- Email: [email protected]
Dexamethasone Intracameral Drug-Delivery Suspension for Inflammation Associated with Cataract Surgery
Dexamethasone Intracameral Drug-Delivery Suspension for Inflammation Associated with Cataract Surgery A Randomized, Placebo-Controlled, Phase III Trial Eric Donnenfeld, MD,1 Edward Holland, MD2 Purpose: To evaluate the safety and efficacy of an anterior chamber intracameral dexamethasone drug-delivery suspension (IBI-10090; DEXYCU; Icon Bioscience Inc., Newark, CA) that provides medication for up to 21 days with a single application in treating postoperative inflammation in patients undergoing cataract surgery. Design: Prospective, randomized, double-masked, multicenter trial. Participants: Patients with preoperative best-corrected visual acuity of 20/30 to 20/200 undergoing unilateral cataract surgery by phacoemulsification were randomized to receive IBI-10090 or placebo. Methods: Three hundred ninety-four patients were randomized 1:2:2 to receive 5-ml injections of placebo or 5-ml injections of 342 or 517 mg IBI-10090 dexamethasone drug delivery suspension injected into the anterior chamber at the conclusion of cataract surgery. Patients were followed for 90 days after surgery. Main Outcome Measures: Primary outcome was anterior chamber cell (ACC) clearing (ACC score of 0) in the study eye at postoperative day (POD) 8. Secondary outcome measures were anterior chamber flare and ACC plus flare clearing in the study eye. Ocular and nonocular adverse events were assessed. Results: Anterior chamber cell clearing at POD 8 was achieved in 25.0% of eyes in the placebo group and in 63.1% and 66.0% of eyes in the 342- and 517-mg treatment groups, respectively (P < 0.001). Anterior chamber flare clearing at POD 8 was achieved by 63.8% of eyes in the placebo group and in 92.4% and 89.1% of eyes in the 342- and 517-mg IBI-10090 treatment groups, respectively (P < 0.001). Anterior chamber cell plus flare clearing at POD 8 was achieved in 33.8% of eyes receiving placebo and in 63.1% and 67.3% of eyes receiving 342- and 517-mg IBI-10090, respectively (P < 0.001). Adverse events among the 3 groups were similar, and no serious ocular adverse events were reported up to POD 90. Conclusions: The IBI-10090 dexamethasone drug-delivery suspension placed in the anterior chamber after cataract surgery at concentrations of 342 and 517 mg was safe and effective in treating inflammation occurring after cataract surgery and may be an alternative to corticosteroid drop installation in this patient population. Ophthalmology 2018;-:1e8 ª 2018 by the American Academy of Ophthalmology
Cataract is the leading cause of blindness in the world.1 In the United States alone, cataract affects 20.5 million (17.2%) Americans older than 40 years2; by 80 years of age, its prevalence increases to 1 in every 2 Americans. By 2020, the number of Americans with cataract is estimated to increase to 30.1 million, or nearly 10% of the United States population.3 In 2017, it is estimated that 4 million surgeries will be performed on a yearly basis. Most patients (>99.5%) undergoing routine phacoemulsification cataract surgery do not experience serious vision-threatening postsurgical complications. However, each year in the United States, 150 000 complications occur, reported in approximately 5% of patients.4 During phacoemulsification cataract surgery, unavoidable tissue damage can trigger an ocular inflammatory response5 that can induce intraocular vasodilation and increase vascular permeability. This can ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
disrupt and break down the bloodeocular barrier, increasing anterior chamber cells and flare. As a result, patients can experience pain and discomfort as well as impaired vision. After cataract surgery, inflammation remains a leading cause of patient discomfort, delayed recovery, and reduced visual outcomes.6,7 Preventing such complications and effectively managing ophthalmic inflammation after surgery is vital in preventing complications. Immediate postsurgical treatment also can preclude more serious complications such as cystoid macular edema, the most common vision-threatening complication of cataract surgery. To reduce such inflammation risk, ophthalmologists commonly use a prophylactic perioperative regimen consisting of topical corticosteroids and nonsteroidal antiinflammatory drugs (NSAIDs). The only Food and Drug https://doi.org/10.1016/j.ophtha.2017.12.029 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 Administrationeapproved topical corticosteroid formulations (difluprednate 0.05% and rimexolone 1%) are administered as ocular drops 4 times daily for 14 days or more.8,9 Topical dexamethasone sodium 0.1% and prednisone acetate 1% also are used commonly off label with the same dosing schedule10 for managing inflammation. Nonsteroidal anti-inflammatory drug eye drops have become a mainstay of managing ocular pain and inflammation5 and include ketorolac tromethamine 4 times daily, diclofenac 4 times daily, bromfenac once and twice daily, and nepafenac once and thrice daily, all of which have been approved for treating postoperative inflammation. Treatment may be more effective when corticosteroids and NSAIDs are used in combination, as demonstrated by Cable,11 who used both bromfenac and nepafenac after cataract surgery. However, patient compliance and other problems involving administration with elderly patients self-administering medication drops can vary widely.12 In a study of patients treated for glaucoma or ocular hypertension, Schwartz et al13 found that 42% have difficulty administering medication drops and 18% touch the eye or conjunctiva. In another study, 11% of patients older than 80 years failed to deliver drops to the conjunctival pouch and 61% scratched the cornea or conjunctiva with the applicator.14 Adherence to prescribed treatment after cataract surgery has not been assessed fully, but in general, adherence decreases with the number of daily doses. Many patients have mental or physical disabilities that limit their ability to deliver topical eye drops appropriately. Clearly, a more effective method for delivering effective and safe medications to the eye after cataract surgery is needed. IBI-10090 (DEXYCU; Icon Bioscience Inc., Newark, CA) is a novel, bioabsorbable drug-delivery system for anterior chamber intracameral placement of dexamethasone, which is being developed and studied for treating inflammation associated with cataract surgery. In animal models, therapeutic levels of IBI-10090 were maintained for up to 21 days after a single intracameral administration (Vernon Wong, MD, unpublished data, August 2010). In a phase II/ III study, IBI-10090 was dosed at 513, 776, and 1046 mg in more than 170 patients undergoing phacoemulsification cataract surgery. At all 3 doses, IBI-10090 was found to be safe and effective, achieving anterior chamber clearing at postoperative day (POD) 8 and demonstrating favorable efficacy compared with commercially available topical treatments. To extend these findings in a controlled trial, we undertook a phase III randomized, double-masked, controlled, multicenter trial to evaluate the efficacy and safety of 2 concentrations of IBI-10090 versus placebo for reducing ocular inflammation in patients undergoing phacoemulsification cataract surgery.
