Preservative-Free Bimatoprost 0.01% Ophthalmic Gel for Glaucoma Therapy: A Phase III Randomized Controlled Trial

Abstract

Précis:

Noninferiority of efficacy was demonstrated for a preservative-free bimatoprost 0.01% compared with BAK-containing bimatoprost 0.01% following a 12-week treatment period in patients with open angle glaucoma or ocular hypertension. Improved tolerability, in particular conjunctival hyperemia, was also observed.

Purpose:

To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel) compared with preserved bimatoprost 0.01% (PB 0.01%).

Design:

Phase III, international, multicenter, randomized, 2-parallel group, investigator-masked, 3-month treatment duration.

Methods:

Patients with glaucoma or ocular hypertension were randomized after a 7-week run-in/washout period to receive once-daily PFB 0.01% gel (n=236) or PB 0.01% (n=249) for 3 months. The primary efficacy measure was changed from baseline in IOP at week 12. Safety measures included adverse events (AEs) and assessment of conjunctival hyperemia.

Results:

The mean changes from baseline in IOP at week 12 in the PFB 0.01% gel and PB 0.01% were −9.72±2.97 and −9.47±3.06 mm Hg, respectively, at 8 am, −9.41±3.03 and −9.19±3.12 mm Hg at 10 am, and −8.99±3.36 and −8.54±3.44 mm Hg at 4 pm. Noninferiority of PFB 0.01% gel to PB 0.01% was demonstrated at week 12 based on predetermined criteria (upper 95% CI margin of 1.5 mmHg at all time points). The most frequently reported AE was conjunctival hyperemia; 13 (5.5%) patients with PFB 0.01% gel and 17 (6.8%) patients with PB 0.01%. The percentage of patients experiencing a worsening from baseline in conjunctival hyperemia score was lower with PFB 0.01% gel compared to PB 0.01% at week 6 (20.1% vs. 29.3%, respectively) and week 12 (18.3% vs. 30.4%, respectively).

Conclusions:

PFB 0.01% ophthalmic gel has the same efficacy in lowering IOP as PB 0.01% and demonstrated less aggravation of conjunctival hyperemia at weeks 6 and 12.

Bimatoprost, a synthetic prostamide structurally related to prostaglandin F2 alpha (PGF2α), is a potent, commonly prescribed intraocular pressure (IOP)-lowering agent for patients with glaucoma or ocular hypertension (OHT).¹ It has a unique dual mechanism of action to reduce IOP in humans, by increasing aqueous humor outflow through the trabecular meshwork and enhancing uveoscleral outflow.²

Preserved bimatoprost 0.03% ophthalmic solution (Lumigan 0.03%, Allergan, Inc) was introduced into clinical practice in 2000 and was demonstrated to be effective and safe in lowering IOP by 6.5 to 8.9 mm Hg over the long term in patients with glaucoma and OHT.^3–5 However, bimatoprost is associated with a number of adverse events (AEs), most notably, conjunctival hyperemia, which is the most common AE associated with early patient discontinuation from treatment, as demonstrated in 4.0% using once-daily bimatoprost 0.03% and 8.7% of patients using twice-daily bimatoprost 0.03% over 12 months in clinical studies.⁶ In addition, side effects from bimatoprost 0.03% can result in additional office visits and reduced compliance.⁷ Consequently, a new formulation of bimatoprost with a lower concentration of the active substance [bimatoprost 0.01% (Lumigan 0.01%, Allergan, Inc)] was then developed. Bimatoprost 0.01% instilled once daily (in the evening) has been shown to be clinically comparable to bimatoprost 0.03% in IOP-lowering efficacy.^8–10 In large observational studies, additional mean IOP reductions achieved after switching from various hypotensive treatments to bimatoprost 0.01% ranged from 2.3% (vs. bimatoprost 0.03%) up to 26.3% (vs. beta-blockers).^11–13

