FormalPara Key Summary Points

Why carry out this study?

Advances in surgical instruments and techniques have significantly improved post-surgery outcomes reducing postoperative complications. However, some degree of ocular pain and inflammation may still occur after surgery, even in uneventful procedures, leading to possible complications.

A new preservative-free ophthalmic hydrogel formulation of dexamethasone 0.1%/netilmicin 0.3% fixed combination (Netildex® Gel, SIFI SpA, Catania Italy) has been developed to reduce the high-frequency instillation of corticosteroids required with the eye drop formulation. The addition of xanthan gum in this ophthalmic formulation may increase the pseudo-plastic characteristics of the product, prolonging ocular retention time and giving a beneficial hydration to the ocular surface.

What was learned from the study?

The administration of dexamethasone 0.1%/netilmicin 0.3% (Netildex) ophthalmic gel b.i.d. is sufficient to obtain a non-inferior efficacy in the prevention and treatment of post-cataract surgery ocular inflammation compared with dexamethasone 0.1%/netilmicin 0.3% (Netildex) eye drop solution administered q.i.d. for the same period. No infections were reported.

The new ophthalmic gel formulation, therefore, allows a reduced administration frequency while maintaining the same efficacy and simultaneously favouring patients' convenience and comfort, with possible better compliance to treatment and patients' quality of life.

Introduction

Cataract is a common ophthalmic disease, especially among the elderly [1,2,3]. Currently, the most popular procedure for cataract removal is phacoemulsification, followed by the implantation of an artificial intraocular lens (IOL) [1, 2, 4, 5].

Recent advances in surgical instruments and techniques have significantly improved post-surgery outcomes reducing postoperative complications. However, some degree of ocular pain and inflammation may still occur after surgery, even in uneventful procedures [6, 7], leading to possible complications, such as corneal oedema, intraocular pressure (IOP) spikes, posterior capsule opacification and cystoid macular oedema [8,9,10,11].

The two main topical treatments in the management of post-surgical ocular inflammation and pain are non-steroidal anti-inflammatory drugs (NSAIDs) and topical corticosteroids, with the latter being considered the gold standard treatment. Corticosteroids are usually administered through topical eye drop instillation [10, 12,13,14,15,16].

Besides inflammation, one of the main risks of ocular surgery is the occurrence of ocular infection, which can lead to rare but devastating effects, such as postoperative endophthalmitis [16,17,18]. The use of antibiotics in cataract surgery includes a variety of regimens and protocols, including intracameral and postoperative topical antibiotics. Evidence that injecting intracameral antibiotics (cefuroxime, moxifloxacin) at the end of cataract surgery is effective for endophthalmitis prophylaxis is growing [20]. Among postoperative topical antibiotics, aminoglycosides and fluoroquinolones are the most prescribed agents and provide an excellent wide-spectrum coverage [17, 19,20,21,22]. In this respect, it has been established that a patient’s ocular flora is the source of microbes responsible for most cases of intraocular infections [23]. Thus, reducing the number of microbes on the ocular surface or eliminating the organisms that may have reached the eye can decrease the risk of endophthalmitis [19]. Recently, particular attention has been given to avoiding the administration of cytotoxic antibiotics in pre- and post-cataract surgery to ensure good visual and refractive outcomes after cataract surgery [24].

According to these considerations, a new preservative-free ophthalmic hydrogel formulation of dexamethasone 0.1%/netilmicin 0.3% fixed combination (Netildex® Gel, SIFI SpA, Catania Italy) has been developed to reduce the high-frequency instillation of corticosteroids required with the eye drop formulation. This new formulation contains xanthan gum, a high-molecular-weight polysaccharide used in ophthalmic preparations as a viscosity enhancer. The addition of xanthan gum in ophthalmic formulations has been shown to increase the pseudo-plastic characteristics of the product, prolonging ocular retention time [25,26,27] and with beneficial effect on the ocular surface [28, 29]. Furthermore, xanthan gum is a polymer with a well-known lubricant with pseudoplastic behaviour and antioxidant action on the ocular surface [30, 31] and could prevent the exacerbation of low-grade and/or non-symptomatic dry eye disease that often happens after cataract surgery, especially in elderly patients [24].