Methods Study Design This trial was a 90-day randomized, placebo-controlled, doublemasked, multicenter study (ClinicalTrials.gov identifier, NCT02006888) undertaken at 27 US investigator sites that enrolled 394 patients randomized to receive placebo or active treatment. The trial was designed to evaluate the efficacy and safety
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of a novel intracameral dexamethasone drug-delivery suspension (IBI-10090) for treating inflammation associated with cataract surgery. The study was conducted in accordance with Good Clinical Practice (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E6), applicable Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act. The study protocol was approved by an institutional review board at Schulman Associates before the start of the study, and all participants provided written informed consent. The screening period covered up to 45 days. After written informed consent was obtained, eligible patients were assigned randomly in a 1:2:2 ratio to receive 5 ml of placebo or 342 or 517 mg of dexamethasone drug-delivery suspension placed into the anterior chamber after completion of cataract surgery. One eye was chosen as the study eye for each patient. All study site personnel, the designated physicians, the patients, and the sponsor and its agents were masked to treatment drug dose assignment. Only the randomization provider had access to the unmasking code. During the 90-day study duration, patient visits were scheduled on day 0 (baseline) and on PODs 1, 3, 8, 14, 30, and 90 to evaluate safety and efficacy. Patients received their masked assigned treatment on day 0, the day of phacoemulsification cataract surgery. The primary efficacy end point was evaluated at POD 8.
Patients Male or female patients 40 years of age or older scheduled for unilateral cataract surgery by phacoemulsification with posterior chamber intraocular lens implantation were considered for inclusion in this trial.
Patient Inclusion Criteria Patient had to provide written informed consent by signing the informed consent approved by the institutional review board. The patients had to demonstrate best-corrected visual acuity of 20/30 to 20/200 (with glare testing, if necessary) in the study eye and better than 20/200 in the fellow eye. Patients considered by the investigator had to have a visual acuity potential better than 20/30 in the study eye. Patients had to have a corneal endothelial cell count by specular microscopy in the study eye of at least 2000 cells/mm2 with normal cell morphologic features. Women of childbearing potential (premenopausal by medical history) had to demonstrate negative pregnancy test results on day 0 and be using an effective method of birth control from screening for the duration of the study.
Patient Exclusion Criteria Exclusion criteria included the following: use of any ocular, topical, or oral corticosteroids within 7 days before day 0; receipt of a periocular corticosteroid injection in the study eye in the 3 months before screening; receipt of any intravitreal corticosteroid delivery vehicle (e.g., Retisert [Bausch & Lomb Incorporated, Bridgewater, NJ], Ozurdex [Allergan, Inc., Irvine, CA], Iluvien [Alimera Sciences, Inc., Alpharetta, GA]) in the study eye at any time; requiring treatment with any corticosteroids by any route, except inhalation, during the study; allergy or hypersensitivity to dexamethasone; a known response to steroids (corticosteroid-related intraocular pressure [IOP] elevation in either eye); use of topical ocular NSAIDs in the study eye within 15 days before day 0; prior intraocular (nonlaser) surgery in the study eye within 6 months before screening; prior intraocular laser surgery in the study eye within 3 months before screening; and any planned intraocular or laser surgery in the study eye for the duration of the study.
Donnenfeld and Holland
Dexamethasone for Postsurgical Inflammation
Procedure At the conclusion of cataract surgery, the surgeon injected the IBI-10090 suspension of dexamethasone or placebo as a single 5-ml droplet by intracameral injection into the anterior chamber using a 28- or 30-gauge needle. The ophthalmic surgeon monitored the status and pace of drug delivery.
Efficacy End Points Primary End Point. The primary end point was the proportion of eyes with anterior chamber cell (ACC) clearing (ACC score of 0) at POD 8. This end point was assessed using the following ACC scale: 0, absent; 1, 1 to 5 cells; 2, 6 to 15 cells; 3, 16 to 30 cells; and 4, hypopyon (inflammatory cell in eye anterior chamber). Secondary End Points. The secondary end points were as follows. Secondary end point 1 was defined as ACC clearing rates evaluated at follow-up visits on POD 1, 3, 15, and 30. Secondary end point 2 was defined as anterior chamber flare (ACF) clearing (ACF score of 0) using the following ACF grading scale: 0, absent; 1, trace; 2, mild intensity; 3, moderate intensity; and 4, strong intensity. Secondary end point 3 was defined as ACC and ACF grades of 0 at POD 8. Patients who achieved ACC and ACF scores of 0 (clearing) at POD 8 were included in this end point.