Compared with preserved bimatoprost 0.03%, preserved bimatoprost 0.01% has a 4-fold increase in the amount of the quaternary ammonium preservative benzalkonium chloride (BAK; 200 ppm vs. 50 ppm), which was believed to enhance the ocular absorption of hydrophilic drugs by transiently relaxing epithelial tight junctions and allowing a lower concentration of bimatoprost to be used.¹⁴ The use of preservatives in glaucoma medications may cause and/or exacerbate ocular surface disease (OSD), particularly over the long term.¹⁵ It is known that the chronic usage of preservative-containing eye drops correlates well with the signs and symptoms of OSD and that such signs and symptoms can diminish if preserved drops are substituted with nonpreserved drops.¹⁶ In addition, preservatives in glaucoma medications have also been shown to increase the risk of glaucoma surgery failure due to abnormal infiltration of cells expressing inflammatory markers, leading to toxic histopathologic changes,¹⁷ and increase the risk of glaucoma surgery failure as they can accumulate in deeper ocular structures, triggering inflammatory effects and enhanced trabecular degeneration.^18,19 Due to these negative effects, patients may skip doses of preserved eye drops to avoid discomfort or discontinue medical therapy all together. By maintaining patient compliance, preservative-free drops have the potential to provide a therapeutic advantage over preserved formulations and lead to optimized IOP control, greater chance of treatment success, and an improvement in glaucoma patients’ quality of life.^20,21 In addition to the safety aspect, several studies have demonstrated that the removal of preservatives in prostaglandin formulations (latanoprost,²² travoprost,²³ or bimatoprost²⁴) did not alter their IOP-lowering efficacy.

The purpose of this study was to evaluate the IOP-lowering efficacy and safety of preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel) compared to preserved bimatoprost 0.01% ophthalmic solution (PB 0.01%) in patients with glaucoma or OHT.

METHODS

Study Design

This international European, randomized, multicenter (90 participating centers), investigator-masked, parallel-group, phase III study compared PFB 0.01% gel with BAK-preserved bimatoprost 0.01% in patients with glaucoma or OHT (Eudract No. 2017-000846-23). The study was conducted in accordance with Good Clinical Practice ICH (E6 (R2)) applicable and the Declaration of Helsinki. Independent ethics committee approval for the study was obtained before the start of the study.

Study Population

Eligible patients were at least 18 years of age with a diagnosis of open angle glaucoma (OAG) or OHT, initially treated and controlled (including IOP ≤18 mm Hg in both eyes at screening) for at least 6 months by any prostaglandin as monotherapy, and with 500 µm ≤central corneal thickness (CCT) ≤600 µm in both eyes; at randomization (after 7 wk of run-in/washout period), both eyes with 22 mm Hg ≤IOP <34 mm Hg with asymmetry between eyes ≤3 mm Hg.

Patients who had advanced stages of glaucoma [severe visual field loss: mean deviation (MD) <−18 dBs; an absolute defect in the 10 degrees central point of the visual field, and risk of visual field worsening because of participation in the study according to the investigator’s best judgment); significant worsening according to the 2 last visual fields (at least 6 months between them); and any abnormality preventing accurate assessments were excluded. Other main exclusion criteria included the presence of at least 1 severe objective sign (hyperemia grade 5/McMonnies scale, superficial punctate keratitis grade 4/Oxford scale, blepharitis grade 3/0–3 scale); severe dry eye; corneal ulceration; far best-corrected visual acuity (BCVA) of ≥+0.7 LogMAR in at least 1 eye; filtration surgery for glaucoma (at any time), laser procedure for glaucoma and cornea (within the 12 months before screening), and other ocular surgery (6 months before screening); and use of concomitant medications not allowed before and during the study.

At the screening visit, patients stopped their previous treatment and were given brinzolamide 1% (Azopt, Alcon Laboratories) to administer 1 drop in each eye twice a day (morning and evening) for 5 weeks, which was stopped 2 weeks before the randomization visit.

