timolol was administered twice daily at 9 am (timolol only) and 9 pm (latanoprost + timolol), latanoprost monotherapy was administered once daily at 9 pm, and timolol monotherapy was administered twice daily at 9 am and 9 pm. Data shown are from the efficacy analysis (ITT) population. Last observation carried forward was applied for missing observations.

Abbreviations: IOP, intraocular pressure; ITT, intent to treat.

Figure 3 Responder rates (defined as patients having IOP ≤18 mmHg for at least two time points at each follow-up visit) for the four treatment groups.

Notes: P-values were calculated using chi-square test for comparing treatment groups (each treatment group versus latanoprost/timolol fixed-dose combination group). Data shown are from the efficacy analysis (ITT) population. *indicates a statistically significant P-value.
Abbreviations: IOP, intraocular pressure; ITT, intent to treat.

Table 3 Summary of ocular TEAEs reported during the course of the study (safety population)

System Organ Class/Preferred Term	Treatment group
	Latanoprost/timolol fixed-dose combination (n=56)	Latanoprost + timolol (n=58)	Latanoprost (n=55)	Timolol (n=58)	Overall (n=227)
Total number of TEAEs, n	23	14	15	16	68
Total number of patients with at least one TEAE, n (%)*	12 (21.4)	10 (17.2)	8 (14.5)	9 (15.5)	39 (17.2)
Patients reporting TEAEs probably related to treatment, n (%)	1 (1.8)	2 (3.4)	0	0	3 (1.3)
Patients reporting TEAEs possibly related to treatment, n (%)	8 (14.3)	5 (8.6)	3 (5.5)	6 (10.3)	22 (9.7)
Patients reporting TEAEs unlikely or not related to treatment, n (%)	3 (5.4)	3 (5.2)	5 (9.1)	3 (5.2)	14 (6.2)
Eye disorders, n (%)	12 (21.4)	10 (17.2)	8 (14.5)	9 (15.5)	39 (17.2)
Conjunctival hyperemia	1 (1.8)	3 (5.2)	0	1 (1.7)	5 (2.2)
Conjunctivitis	2 (3.6)	0	2 (3.6)	0	4 (1.8)
Corneal disorder	0	0	1 (1.8)	0	1 (0.4)
Diabetic retinopathy	0	0	0	1 (1.7)	1 (0.4)
Dry eye	3 (5.4)	1 (1.7)	1 (1.8)	2 (3.4)	7 (3.1)
Eye irritation	4 (7.1)	6 (10.3)	2 (3.6)	5 (8.6)	17 (7.5)
Eye pain	4 (7.1)	2 (3.4)	2 (3.6)	3 (5.2)	11 (4.8)
Eye pruritus	2 (3.6)	1 (1.7)	1 (1.8)	0	4 (1.8)
Foreign body sensation in eyes	1 (1.8)	1 (1.7)	2 (3.6)	0	4 (1.8)
Lacrimation increased	2 (3.6)	0	1 (1.8)	1 (1.7)	4 (1.8)
Macular edema	0	0	1 (1.8)	1 (1.7)	2 (0.9)
Ocular hyperemia	2 (3.6)	0	0	0	2 (0.9)
Photophobia	2 (3.6)	0	1 (1.8)	0	3 (1.3)
Visual acuity reduced	0	0	1 (1.8)	0	1 (0.4)

Notes:

* All ocular TEAEs were mild or moderate in nature. Patients may have reported more than one event per System Organ Class or Preferred Term. Patients were counted once for each System Organ Class or Preferred Term at the maximum intensity/relationship experienced.

Abbreviation: TEAE, treatment-emergent adverse event.

Table 4 Summary of nonocular TEAEs reported during the course of the study (safety population)

System Organ Class/Preferred Term	Treatment group
	Latanoprost/timolol fixed-dose combination (n=56)	Latanoprost + timolol (n=58)	Latanoprost (n=55)	Timolol (n=58)	Overall (n=227)
Total number of TEAEs, n	0	1	4	5	10
Total number of patients with at least one TEAE, n (%)*	0	1 (1.7)	3 (5.5)	4 (6.9)	8 (3.5)
Patients reporting TEAEs probably related to treatment, n (%)	0	0	0	1 (1.7)	1 (0.4)
Patients reporting TEAEs possibly related to treatment, n (%)	0	0	0	0	0
Patients reporting TEAEs unlikely or not related to treatment, n (%)	0	1 (1.7)	3 (5.5)	3 (5.2)	7 (3.1)
Cardiac disorders, n (%)	0	0	0	1 (1.7)	1 (0.4)
Bradycardia	0	0	0	1 (1.7)	1 (0.4)
Gastrointestinal disorders	0	0	0	1 (1.7)	1 (0.4)
Dyspepsia	0	0	0	1 (1.7)	1 (0.4)
General disorders and administration site conditions	0	1 (1.7)	1 (1.8)	1 (1.7)	3 (1.3)
Peripheral edema	0	1 (1.7)	0	0	1 (0.4)
Pyrexia	0	0	1 (1.8)	1 (1.7)	2 (0.9)
Infections and infestations	0	0	0	2 (3.4)	2 (0.9)
Amebiasis	0	0	0	1 (1.7)	1 (0.4)
Nasopharyngitis	0	0	0	1 (1.7)	1 (0.4)
Metabolism and nutrition disorders	0	0	1 (1.8)	0	1 (0.4)
Vitamin B12 deficiency	0	0	1 (1.8)	0	1 (0.4)
Nervous system disorders	0	0	2 (3.6)	0	2 (0.9)
Headache	0	0	1 (1.8)	0	1 (0.4)
Muscle spasticity	0	0	1 (1.8)	0	1 (0.4)

Notes:

* All nonocular TEAEs were mild or moderate in nature. Patients may have reported more than one event per System Organ Class or Preferred Term. Patients were counted once for each System Organ Class or Preferred Term at the maximum intensity/relationship experienced.

Abbreviation: TEAE, treatment-emergent adverse event.