Safety Outcomes Safety was assessed by recording adverse events (AEs), IOP, visual acuity, corneal endothelial cell density, other eye examination outcomes, the use of concomitant medications, and concurrent procedures up to POD 90. At each study visit, nondirective questioning was used to elicit AE reports from patients. All AEs and serious AEs (SAEs), whether volunteered by the patient, discovered by study site personnel during questioning, or detected by examination, laboratory testing, or other means, were recorded in the patient record and case report forms.
Determination of Sample Size A target sample size of 390 patients (156 patients per active dose group and 78 patients in the placebo group) was chosen to provide more than 90% overall study power for detecting a 0.20 difference in the proportion of patients achieving the primary end point in one of the IBI-10090 dose groups compared with the placebo group. This sample size estimation is based on a 2-sided, 2-group chisquare test (continuity corrected) of equal proportion at a significance level of 0.025.
Randomization and Masking of Treatment Assignment Randomization was stratified (or balanced) by study center. Patients were randomized to receive placebo plus vehicle, 342 mg of IBI-10090, or 517 mg of IBI-10090 in a 1:2:2 ratio within each study center. Randomized treatment assignment was balanced for every 5 patients. Patients, investigators, and assessors performing evaluations were masked from the assignment of treatment group. Randomization assignments of study drug vials to study patients were performed using a procedure administered by study site personnel trained in the randomization assignment by the sponsor or designated party.
Statistical Analysis Efficacy Analyses. Unless otherwise specified, the intent-to-treat principle was used for efficacy analyses, with missing data imputed using the last observation carried forward method. Patients
were analyzed according to the treatment assignment at randomization. For the analysis of the primary efficacy parameter, a chisquare test was used for the overall comparison. Data were pooled from all centers for this analysis. A P value less than 0.05 was considered statistically significant. Safety Analyses. All patients who received the drug-delivery system were evaluated for safety. Descriptive statistics were reported.
Results Patient Characteristics and Disposition Between January 2014 and June 2014, 394 patients were enrolled at 27 study centers in the United States; 80 patients were assigned to receive 5 ml of placebo, 158 were assigned to receive 5 ml containing 342 mg of IBI-10090 dexamethasone drug, and 156 patients were assigned to receive 5 ml containing 517 mg of IBI-10090 dexamethasone drug, as outlined in the procedure. Of the 80 patients in the placebo group, 7 (8.7%) terminated the trial, 3 patients before POD 30 and 4 patients before POD 90. Of the158 patients in the IBI-10090 group, 157 (99%) completed the study; of 156 patients in the 517-mg group, 154 (99%) completed the study through POD 90 (Fig 1). Treatment groups were similar in demographic and baseline characteristics (Table 1). The mean age of patients was 70.0 years; 53.6% were women, and most were white.
Efficacy Outcomes Primary End Point. Both IBI-10090 treatment groups showed significantly (P 0.001) greater ACC clearing (ACC score, 0) at POD 8 compared with the placebo group. Anterior chamber cell clearing at POD 8 was achieved by 25.0% of patients in the placebo group and by 63.1% and 66.0% of patients in the 342- and 517-mg treatment groups, respectively (Fig 2). Rescue medication was used on POD 1 in 6 patients (7.5%) receiving placebo and in no patients in either IBI-10090 treatment group. On POD 3, 14 patients (17.5%) treated with placebo used rescue medication; no patients in the 342-mg treatment group and 4 patients (2.3%) in the 517-mg treatment group used rescue medications. On POD 8, rescue medications were used by 13 patients (16.3%) in the placebo group, 3 patients (1.9%) in the 342-mg treatment group, and 3 patients (1.9%) in the 517-mg treatment group. Secondary End Points. The proportion of patients demonstrating ACC clearing over time is shown in Figure 3A. In the placebo group, ACC clearing (ACC score of 0) was recorded in 26.3% of eyes at POD 8, increasing to 50.0% by POD 30. In the 342-mg dose group, 63.1% of eyes showed ACC clearing at POD 8, increasing to 80.9% by POD 30. In the 517-mg dose group, 65.4% of eyes showed ACC clearing at POD 8, increasing to 78.2% by POD 30. The difference between placebo and treatment groups at all time points was significant after POD 1 (P < 0.05). The percentages of patients with ACF clearing (ACF score of 0) at POD 8 are shown in Figure 3B. At POD 8, 63.8% of eyes in the placebo group, 92.4% of eyes in the 342-mg treatment group, and 89.1% of eyes in the 517-mg treatment group achieved an ACF grade of 0. The differences between the IBI-10090 and placebo groups were statistically significant (P < 0.001). The percentages of eyes with ACC and ACF scores of 0 at POD 8 are shown in Figure 3C. At POD 8, 33.8% of eyes in the placebo group, 63.1% of the 342-mg treatment group, and 67.3% of the 517-mg treatment group achieved ACC and ACF grades of 0.
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Figure 1. Diagram showing patient disposition. POD ¼ postoperative day.