The aim of this study was to investigate whether a reduced frequency of administration of an innovative hydrogel formulation containing dexamethasone 0.1%/netilmicin 0.3%, instilled twice daily (b.i.d.), was non-inferior to dexamethasone 0.1%/netilmicin 0.3% fixed combination formulated in eye drop solution administered four-times daily (q.i.d.), in the treatment and prevention of ocular inflammation after phacoemulsification and IOL implantation.

Methods

Study Design and Subjects

This was an international phase III, randomised, double-blind study to evaluate the non-inferiority of a hydrogel formulation administered b.i.d. (Netildex gel) as compared to the eye drops formulation q.i.d. (Netildex® Eye drops, SIFI SpA, Catania, Italy) in patients undergoing phacoemulsification and IOL implantation. Both formulations are a fixed combination of netilmicin sulphate 3 mg/ml and dexamethasone phosphate 1 mg/ml. The preservative-free ophthalmic gel single-dose formulation contains xanthan gum, which acts as a viscosity enhancer by increasing the retention of the product on the ocular surface [24,25,26,27].

The study adhered to the tenets of the Declaration of Helsinki and was approved by the independent Ethics Committees of the participating institutions. Written informed consent was obtained from all patients before randomisation.

The study was conducted in five centres located in Italy (3 centres) and Germany (2 centres). Patients were included if they were aged ≥ 40 years and undergoing phacoemulsification with IOL implantation, with a grade 2 or 3 cataract according to the lens opacity classification system III (LOCS III) and an endothelial cell count within limits for age but not < 1200 cell/mm2. The main exclusion criteria included patients with a medical history of ocular inflammatory disease, trauma, herpes infections, uveitis or Sjogren’s syndrome and those with at least one of the following concomitant ocular diseases: ocular infections, glaucoma, diabetic retinopathy, uncontrolled diabetes, maculopathy, shallow anterior chamber, pseudo-exfoliation syndrome, poor mydriasis and IOP > 24 mmHg; patients who had been treated for external ocular infections within 1 month before the study enrollment and those receiving any ocular treatment apart from artificial tears were also excluded.

Patients were randomised to receive either single-dose ophthalmic hydrogel b.i.d. (group 1) or single-dose eye drops solution (group 2) q.i.d., administered topically in the conjunctival sac of the operated eye starting on the day of cataract surgery (day 0) until day 14 after surgery. To ensure masking, patients treated with the ophthalmic hydrogel also received two daily doses of placebo (single-dose ophthalmic hydrogel, containing sodium hyaluronate and xanthan gum) to reach four daily administrations. In both treatment groups, almost all patients (99.4%) received bromfenac (a non-steroidal anti-inflammatory drug) for a maximum of one drop twice daily (b.i.d.) from day − 3 to day − 1 (the day before surgery). Concomitant medications included intracameral injection of cefuroxime 1 mg/0.1 ml in the anterior chamber at the end of the surgery according to participating centres preference.

Measurements

Patients were evaluated 4–7 days before cataract surgery (screening visit), on the day of surgery and at 1, 7 and 15 days after surgery; an additional follow-up visit was performed 60 days after surgery.

The primary efficacy endpoint was the evaluation of inflammation (cellularity and flare) in the anterior chamber using slit-lamp biomicroscopy on day 7 after surgery. The scoring system is shown in Table 1, adapted from Hogan, 1964, and Jobs, 2005 [32, 33]. Patients were classified as full responders if both cellularity and flare were zero, partial responders if at least one of the 2 measurements were zero and non-responders if both cellularity and flare were greater than zero. The same evaluation was repeated 15 days after surgery.

Table 1 Scoring system for inflammation in the anterior chamber
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The secondary endpoints included: (1) the presence of clinical signs/symptoms of ocular inflammation (anterior chamber flare, cellularity, conjunctival hyperaemia, lid oedema, corneal oedema, ocular pain, photophobia, tearing) assessed at days 1, 7 and 15 after surgery; (2) incidence of infection, assessed by clinical evaluation, and in the case of suspected infection ocular swabs were performed.