Patient Randomization and Study Treatment

At baseline (day 1), patients who met all eligibility criteria were randomized using a computer-generated randomization schedule in a 1:1 ratio to treatment with PFB 0.01% gel or PB 0.01% (Lumigan 0.01%, Allergan) for 3 months. A double-masked study design was not feasible due to a difference in packaging between PFB 0.01% gel (single dose) and PB 0.01% (multidose packaging). However, the 2 different treatment kits were identical in external appearance to respect the masking. The identity of the investigational medicinal product (IMP) given to each patient was not known by the investigator in charge of the ophthalmic examination (first investigator, considered masked). The dispensing of treatments and explanations on the dosing regimen for the study treatment was performed by another investigator (second investigator) or the designated site team member responsible for dispensation. The first investigator was in charge of all ophthalmic examinations carried out during the study visits. Patients were instructed not to disclose IMP information to other staff members or any investigators other than the second investigator.

Patients were instructed to instill the study medication (1 drop in each eye) once a day at 8 pm (±1 h) for the duration of the study. The first dose of study medication was instilled on day 1 after all baseline ocular assessments were completed. Follow-up visits were scheduled for weeks 6 and 12. IOP was measured at 8 am, 10 am, and 4 pm at all visits.

Outcome Measures

The primary efficacy outcome measure was the change in IOP from baseline to week 12 at 3 time points (8 am, 10 am, and 4 pm) in the worse eye (see definition in statistical analyses). Secondary efficacy measures included change in IOP from baseline to week 12 at 3 time points in the contralateral eye, change in IOP from baseline to week 6 at 3 time points in the worse and contralateral eye, and efficacy assessed by the investigator at weeks 6 and 12. IOP was measured in each eye by the same investigator, using the same calibrated Goldmann applanation tonometer at each visit. Two measurements were taken at each time point in each eye, and if the difference between these readings was more than 2 mm Hg, a third reading was taken. The IOP for each eye was determined as the mean of the readings whether it was performed 2 or 3 times.

Safety measures evaluated at each study visit included AEs, slit lamp examination to assess conjunctival hyperemia (evaluated by McMonnies photographic scale 0–5), corneal fluorescein staining (evaluated on Oxford grading scale 0–5), and other ocular signs (blepharitis, eyelid edema, abnormal eyelashes aspect, folliculo-papillary conjunctivitis, and iris pigmentation; graded using a 0–3 point severity scale: 0—none, 1—mild, 2—moderate, and 3—severe). Other safety measures included ocular symptoms (irritation/burning, stinging, itching, tearing, eye dryness feeling, and foreign body sensation) that occurred throughout the day (recorded at each visit) and upon instillation (recorded at weeks 6 and 12) based on a 4-point scale (none, present not disturbing, disturbing, and very disturbing). In addition, far BCVA (recorded at screening, baseline, and week 12), fundoscopy, CCT, and automated visual field were performed at screening and week 12, if deemed necessary by the investigator. Global tolerance was assessed by the investigator and by the patient at weeks 6 and 12 as very satisfactory, satisfactory, not very satisfactory, or unsatisfactory.

Statistical Analyses

Statistical analyses were performed using SAS software version 9.4 (SAS Institute). Inferential analyses of the primary efficacy endpoint aimed to assess the noninferiority (1.5 mm Hg margin) of PFB 0.01% gel to PB 0.01% were carried out. The noninferiority testing was performed on the basis of the 95% CIs for the difference between the 2 treatment groups in the change from baseline in IOP at week 12 at the 3 time points using mixed models with repeated measures (MMRM models). Each model included as fixed factors, treatment, scheduled visit time point (weeks 6 and 12), baseline IOP, washout duration, the country as covariates, treatment by visit interaction, and baseline IOP by visit interaction, and patient as random factor. Sensitivity analyses were performed using an analysis of covariance (ANCOVA) including treatment, baseline IOP, washout duration, and country. These models were based on the last observation carried forward method and performed to explore any possible impact of patient dropout on the noninferiority analysis.

The main efficacy analysis was performed on the modified intent-to-treat (mITT) set including all randomized patients who received at least 1 dose of the IMP (PFB 0.01% gel or PB 0.01%), with at least 1 baseline and 1 postbaseline efficacy assessment and considered as randomized. The per-protocol (PP; all mITT patients without a major protocol deviation) and intention-to-treat (ITT; all randomized patients who received at least 1 dose of the IMP) sets were used for confirmation for the main analysis. Safety analyses were performed on the Safety set (all enrolled patients who received at least 1 dose of the IMP) and distributions in ordinal categories were compared using Cochran Mantel Haenszel (CMH) tests.