70.78.8
69.78.8
70.19.0
patients in the 342-mg treatment group, and in 2.6% of patients in the 517-mg treatment group. Nonocular SAEs were deemed by the treatment investigator as unlikely or not related to the study drug and were consistent with the age group studied. Intraocular pressure increases were recorded in more patients within the active treatment group, but the mean IOP did not exceed 21 mmHg in any treatment group up to POD 90. An IOP increase of 10 mmHg or more from baseline to any time point up to POD 90 was observed in 13% of placebo-treated patients, 21% of patients in the 342-mg group, and 29% of patients in the 517-mg group. Other treatment-emergent AEs were corneal edema, eye pain, inflammation in anterior eye chamber, and dry eye, all of which occurred in less than 15% of patients in any group (Table 2). Rates of inflammatory ocular AEs (anterior chamber inflammation, eye inflammation, and iritis) consistently were higher in the placebo group than in either of the active treatment groups (Tables 2 and 3).
63 (78.8) 48.8
117 (74.1) 47.5
115 (73.7) 44.2
Discussion
67 (83.8) 11 (13.6) 2 (2.6)
129 (81.6) 17 (10.8) 12 (7.6)
123 (78.8) 21 (13.5) 12 (7.6)
37 (46.3) 43 (53.8)
87 (55.1) 71 (44.9)
75 (48.1) 81 (51.9)
This phase III randomized, double-masked, multicenter trial was designed to evaluate the safety and efficacy of a novel intracameral dexamethasone drug-delivery suspension for treating postoperative inflammation associated with cataract surgery. In this trial, we found that a significantly greater percentage of patients treated with 342 or 517 mg IBI-10090 reached the primary and secondary end points compared with patients receiving placebo. Specifically, ACC clearing
The differences between IBI-10090 and placebo groups were statistically significant (P < 0.001).
Safety Fewer patients in either of the IBI-10090 treatment groups (50.0% and 46.2%) reported any treatment-emergent AEs up to POD 90 compared with patients in the placebo group (63.8%; Table 2). No ocular SAEs were reported up to POD 90 in any group. Nonocular SAEs were observed in 5% of patients receiving placebo, in no Table 1. Patient Demographics and Baseline Characteristics IBI-10090 Placebo IBI-10090 (n [ 80) 342 mg (n [ 158) 517 mg (n [ 156) Age (yrs), mean SD 65, no. (%) Male gender (%) Race, no. (%) White Black Other Study eye, no. (%) Right Left
SD ¼ standard deviation.
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Dexamethasone for Postsurgical Inflammation
Figure 2. Bar graph showing primary end point: percentage of patients with anterior chamber cell (ACC) grade of 0 at postoperative day (POD) 8.
at POD 8 was 63% and 66% in the 342- and 517-mg groups, respectively, both significantly greater compared with 25% of placebo-treated eyes; further, at POD 30, this significant relationship held. This complete ACC clearing rate was significantly more than the approximately 20% to 30% range typically observed for current eye drop treatments.15 Treatment with IBI-10090 was safe and well tolerated. No ocular SAEs were reported up to POD 90, and AEs among the 3 treatment groups were similar. The 5% to 15% of ocular AEs seen in the active drug groups were similar to those observed in the placebo group. Most of the AEs in the patients receiving IBI-10090 treatment may have been a consequence of the surgical procedure. Other studies have demonstrated efficacy and safety using intracameral dexamethasone injections in controlling postoperative inflammation. Gungor et al16 found that intracameral dexamethasone and intracameral triamcinolone acetonide were similarly effective in controlling postoperative inflammation after phacoemulsification; the authors concluded that intracameral dexamethasone may be a better alternative to apply at the end of surgery to suppress inflammation during the first 24 hours. Inflammation after cataract surgery, which can persist, remains an undesirable consequence despite many advances in surgical techniques and remains a common cause of patient discomfort, delayed recovery, and reduced visual outcomes.6,7 Although corticosteroids traditionally are the therapy of choice for inflammation,17 their long-term use for managing ocular inflammation can produce unwanted adverse events such as increased IOP. Nonsteroidal anti-inflammatory drugs are a common postoperative treatment, but their use is not without risk;
some patients have reported corneal melting and perforation after treatment with NSAIDs.18 The duration and degree of postoperative anti-inflammatory therapy also are debated, as improved surgical approaches have minimized the need to control more aggressive inflammation after cataract surgery compared with previous surgical techniques.17 It is clear, however, that there remains an unmet medical need for an effective anti-inflammatory treatment with an improved safety profile that does not elevate IOP significantly and reduces inflammationrelated complications significantly after cataract surgery. In this multicenter controlled trial, the IBI-10090 dexamethasone drug-delivery system was a safe and significantly effective treatment in patients undergoing cataract surgery and may be an alternative to corticosteroid drops and NSAIDs in this patient population. The delivery system, a one-time administration by physician-controlled injection after the completion of cataract surgery, eliminates the compliance problem in patients selfadministering eye drops. This formulation acts immediately to reduce inflammation compared with eye drops. A small dropletd5 mldinjected into the eye after cataract surgery forms a surface tensionebased sphere, and the drug is released into the eye as the droplet is absorbed, providing controlled delivery directly to the target tissue for up to 21 days, depending on the formulation. When the drug depot is fully absorbed, drug delivery stops. The concentration of drug delivered is highest on the day of application, and as the medication dissipates, the concentration in the anterior chamber should taper slowly at the same time as the need for anti-inflammatory therapy decreases.
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Figure 3. A, Graph showing secondary end point of percentage of patients with anterior chamber cell (ACC) grade of 0 over 30 postoperative days (PODs) of the study. B, Bar graph showing secondary end point of percentage of patients with anterior chamber flare (ACF) grade of 0 at POD 8. C, Bar graph showing secondary end point of percentage of patients with ACC plus ACF grades of 0 at POD 8. LOCF ¼ last observation carried forward.