Global tolerability was measured at days 1, 7 and 15 after surgery through a standard questionnaire, classified on a categorical scale from 0 to 3: (0) none; (1) mild (present but not distressing); (2) moderate (distressing but not interfering with daily life); (3) severe (very distressing and interfering with daily life). Subjective tolerability was also assessed at days 1, 7 and 15 after surgery by interviewing patients about their symptoms, such as burning, stinging and blurred vision, and it was scored using the above-mentioned scale.

Safety was assessed by measuring frequency and severity of adverse events (AEs), changes in IOP (assessed by the Goldman applanation tonometry, CSO, Florence, Italy) and visual acuity, clinically significant laboratory abnormalities and physical examination findings.

Compliance was evaluated through direct interviews with the participating patients.

Statistical Analysis

A drop-out rate of 28% was considered. The sample size was calculated considering the detection of a true difference in favour of the reference treatment of 5% and required 130 patients to be 90% sure that the upper limit of a one-sided 97.5% confidence interval (CI) excluded a difference in favour of the reference group of > 10%. The difference in the primary efficacy endpoint, namely the proportion of full responders, was analysed by a chi-square test for proportion along with a one-sided 97.5% CI of the difference based on Student’s t distribution.

Secondary endpoints were tabulated with frequency and percentages at each time point during the study. The two treatment groups were compared by means of logistic regression techniques in univariate and multivariate models, adjusted for demographic and clinical factors. A per-protocol analysis was performed, which excluded ten patients in group 1 for protocol violations.

The non-inferiority analysis to obtain the difference in the proportion was performed using the Proc Freq in SAS v. 9.4, with one-sided 97.5% confidence intervals and a non-inferiority margin of 0.10.

Results

Patient Demographics and Treatment Adherence

The enrolment at the investigational sites was competitive to reach the target of 180 patients. Moreover, the study was stopped after 173 had been randomised patients since the number of statistically evaluable patients had already been reached (168 patients in ITT population patients versus the 130 requested in the protocol). The mean age was 72.6 (range 38–89) years, although this resulted in a protocol minor violation for patients aged 30–39 years. Age and gender were well matched among treatment groups. Patient disposition, according to the CONSORT diagram, is displayed in Fig. 1.

Fig. 1
figure 1

Patient’s disposition. Group 1 = hydrogel; group 2 = eye drops

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Almost all randomised patients received the first dose of treatment on the day of surgery (168/173, 97.1%). Five patients were randomised but had not received any study treatments (3 to hydrogel, 2 to eye drops formulation); thus, the number of patients reported in the baseline period is 168 (85 in group 1 and 83 in group 2).

After 7 days from surgery the treatment compliance was high for both treatments: 96.4% in group 1 and 100% in group 2. Demographic and baseline characteristics (age, gender and race) of the intention-to-treat (ITT) and safety population were similar across treatment groups, with no statistically significant differences (p > 0.05) (Table 2). Almost all patients (99.4%) received bromfenac 0.1% eye drops for a maximum of one drop twice daily (b.i.d.) from day − 3 to day − 1 (the day before surgery), and most of the patients received an intracameral injection of cefuroxime at the end of surgery in accordance with the ESCRS Guidelines [34].

Table 2 Demographic and baseline characteristics of the safety population and intention-to-treat population
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Primary Endpoint (Cellularity and Flare Responder Rate)

Based on the ITT dataset, which included 168 patients receiving the treatment at day 7 post-surgery (85 in group 1 and 83 in group 2), 75 patients (88.2%) in group 1 and 78 patients (93.9%) in group 2 showed no signs of ocular inflammation (no flare and no cellularity in the anterior chamber) and were classified as full responders (Table 3).

Table 3 Cellularity and flare responders 7 days after surgery
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The non-inferiority analysis (non-inferiority margin of − 0.10 and 97.5% CI) showed that the hydrogel administered b.i.d. was non-inferior to the eye drops formulation administered q.i.d. since the lower limit of the 97.5% CI (− 0.0535) was greater than the non-inferiority limit of − 0.10. The non-inferiority was also confirmed by the multivariate analysis, in which patients' sex and/or age were considered as cofactors (Fig. 2).