For data recorded in both eyes, the analysis was performed separately for each eye. The worse eye was defined as the eligible eye with the highest average IOP at baseline (if IOP was the same in both eyes, the right eye was considered the worse eye). Data in the results section is presented for the worse eye. Results for the contralateral eye were consistent with those observed for the worse eye.

A sample size of 180 patients in each treatment arm was expected to give more than 90% power to show that PFB 0.01% gel was noninferior to PB 0.01%.

RESULTS

Patient Characteristics and Disposition

A total of 485 patients were randomized and treated in the study, 236 in the PFB 0.01% gel group and 249 in the PB 0.01% group (Fig. 1). Patient demographics were similar among the 2 treatment groups (Table 1). Patients ranged in age from 30 to 91 years (mean, 63.4 years). Most patients were female (60.6%). The main diagnosis was primary OAG (73.0%), followed by OHT (25.2%), and the most frequent previous glaucoma treatment was latanoprost (59.4%).

FIGURE 1.

Patient disposition. Patient disposition based on the ITT/Safety set; PFB 0.01% gel=preservative-free bimatoprost 0.01% gel; PB 0.01%=preserved bimatoprost 0.01% ophthalmic solution. PB 0.01% indicates preserved bimatoprost 0.01%; PFB 0.01%, preservative-free bimatoprost 0.01%.

TABLE 1.

Demographics and Characteristics of Randomized Patients at Baseline (Safety Set)

Screening characteristics	PFB 0.01% gel (N=236)	PB 0.01% (N=249)	Total (N=485)
Age (y)
Mean±SD	63.0±11.9	63.7±10.9	63.4±11.4
Min; Max	32.0; 91.0	30.0;90.0	30.0;91.0
Gender, n (%)
Male	95 (40.3)	96 (38.6)	191 (39.4)
Female	141 (59.7)	153 (61.4)	294 (60.6)
Diagnosis, n (%)
Primary OAG	166 (70.3)	188 (75.5)	354 (73.0)
Ocular hypertension	66 (28.0)	56 (22.5)	122 (25.2)
Secondary OAG: exfoliation glaucoma	3 (1.3)	2 (0.8)	5 (1.0)
Secondary OAG: pigmentary glaucoma	1 (0.4)	3 (1.2)	4 (0.8)
Time between diagnosis and randomization (mo)
Median	45.4	56.0	49.1
Previous treatment, n (%)
Latanoprost	137 (58.1)	151 (60.6)	288 (59.4)
Tafluprost	39 (16.5)	42 (16.9)	81 (16.7)
Bimatoprost	36 (15.3)	40 (16.1)	76 (15.7)
Travoprost	24 (10.2)	16 (6.4)	40 (8.2)
Central corneal thickness (µm)
Mean±SD	547.1±25.7	544.8±24.5	546.0±25.1

PFB 0.01% gel group patients received preservative-free bimatoprost 0.01% ophthalmic gel; PB 0.01% group patients received preserved bimatoprost 0.01% ophthalmic solution.

Max indicates maximum; Min, minimum; OAG, open angle glaucoma; PB 0.01%, preserved bimatoprost 0.01%; PFB 0.01%, preservative-free bimatoprost 0.01%.

Forty (8.2%) patients prematurely discontinued the study: 18 (7.6%) in the PFB 0.01% gel group and 22 (8.8%) in the PB 0.01% group. The most common reason for study discontinuation was due to the COVID-19 crisis; 10 patients in the PFB 0.01% gel group and 14 patients in the PB 0.01% group.