Table 2. Treatment-Emergent Adverse Events to Postoperative Day 90 Preferred Term Any TEAE in study eye or both eyes Any ocular SAE* Any nonocular SAE* Study eye AEs occurring in 5% of at least 1 active treatment group IOP increase Patients with maximum increase in IOP 10 mmHg between PODs 1 and 90 Corneal edema Eye pain Anterior chamber inflammation Dry eye
Placebo (n [ 80)
IBI-10090 342 mg (n [ 158)
IBI-10090 517 mg (n [ 156)
51 (63.8) 0 (0.0) 4 (5.0)
79 (50.0) 0 (0.0) 0 (0.0)
72 (46.2) 0 (0.0) 4 (2.6)
7 (8.8) 7 (13.0)
18 (11.4) 29 (21.0)
21 (13.5) 38 (29.0)
10 16 2 12
12 4 8 6
8 7 10 0
(10.0) (8.8) (12.5) (0.0)
(6.3) (10.1) (1.3) (12.6)
(7.7) (2.6) (5.1) (3.8)
AE ¼ adverse event; IOP ¼ intraocular pressure; POD ¼ postoperative day; SAE ¼ serious adverse event; TEAE ¼ treatment-emergent adverse event. Data are no. (%). *An adverse event was classified as serious (SAE) if it caused or led to death, required prolonged hospitalization, resulted in persistent or significant disability, or was considered a significant medical event by the investigating physician.
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Dexamethasone for Postsurgical Inflammation
Table 3. Adverse Events Occurring in 2% or More of Any Treatment Group to Postoperative Day 90
Preferred Term Patients reporting any TEAE in study eye or both eyes Iritis Anterior chamber cells Cystoid macular edema* Eye inflammation Posterior capsule opacification Visual acuity reduced Foreign body sensation Vitreous floaters Photophobia Macular edema
Placebo (n [ 80)
IBI-10090 342 mg (n [ 158)
IBI-10090 517 mg (n [ 156)
51 (63.8)
79 (50.0)
72 (46.2)
11 8 3 6 2
(13.8) (10.0) (3.8) (7.5) (2.5)
4 6 6 4 3
(2.5) (3.8) (3.8) (2.5) (1.9)
5 2 5 3 6
(3.2) (1.2) (3.2) (1.9) (3.8)
2 0 0 3 2
(2.5) (0.0) (0.0) (2.8) (2.5)
4 3 3 3 2
(2.5) (1.9) (1.9) (1.9) (1.3)
4 4 4 0 1
(2.6) (2.6) (2.6) (0.0) (0.6)
TEAE ¼ treatment-emergent adverse event. Data are no. (%). *Cystoid macula edema was evaluated by OCT.
A strength of this trial was its large, randomized, doubleblind design and robust primary and secondary end points to evaluate the active drug’s effect in 2 dose groups. However, one limitation is that we did not compare active drug with current standard-of-care treatments. Future trials are planned to evaluate IBI-10090 versus standard treatments (eye drops) for inflammation occurring after cataract surgery. In conclusion, the IBI-10090 dexamethasone drugdelivery suspension at concentrations of 342 and 517 mg placed in the anterior chamber at the conclusion of cataract surgery was safe and effective in treating inflammation occurring after cataract surgery and may be an alternative to corticosteroid drop application in patients undergoing cataract surgery. Acknowledgments The authors thank the C13-04 study site principal investigators.
References 1. Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82:844e851.
2. Centers for Disease Control and Prevention. Eye disorders. http:// www.cdc.gov/visionhealth/basic_information/eye_disorders.htm; 2015. Accessed December 18, 2017. 3. Congdon N, Vingerling JR, Klein BE, et al. Prevalence of cataract and pseudophakia/aphakia among adults in the United States. Arch Ophthalmol. 2004;122:487e494. 4. American Academy of Ophthalmology. Preferred Practice Pattern: cataract in the adult eye. American Academy of Ophthalmology; 2008. 5. Donnenfeld E. Current use of non-steroidal anti-inflammatory drugs in the treatment of ocular inflammation related to cataract surgery. Eur Ophthal Rev. 2012;6(3):173e177. 6. McColgin AZ, Heier JS. Control of intraocular inflammation associated with cataract surgery. Curr Opin Ophthalmol. 2000;11:3e6. 7. Mentes J, Erakgun T, Afrashi F, Kerci G. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Int J Ophthalmol. 2003;217:408e412. 8. Alcon. Vexol package insert. http://www.drugs.com/pro/vexol. html; 2015. Accessed December 18, 2017. 9. Alcon. Durezol package insert. Fort Worth, TX: Alcon Pharmaceuticals; 2013. 10. Grob SR, Gonzalez-Gonzalez LA, Daly MK. Management of mydriasis and pain in cataract and intraocular lens surgery: review of current medications and future directions. Clin Ophthalmol. 2014;8:1281e1289. 11. Cable M. Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. Clin Ophthalmol. 2012;6:997e1004. 12. Tsai T, Robin AL, Smith 3rd JP. An evaluation of how glaucoma patients use topical medications: a pilot study. Trans Am Ophthalmol Soc. 2007;105:29e33; discussion 35. 13. Schwartz GF, Hollander DA, Williams JM. Evaluation of eye drop administration technique in patients with glaucoma or ocular hypertension. Curr Med Res Opin. 2013;29:1515e1522. 14. Dietlein TS, Jordan JF, Luke C, et al. Self-application of single-use eyedrop containers in an elderly population: comparisons with standard eyedrop bottle and with younger patients. Acta Ophthalmol. 2008;86:856e859. 15. Kurt E, Mayali H. Early post-operative complications in cataract surgery. Cataract Surg. 2012;39:247e258. 16. Gungor SG, Bulam B, Akman A, Colak M. Comparison of intracameral dexamethasone and intracameral triamcinolone acetonide injection at the end of phacoemulsification surgery. Indian J Ophthalmol. 2014;62:861e864. 17. DeCroos FC, Afshari NA. Perioperative antibiotics and antiinflammatory agents in cataract surgery. Curr Opin Ophthalmol. 2008;19:22e26. 18. Miyanaga M, Miyai T, Nejima R, et al. Effect of bromfenac ophthalmic solution on ocular inflammation following cataract surgery. Acta Ophthalmol. 2009;87:300e305.