Fig. 2
figure 2

Cellularity and flare responders 7 days after surgery

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The per-protocol analysis, which excluded two patients in group 1 for protocol violations (inclusion criteria), showed similar results, with 89.7% and 95% of the patients classified as full responders 7 days post-cataract surgery, respectively, in the ophthalmic gel and eye drops treatment arms. The results confirmed the non-inferiority of the hydrogel compared with eye drop formulation, with an estimated risk difference at the univariate analysis of -0.0526 (95% CI − 0.0562 to 0.1613) and a lower limit of 97.5% CI equal to − 0.0562, therefore greater than the non-inferiority limit of − 0.10.

Secondary Endpoints

Clinical Signs and Symptoms of Ocular Inflammation

No significant difference was detected between the two groups in terms of ocular inflammation signs and symptoms (anterior chamber flare, cellularity, conjunctival hyperaemia, lid oedema, corneal oedema, ocular pain, photophobia, tearing) from day 1 up to 15 days post-surgery. All patients recovered by day 15 post-surgery, reporting no signs of ocular inflammation, apart from one patient in group 2 who had a few cells (score 0.5) on day 15 post-surgery. Furthermore, the ophthalmoscopy evaluation indicated no relevant differences throughout the study between the two groups.

Tolerability

In group 1 at day 1, 81 patients (97.6%) reported no discomfort at all, and 2 patients (2.4%) reported mild discomfort (present but not distressing); at day 7, all patients reported no discomfort; at day 15, 79 patients (98.8%) had no discomfort, and only 1 patient (1.3%) reported moderate discomfort, which was distressing but did not interfere with daily life.

In group 2 at day 1, 81 patients (98.8%) reported no discomfort, and 1 patient (1.2%) reported severe discomfort; at day 7, all patients reported no discomfort; at day 15, 80 patients (98.8%) had no discomfort, and only one patient (1.2%) reported mild discomfort.

Regarding symptoms of burning, stinging or blurred vision, there was no difference between the groups.

Safety Results

Ten out of 168 patients experienced at least one AE, 4 (4.7%) in group 1 and 6 (7.2%) in group 2. All AEs were classified as expected and of mild or moderate grade. Only two patients in group 2 experienced serious AEs (2.4%), vascular occlusion and macular oedema, which were assessed as not related to the study arm, and they completely recovered after appropriate treatment. Only one patient in group 1 reported a treatment-related AE, namely drug hypersensitivity. No patient showed signs of infection or endophthalmitis.

No between-group difference was found for visual acuity and IOP. IOP for the treated and non-treated eye was within the normal range (12–22 mmHg) and did not change during treatment in both arms, except for one patient in the group 1 arm who had increased IOP on day 1 only, which decreased by day 7 and remained stable and within the normal range at the following visits (Table 4).

Table 4 Slit-lamp evaluation during the study. Unit-variable association between study drug and occurrence of full-responder at endpoint ITT sample
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Discussion

The management of ocular inflammation and prevention of infection after cataract surgery are of capital importance to reduce postoperative complications and to improve patients' subjective comfort. Among different anti-inflammatory and antibiotic perioperative protocols, postoperative antibiotic and steroid eye drops (in either fixed combinations or in separated formulations) are the most commonly prescribed [20].

Regarding the prophylaxis of infections, it has been established that a patient's ocular flora is the source of microbes responsible for most cases of intraocular infections [23]. Thus, reducing the number of microbes on the ocular surface or eliminating the organisms that may have reached the eye can decrease the risk for endophthalmitis. [20].

Both formulations used in this study, hydrogel and eyedrops, contain dexamethasone 0.1%/netilmicin 0.3%. Netilmicin is an antibiotic with an effective wide-spectrum antimicrobial activity, including methicillin-resistant (MR) strains (such as MR Staphylococcus aureus and MR coagulase-negative Staphylococci) [35, 36]. In an in vitro evaluation has been demonstrated that netilmicin has better tolerability and is less cytotoxic regarding the antimicrobial agents commonly used in clinical ophthalmological practice as fluoroquinolones [37]. Marino et al., in an in vivo study on rabbits, demonstrated that netilmicin, in respect to ofloxacin, may offer a superior toxicological profile in both normal eyes and clinical situations where the integrity of the ocular epithelium is altered [38, 39].