IOP-lowering Efficacy

The mean IOP in both groups at each time point in the worse eye is presented for the mITT set in Figure 2A. At week 12, the mean change from baseline in IOP was −9.72±2.97 mm Hg in the PFB 0.01% gel group versus −9.47±3.06 mm Hg in the PB 0.01% group at 8 am, −9.41±3.03 versus −9.19±3.12 mm Hg, respectively, at 10 am, and ­8.99±3.36 versus −8.54±3.44 mm Hg, respectively, at 4 pm. The upper limit of the 95% CI of the adjusted mean difference between treatment groups from the main analysis (MMRM model) was below the noninferiority margin of 1.5 mm Hg at each time point (Fig. 2B), confirming the noninferiority of PFB 0.01% gel to PB 0.01%. These results were confirmed in the PP and ITT sets. The sensitivity analysis using ANCOVA also supported the result of noninferiority (upper limits of 95% CIs of 0.29, 0.26, and 0.24 mm Hg at 8 am, 10 am, and 4 pm, respectively).

FIGURE 2.

Mean±SD IOP at baseline, weeks 6 and 12 at 8 am, 10 am, and 4 pm in the worse eye for the mITT set. Forest plot of adjusted mean difference (PFB 0.01% gel minus PB 0.01%) and 95% CIs for the main analysis of IOP change from baseline at week 6s and 12 at each time point (mITT set). The noninferiority margin of the study (1.5 mm Hg) and the more stringent noninferiority margin (1.0 mm Hg) are included. IOP indicates intraocular pressure; PB 0.01%, preserved bimatoprost 0.01%; PFB 0.01%, preservative-free bimatoprost 0.01%.

Similar mean IOP reductions were shown in both groups at week 6 (Fig. 2A) and in the contralateral eye at weeks 6 and 12 (not shown). The proportion of patients with IOP <18 mm Hg in the worse and contralateral eye was consistent and above 80% at any time point at weeks 6 and 12 in both treatment groups. The investigator assessed the global efficacy of the study medication as “very satisfactory” or “satisfactory” for at least 96% of patients in both treatment groups at each visit.

Safety and Tolerability

Adverse Events

Ocular AEs were reported in 54 (22.9%) patients treated with PFB 0.01% gel and 62 (24.9%) patients treated with PB 0.01%. The most frequent treatment-related AE, regardless of treatment group, was hyperemia (conjunctival and ocular), reported in 15 (6.4%) patients in the PFB 0.01% gel group and 26 (10.4%) patients in the PB 0.01% group (Table 2). No serious ocular AEs were reported during the study. Three patients experienced a serious systemic TEAE, 1 patient in the PFB 0.01% gel group (asthma) and 2 patients in the PB 0.01% group (1 patient with cholecystitis acute and 1 patient with pneumonia), which were not considered treatment-related. Ocular AEs were of mild or moderate intensity, except for 1 patient in the PFB 0.01% gel group (severe eczema) and 2 patients in the PB 0.01% group (severe dry eye and severe instillation site burn), all of which were considered related to the study treatment in the investigator’s judgment.

TABLE 2.

Summary of AEs Related to Treatment (Safety Set)

System organ class (preferred term)	PFB 0.01% gel (N=236)	PB 0.01% (N=249)
Eye disorders, n (%)	32 (13.6)	42 (16.9)
Abnormal sensation in the eye	1 (0.4)	2 (0.8)
Blepharal pigmentation	1 (0.4)	—
Blepharitis	1 (0.4)	3 (1.2)
Conjunctival hyperemia	12 (5.1)	15 (6.0)
Conjunctival irritation	1 (0.4)	—
Conjunctivitis allergic	1 (0.4)	4 (1.6)
Dry eye	—	4 (1.6)
Eye irritation	5 (2.1)	9 (3.6)
Eye pain	2 (0.8)	4 (1.6)
Eye pruritus	—	4 (1.6)
Eyelash changes	1 (0.4)	—
Eyelid edema	1 (0.4)	2 (0.8)
Foreign body sensation in the eyes	4 (1.7)	5 (2.0)
Keratitis	—	1 (0.4)
Lacrimation increased	1 (0.4)	—
Noninfective conjunctivitis	2 (0.8)	2 (0.8)
Ocular hyperemia*	3 (1.3)	12 (4.8)
Photophobia	1 (0.4)	—
Punctate keratitis	1 (0.4)	1 (0.4)
Vision blurred	—	2 (0.8)
General disorders and administration site conditions, n (%)	15 (6.4)	18 (7.2)
Instillation site burn	3 (1.3)	6 (2.4)
Instillation site dryness	3 (1.3)	3 (1.2)
Instillation site erythema	1 (0.4)	1 (0.4)
Instillation site foreign body sensation	2 (0.8)	1 (0.4)
Instillation site irritation	3 (1.3)	4 (1.6)
Instillation site lacrimation	1 (0.4)	1 (0.4)
Instillation site pain	3 (1.3)	7 (2.8)
Instillation site paresthesia	1 (0.4)	—
Instillation site pruritus	3 (1.3)	3 (1.2)
Instillation site reaction†	5 (2.1)	1 (0.4)
Investigations, n (%)	1 (0.4)	—
Vital dye staining cornea present	1 (0.4)	—
Skin and subcutaneous disorders, n (%)	2 (0.8)	—
Eczema	1 (0.4)	—
Madarosis	1 (0.4)	—