Footnotes and Financial Disclosures Originally received: June 12, 2017. Final revision: December 1, 2017. Accepted: December 20, 2017. Available online: ---.
Presented at: American Society of Cataract and Refractive Surgeons Annual Meeting, April 2015, San Diego, CA. Manuscript no. 2017-1256.
1
Ophthalmic Consultants of Long Island, Garden City, New York, and Department of Ophthalmology, New York University, New York, New York.
2
Cornea Services, Cincinnati Eye Institute, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio.
Financial Disclosure(s): The author(s) have made the following disclosure(s): E.H.: Consultant e Alcon Laboratories, Inc., Allergan, Kala Corporation, Mati Therapeutics, Omeros, PRN, Senju Pharmaceuticals, Shire, TearLab, TearScience; Financial support e Alcon Laboratories, Inc., Allergan, Mati Therapeutics, Omeros, PRN, Senju Pharmaceuticals; Lecturer e Alcon Laboratories, Inc., Allergan, Omeros, Senju Pharmaceuticals, Shire, TearScience
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Ophthalmology Volume -, Number -, Month 2018 Icon Bioscience participated in the design of the study, conduct of the study, data collection, data management, data analysis, interpretation of the data, and preparation, review, and approval of the manuscript. HUMAN SUBJECTS: Human subjects were included in this study. The institutional review board approved the study, and informed consent to participate in the study was obtained from all patients. The study complied with the Health Insurance Portability and Accountability Act of 1996. Author Contributions: Conception and design: Donnenfeld Analysis and interpretation: Donnenfeld Data collection: Donnenfeld
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Obtained funding: none Overall responsibility: Donnenfeld, Holland Abbreviations and Acronyms: ACC ¼ anterior chamber cell; ACF ¼ anterior chamber flare; AE ¼ adverse event; IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; POD ¼ postoperative day; SAE ¼ serious adverse event. Correspondence: Eric Donnenfeld, MD, Ophthalmic Consultants of Long Island, 2000 North Village Avenue, Suite 402, Rockville Centre, NY 11570. E-mail: [email protected].
Cataract is the leading cause of blindness in the world.1 In the United States alone, cataract affects 20.5 million (17.2%) Americans older than 40 years2; by 80 years of age, its prevalence increases to 1 in every 2 Americans. By 2020, the number of Americans with cataract is estimated to increase to 30.1 million, or nearly 10% of the United States population.3 In 2017, it is estimated that 4 million surgeries will be performed on a yearly basis. Most patients (>99.5%) undergoing routine phacoemulsification cataract surgery do not experience serious vision-threatening postsurgical complications. However, each year in the United States, 150 000 complications occur, reported in approximately 5% of patients.4 During phacoemulsification cataract surgery, unavoidable tissue damage can trigger an ocular inflammatory response5 that can induce intraocular vasodilation and increase vascular permeability. This can ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
disrupt and break down the bloodeocular barrier, increasing anterior chamber cells and flare. As a result, patients can experience pain and discomfort as well as impaired vision. After cataract surgery, inflammation remains a leading cause of patient discomfort, delayed recovery, and reduced visual outcomes.6,7 Preventing such complications and effectively managing ophthalmic inflammation after surgery is vital in preventing complications. Immediate postsurgical treatment also can preclude more serious complications such as cystoid macular edema, the most common vision-threatening complication of cataract surgery. To reduce such inflammation risk, ophthalmologists commonly use a prophylactic perioperative regimen consisting of topical corticosteroids and nonsteroidal antiinflammatory drugs (NSAIDs). The only Food and Drug https://doi.org/10.1016/j.ophtha.2017.12.029 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 Administrationeapproved topical corticosteroid formulations (difluprednate 0.05% and rimexolone 1%) are administered as ocular drops 4 times daily for 14 days or more.8,9 Topical dexamethasone sodium 0.1% and prednisone acetate 1% also are used commonly off label with the same dosing schedule10 for managing inflammation. Nonsteroidal anti-inflammatory drug eye drops have become a mainstay of managing ocular pain and inflammation5 and include ketorolac tromethamine 4 times daily, diclofenac 4 times daily, bromfenac once and twice daily, and nepafenac once and thrice daily, all of which have been approved for treating postoperative inflammation. Treatment may be more effective when corticosteroids and NSAIDs are used in combination, as demonstrated by Cable,11 who used both bromfenac and nepafenac after cataract surgery. However, patient compliance and other problems involving administration with elderly patients self-administering medication drops can vary widely.12 In a study of patients treated for glaucoma or ocular hypertension, Schwartz et al13 found that 42% have difficulty administering medication drops and 18% touch the eye or conjunctiva. In another study, 11% of patients older than 80 years failed to deliver drops to the conjunctival pouch and 61% scratched the cornea or conjunctiva with the applicator.14 Adherence to prescribed treatment after cataract surgery has not been assessed fully, but in general, adherence decreases with the number of daily doses. Many patients have mental or physical disabilities that limit their ability to deliver topical eye drops appropriately. Clearly, a more effective method for delivering effective and safe medications to the eye after cataract surgery is needed. IBI-10090 (DEXYCU; Icon Bioscience Inc., Newark, CA) is a novel, bioabsorbable drug-delivery system for anterior chamber intracameral placement of dexamethasone, which is being developed and studied for treating inflammation associated with cataract surgery. In animal models, therapeutic levels of IBI-10090 were maintained for up to 21 days after a single intracameral administration (Vernon Wong, MD, unpublished data, August 2010). In a phase II/ III study, IBI-10090 was dosed at 513, 776, and 1046 mg in more than 170 patients undergoing phacoemulsification cataract surgery. At all 3 doses, IBI-10090 was found to be safe and effective, achieving anterior chamber clearing at postoperative day (POD) 8 and demonstrating favorable efficacy compared with commercially available topical treatments. To extend these findings in a controlled trial, we undertook a phase III randomized, double-masked, controlled, multicenter trial to evaluate the efficacy and safety of 2 concentrations of IBI-10090 versus placebo for reducing ocular inflammation in patients undergoing phacoemulsification cataract surgery.