The second main component is dexamethasone phosphate, a potent steroid, well absorbed, especially in the presence of ocular inflammation [32]. The efficacy of this formulation in controlling ocular inflammation after cataract surgery has been proved in previous studies [40, 41]. Recently, a new single-dose dexamethasone 0.1%/netilmicin 0.3% ophthalmic hydrogel containing xanthan gum has been marketed. This hydrogel formulation has shown a longer retention time on the ocular surface than the eye drop solution [27], possibly increasing the interval between instillations and reducing the frequency of administration. Moreover, the presence of xanthan gum fosters the healing process after the preoperative disinfection [28, 29].

In this context, the purpose of our study was to assess whether the dexamethasone/netilmicin ophthalmic gel administered b.i.d. is non-inferior to the ophthalmic solution instilled q.i.d. in controlling post-cataract surgery inflammation and in preventing infection.

In this study and considering the ITT population of 168 patients, 7 days of treatment were sufficient to control the post-surgical inflammation in both groups: most patients (88.2% in group 1 and 93.9% in group 2) showed no signs of inflammation of the anterior chamber after 7 days of treatment, and all patients, except one who received the eye drop formulation, completely recovered within 15 days post-surgery. The non-inferiority of the hydrogel in terms of reduction of ocular flare and cellularity reported in the univariate analysis (lower 97.5% CI − 0.0535, greater than the non-inferiority limit of -0.10) was confirmed by both the multivariate analysis and the per-protocol analysis, which excluded seven patients in the hydrogel arm and three in the eye drops arm for deviations to the protocol (lower 97.5% CI − 0.0526).

The results obtained for secondary variables (clinical signs and symptoms of ocular inflammation, visual acuity) confirmed no differences between the two arms.

Moreover, the hydrogel proved to be equal to the Netildex eye drops in terms of global patient tolerability. Indeed, both treatments were well tolerated with very few mild and reversible AEs, which were not considered as related to the study drug, and only one case of drug hypersensitivity was reported in the hydrogel arm.

In the ophthalmic gel formulation, the presence of xanthan gum which acts as a viscosity enhancer increases the retention of the product on the ocular surface and reduces the number of instillations necessary to maintain an adequate concentration of corticosteroids [25, 26]. Moreover, it keeps the ocular surface hydrated and creates a coating that fosters the healing process. One of the main disadvantages of the eye drop formulation is that after topical administration, the concentration of corticosteroids in the anterior chamber increases and declines within hours [42], necessitating frequent daily instillations, with a consequential negative effect on patient compliance and a potential decrease of therapeutic efficacy. It is important to notice that, for double masking reasons, patients in the hydrogel arm also received two placebo administrations. Therefore, it was not possible to evaluate the favourable impact of a reduced number of administrations per day provided by the hydrogel formulation regarding patient compliance and quality of life. The reduction of the number of daily instillations may improve patient adherence to treatment, especially in the case of concomitant use of other topical medications (e.g., anti-glaucoma drugs, non-steroidal anti-inflammatory drugs or artificial tears). The formulation may also act as artificial tears.

As a potential limitation of the study, anterior chamber inflammation was measured, for practical reasons, by slit-lamp examination rather than by a laser flare and cell metre. Even if the scoring system used to measure flare and cells by slit-lamp examination is subjective and semiquantitative, it still corresponds to the actual daily routine of practice [43].

Conclusions

In conclusion, this large, international clinical trial shows that the administration of Netildex ophthalmic gel b.i.d. is sufficient to obtain a non-inferior efficacy in the prevention and treatment of post-cataract surgery ocular inflammation compared with Netildex eye drop solution administered q.i.d. for the same period. The new ophthalmic gel formulation, therefore, allows a reduced administration frequency while maintaining the same efficacy and simultaneously favouring patients' convenience and comfort, with possible better compliance to treatment and patients' quality of life.