PFB 0.01% gel group patients received preservative-free bimatoprost 0.01% ophthalmic gel; PB 0.01% group patients received preserved bimatoprost 0.01% ophthalmic solution.

^*One patient from the PB 0.01% group reported 2 events, 1 event coded “conjunctival hyperemia” and 1 event coded “ocular hyperemia.”

^†Instillation site reaction in both groups was considered as a blurred vision by the investigator.

PB 0.01% indicates preserved bimatoprost 0.01%; PFB 0.01%, preservative-free bimatoprost 0.01%.

Slit Lamp Examination

At baseline, the percentage of patients with a presence of conjunctival hyperemia (McMonnies score >0) was similar between treatment groups (44.5% in the PFB 0.01% gel group and 43.4% in the PB 0.01% group). The presence of conjunctival hyperemia was lower in the PFB 0.01% gel group compared to the PB 0.01% group at week 6 (47.6% vs. 58.2%, respectively) and week 12 (42.7% vs. 56.4%, respectively). The between-group difference in conjunctival hyperemia was statistically significant in favor of PFB 0.01% gel at both week 6 (P=0.007) and week 12 (P=0.004). The percentage of patients who experienced a worsening from baseline in their conjunctival hyperemia score was lower in the PFB 0.01% gel group (20.1%) compared to the PB 0.01% group (29.3%) at week 6 and at week 12 (18.3% vs. 30.4%, respectively) (Fig. 3A). Between-group difference of change from baseline was statistically significant in favor of PFB 0.01% gel at week 6 (P=0.016) and week 12 (P=0.007).

FIGURE 3.

Percentage of patients experiencing a worsening, no change or improvement change from baseline in conjunctival hyperemia at weeks 6 and 12 in the PFB 0.1% gel group and PB 0.01% group. Percentage of patients with an absence or presence of corneal fluorescein staining at baseline, weeks 6, and 12 in the PFB 0.1% gel group and PB 0.01% group. PB 0.01% indicates preserved bimatoprost 0.01%; PFB 0.01%, preservative-free bimatoprost 0.01%.

The percentage of patients with a presence of corneal staining (CFS grade >0) was similar between groups at baseline (33.9% in the PFB 0.01% gel group and 35.3% in the PB 0.01% group), and lower in the PFB 0.01% gel group compared to the PB 0.01% group at week 6 (33.2% vs. 42.3%, respectively) and week 12 (31.6% vs. 41.9%, respectively) (Fig. 3B). A statistically significant between-group difference of corneal staining in favor of PFB 0.01% gel was shown at week 12 (P=0.037).

There was no statistically significant between-group difference in other ocular signs (blepharitis, eyelid edema, abnormal eyelash aspect, folliculo-papillary conjunctivitis, or iris pigmentation) throughout the study.

Ocular Symptoms

Irritation/burning upon instillation was less frequent in the PFB 0.01% gel group compared to the PB 0.01% group at week 12 (12.7% vs. 21.2%, respectively), unlike at week 6 (18.2% vs. 19.4%). There was a statistically significant between-group difference in favor of PFB 0.01% gel for irritation/burning (P=0.018) at week 12. This was also observed at week 12 for itching (P=0.048) and eye dryness feeling (P=0.012). Although the differences in other ocular symptoms upon instillation were not statistically significant, there was a numerical trend in favor of PFB 0.01% gel for stinging, tearing, and foreign body sensation.