Methods Study Design This trial was a 90-day randomized, placebo-controlled, doublemasked, multicenter study (ClinicalTrials.gov identifier, NCT02006888) undertaken at 27 US investigator sites that enrolled 394 patients randomized to receive placebo or active treatment. The trial was designed to evaluate the efficacy and safety
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of a novel intracameral dexamethasone drug-delivery suspension (IBI-10090) for treating inflammation associated with cataract surgery. The study was conducted in accordance with Good Clinical Practice (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E6), applicable Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act. The study protocol was approved by an institutional review board at Schulman Associates before the start of the study, and all participants provided written informed consent. The screening period covered up to 45 days. After written informed consent was obtained, eligible patients were assigned randomly in a 1:2:2 ratio to receive 5 ml of placebo or 342 or 517 mg of dexamethasone drug-delivery suspension placed into the anterior chamber after completion of cataract surgery. One eye was chosen as the study eye for each patient. All study site personnel, the designated physicians, the patients, and the sponsor and its agents were masked to treatment drug dose assignment. Only the randomization provider had access to the unmasking code. During the 90-day study duration, patient visits were scheduled on day 0 (baseline) and on PODs 1, 3, 8, 14, 30, and 90 to evaluate safety and efficacy. Patients received their masked assigned treatment on day 0, the day of phacoemulsification cataract surgery. The primary efficacy end point was evaluated at POD 8.
Patients Male or female patients 40 years of age or older scheduled for unilateral cataract surgery by phacoemulsification with posterior chamber intraocular lens implantation were considered for inclusion in this trial.
Patient Inclusion Criteria Patient had to provide written informed consent by signing the informed consent approved by the institutional review board. The patients had to demonstrate best-corrected visual acuity of 20/30 to 20/200 (with glare testing, if necessary) in the study eye and better than 20/200 in the fellow eye. Patients considered by the investigator had to have a visual acuity potential better than 20/30 in the study eye. Patients had to have a corneal endothelial cell count by specular microscopy in the study eye of at least 2000 cells/mm2 with normal cell morphologic features. Women of childbearing potential (premenopausal by medical history) had to demonstrate negative pregnancy test results on day 0 and be using an effective method of birth control from screening for the duration of the study.
Patient Exclusion Criteria Exclusion criteria included the following: use of any ocular, topical, or oral corticosteroids within 7 days before day 0; receipt of a periocular corticosteroid injection in the study eye in the 3 months before screening; receipt of any intravitreal corticosteroid delivery vehicle (e.g., Retisert [Bausch & Lomb Incorporated, Bridgewater, NJ], Ozurdex [Allergan, Inc., Irvine, CA], Iluvien [Alimera Sciences, Inc., Alpharetta, GA]) in the study eye at any time; requiring treatment with any corticosteroids by any route, except inhalation, during the study; allergy or hypersensitivity to dexamethasone; a known response to steroids (corticosteroid-related intraocular pressure [IOP] elevation in either eye); use of topical ocular NSAIDs in the study eye within 15 days before day 0; prior intraocular (nonlaser) surgery in the study eye within 6 months before screening; prior intraocular laser surgery in the study eye within 3 months before screening; and any planned intraocular or laser surgery in the study eye for the duration of the study.
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Procedure At the conclusion of cataract surgery, the surgeon injected the IBI-10090 suspension of dexamethasone or placebo as a single 5-ml droplet by intracameral injection into the anterior chamber using a 28- or 30-gauge needle. The ophthalmic surgeon monitored the status and pace of drug delivery.
Efficacy End Points Primary End Point. The primary end point was the proportion of eyes with anterior chamber cell (ACC) clearing (ACC score of 0) at POD 8. This end point was assessed using the following ACC scale: 0, absent; 1, 1 to 5 cells; 2, 6 to 15 cells; 3, 16 to 30 cells; and 4, hypopyon (inflammatory cell in eye anterior chamber). Secondary End Points. The secondary end points were as follows. Secondary end point 1 was defined as ACC clearing rates evaluated at follow-up visits on POD 1, 3, 15, and 30. Secondary end point 2 was defined as anterior chamber flare (ACF) clearing (ACF score of 0) using the following ACF grading scale: 0, absent; 1, trace; 2, mild intensity; 3, moderate intensity; and 4, strong intensity. Secondary end point 3 was defined as ACC and ACF grades of 0 at POD 8. Patients who achieved ACC and ACF scores of 0 (clearing) at POD 8 were included in this end point.