Irritation/burning between instillations was less frequent in the PFB 0.01% gel group compared to the PB 0.01% group at week 6 (18.6% vs. 23.1%) and week 12 (12.3% vs. 19.5%). At week 12, there was a statistically significant between-group difference of irritation/burning in favor of PFB 0.01% gel (P=0.036). A similar pattern was also observed for eye dryness feeling at week 6 (17.3% in the PFB 0.01% gel group vs. 27.3% in the PB 0.01% gel group) and week 12 (16.4% vs. 25.6%, respectively). A statistically significant between-group difference for eye dryness feeling in favor of PFB 0.01% gel was observed at week 6 (P=0.015) and week 12 (P=0.013). Although the differences in other subjective ocular symptoms between instillations were not statistically significant, there was a numerical trend in favor of PFB 0.01% gel for stinging, tearing, itching, and foreign body sensation.

Global Local Tolerance

Assessment of IMP tolerance by the investigator as very satisfactory/satisfactory was higher in the PFB 0.01% gel versus PB 0.01% group at week 6 (93.0% vs. 88.7%) and week 12 (95.0% vs. 89.9%). At week 12, there was a statistically significant between-group difference favoring PFB 0.01% gel (P=0.045).

At weeks 6 and 12, more than 90% of patients in both treatment groups assessed the treatment tolerance as satisfactory or very satisfactory, with no statistically significant between-group difference.

Other Safety Parameters

There were no clinically important changes in corneal thickness, fundoscopy, visual field examinations, and far BCVA in either group during the study.

DISCUSSION

In this phase III study, noninferiority of PFB 0.01% gel compared to the reference product, PB 0.01% (Lumigan 0.01%), was demonstrated at week 12 in patients with OAG or OHT. Local tolerability, particularly conjunctival hyperemia, corneal fluorescein staining, and ocular symptoms including irritation/burning and eye dryness feeling were milder with PFB 0.01% gel compared with PB 0.01% over this 3-month trial.

The noninferiority claim required that the upper limit of the 95% CIs of between-group differences in mean change from baseline in IOP was within 1.5 mm Hg at all time points at week 12. The 1.5 mm Hg margin is widely accepted for glaucoma clinical studies,^25,26 although noninferiority would have also been demonstrated had the more stringent margin of 1.0 mm Hg been used. The upper limit of the 95% CIs was also below the 1.5 and 1.0 mm Hg margins at week 6. These results indicate that the removal of preservatives in antiglaucoma medications does not have a clinically relevant impact on IOP-lowering efficacy.^25,27,28

Of note, there was a greater IOP reduction in both treatment groups compared to many previous clinical studies with bimatoprost. In the PFB 0.01% gel group, a reduction from baseline to week 12 of −9.72 mm Hg was observed compared to a number of other studies: −3.8 mm Hg,⁹ −5.0±4.7 mm Hg,¹⁶ and −4.1 mm Hg.¹² This can be explained by the minimum 6-week run-in/washout period before starting the study treatment, which meant the IOP was greater (around 24 mm Hg) at baseline, compared to studies where there was no washout period: 22.2±0.3 mm Hg,⁹ 21.2±5.3 mm Hg,¹⁶ and 20.1±4.5 mm Hg.¹²

Preserved bimatoprost 0.01% contains a 4-fold greater concentration of BAK than most standard preserved formulations, due to in vitro evidence suggesting that BAK may facilitate topical ocular drug delivery.²⁹ However, due to the negative effects of preservatives on the ocular surface, and the long-term impact on the interior ocular structure's stability, research is focusing on ocular drug delivery which aims at prolonging the residence time of topically applied drugs in the conjunctival sac and on the cornea.²⁷ It has been reported that gel formulations have an advantage over ophthalmic solutions due to the carbomer's mucoadhesive properties which allow for a prolonged ocular contact time.²⁸ It has been demonstrated that corneal contact time with a mucoadhesive gel lasts for over 40 minutes after instillation, while standard saline solutions disappear in less than 20 minutes.³⁰ Therefore, the encouraging results on the efficacy of PFB 0.01% gel suggest that the use of a gel formulation may improve the ocular penetration of the active substance (bimatoprost 0.01%) without the need for a preservative, as is present in the currently marketed formulation.

Historically, most topical glaucoma eye drops have been preserved with BAK, an antimicrobial with broad activity on bacteria and fungi. However, it is recognized that preservatives also pose 2 significant long-term risks to ocular health. Preservatives have been shown to cause ocular surface damage via tear film instability, conjunctival squamous metaplasia and apoptosis, and disruption of the corneal epithelium barrier.^31,32 The other main side effect is the accumulation of preservatives in deeper ocular structures, such as the trabecular meshwork, which triggers inflammatory effects and enhanced trabecular degeneration and can increase the risk of glaucoma surgery failure.¹⁸ It could therefore be expected that PFB 0.01% gel should be better tolerated than bimatoprost 0.01% over the long term. In this study, fewer patients in the PFB 0.01% gel group compared to the PB 0.01% group experienced a worsening of conjunctival hyperemia at week 6 (20.1% vs. 29.3%) and week 12 (18.3% vs. 30.4%). Similar findings were also observed for corneal fluorescein staining. There was a numerical trend for all ocular symptoms in favor of PFB 0.01% gel, with a statistically significant between-group difference for irritation/burning, eye dryness feeling, and itching, which is encouraging for PFB 0.01% gel. This is of particular importance as signs and symptoms associated with OSD are often present in patients with glaucoma,³³ which can result in additional office visits, reduced compliance, and patient discontinuation from treatment.⁷ For instance, in a study conducted on 233 patients (most with primary OAG), the prevalence of OSD was 41.6% and was statistically significantly related to total preservative exposure (P<0.001) and prolonged use of preserved medication (P=0.005).³⁴ Furthermore, the quality of life of patients with OSD was considerably lower than that of patients with glaucoma but without OSD. These findings are also in agreement with those presented in a review article by Baudouin,³⁵ which showed the incidence of signs (including hyperemia and fluorescein staining) decreased significantly (P<0.0001) when patients switched from a preserved to a preservative-free formulation.

The encouraging results of ocular tolerance of PFB 0.01% gel may also be due to the viscosity properties of ophthalmic gels. These have been widely used to treat dry eye syndrome, as they have been shown to prolong symptomatic relief.³⁶ Studies have also confirmed the use of carbomers as the first-choice therapy for patients with ocular surface disease, demonstrating an improvement in both tear break-up time and Schirmer’s test results, even in healthy patients.²⁸ Consequently, the removal of a preservative and the gel formulation of PFB 0.01% gel may have a dual protective effect in reducing damage to the ocular surface and cornea,³⁷ and the lubrication and hydration of the ocular surface from the gel formulation, relieving the symptoms associated with ocular surface disease.³⁸

The main limitation of the study was the lack of an earlier ophthalmic assessment. While this clinical study is robust and noninferiority was demonstrated at all time points at week 12 and would have been demonstrated at week 6 with a noninferiority margin of 1 mm Hg, it is clear that an early time point (at weeks 1 or 2) to assess IOP would be relevant to have a more complete kinetics of efficacy of PFB 0.01% gel versus PB 0.01%. However, as bimatoprost is known to be effective within 24 hours of its first use,³⁹ it is unlikely that weeks 1 or 2 data would be significantly different from the consistent results observed at weeks 6 and 12.

In conclusion, the noninferiority of PFB 0.01% gel compared to PB 0.01% (Lumigan 0.01%) in lowering IOP at week 12 was demonstrated with a noninferiority margin of 1.5 mm Hg and would have also been demonstrated with a margin of 1 mm Hg. These results, coupled with improved tolerability in terms of conjunctival hyperemia and some ocular symptoms, suggest that this new preservative-free gel formulation of bimatoprost 0.01% could provide a therapeutic advantage over preservative-containing formulations in terms of patient adherence and persistence.