Safety Outcomes Safety was assessed by recording adverse events (AEs), IOP, visual acuity, corneal endothelial cell density, other eye examination outcomes, the use of concomitant medications, and concurrent procedures up to POD 90. At each study visit, nondirective questioning was used to elicit AE reports from patients. All AEs and serious AEs (SAEs), whether volunteered by the patient, discovered by study site personnel during questioning, or detected by examination, laboratory testing, or other means, were recorded in the patient record and case report forms.
Determination of Sample Size A target sample size of 390 patients (156 patients per active dose group and 78 patients in the placebo group) was chosen to provide more than 90% overall study power for detecting a 0.20 difference in the proportion of patients achieving the primary end point in one of the IBI-10090 dose groups compared with the placebo group. This sample size estimation is based on a 2-sided, 2-group chisquare test (continuity corrected) of equal proportion at a significance level of 0.025.
Randomization and Masking of Treatment Assignment Randomization was stratified (or balanced) by study center. Patients were randomized to receive placebo plus vehicle, 342 mg of IBI-10090, or 517 mg of IBI-10090 in a 1:2:2 ratio within each study center. Randomized treatment assignment was balanced for every 5 patients. Patients, investigators, and assessors performing evaluations were masked from the assignment of treatment group. Randomization assignments of study drug vials to study patients were performed using a procedure administered by study site personnel trained in the randomization assignment by the sponsor or designated party.
Statistical Analysis Efficacy Analyses. Unless otherwise specified, the intent-to-treat principle was used for efficacy analyses, with missing data imputed using the last observation carried forward method. Patients
were analyzed according to the treatment assignment at randomization. For the analysis of the primary efficacy parameter, a chisquare test was used for the overall comparison. Data were pooled from all centers for this analysis. A P value less than 0.05 was considered statistically significant. Safety Analyses. All patients who received the drug-delivery system were evaluated for safety. Descriptive statistics were reported.
Results Patient Characteristics and Disposition Between January 2014 and June 2014, 394 patients were enrolled at 27 study centers in the United States; 80 patients were assigned to receive 5 ml of placebo, 158 were assigned to receive 5 ml containing 342 mg of IBI-10090 dexamethasone drug, and 156 patients were assigned to receive 5 ml containing 517 mg of IBI-10090 dexamethasone drug, as outlined in the procedure. Of the 80 patients in the placebo group, 7 (8.7%) terminated the trial, 3 patients before POD 30 and 4 patients before POD 90. Of the158 patients in the IBI-10090 group, 157 (99%) completed the study; of 156 patients in the 517-mg group, 154 (99%) completed the study through POD 90 (Fig 1). Treatment groups were similar in demographic and baseline characteristics (Table 1). The mean age of patients was 70.0 years; 53.6% were women, and most were white.
Efficacy Outcomes Primary End Point. Both IBI-10090 treatment groups showed significantly (P 0.001) greater ACC clearing (ACC score, 0) at POD 8 compared with the placebo group. Anterior chamber cell clearing at POD 8 was achieved by 25.0% of patients in the placebo group and by 63.1% and 66.0% of patients in the 342- and 517-mg treatment groups, respectively (Fig 2). Rescue medication was used on POD 1 in 6 patients (7.5%) receiving placebo and in no patients in either IBI-10090 treatment group. On POD 3, 14 patients (17.5%) treated with placebo used rescue medication; no patients in the 342-mg treatment group and 4 patients (2.3%) in the 517-mg treatment group used rescue medications. On POD 8, rescue medications were used by 13 patients (16.3%) in the placebo group, 3 patients (1.9%) in the 342-mg treatment group, and 3 patients (1.9%) in the 517-mg treatment group. Secondary End Points. The proportion of patients demonstrating ACC clearing over time is shown in Figure 3A. In the placebo group, ACC clearing (ACC score of 0) was recorded in 26.3% of eyes at POD 8, increasing to 50.0% by POD 30. In the 342-mg dose group, 63.1% of eyes showed ACC clearing at POD 8, increasing to 80.9% by POD 30. In the 517-mg dose group, 65.4% of eyes showed ACC clearing at POD 8, increasing to 78.2% by POD 30. The difference between placebo and treatment groups at all time points was significant after POD 1 (P < 0.05). The percentages of patients with ACF clearing (ACF score of 0) at POD 8 are shown in Figure 3B. At POD 8, 63.8% of eyes in the placebo group, 92.4% of eyes in the 342-mg treatment group, and 89.1% of eyes in the 517-mg treatment group achieved an ACF grade of 0. The differences between the IBI-10090 and placebo groups were statistically significant (P < 0.001). The percentages of eyes with ACC and ACF scores of 0 at POD 8 are shown in Figure 3C. At POD 8, 33.8% of eyes in the placebo group, 63.1% of the 342-mg treatment group, and 67.3% of the 517-mg treatment group achieved ACC and ACF grades of 0.
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Figure 1. Diagram showing patient disposition. POD ¼ postoperative day.
70.78.8
69.78.8
70.19.0
patients in the 342-mg treatment group, and in 2.6% of patients in the 517-mg treatment group. Nonocular SAEs were deemed by the treatment investigator as unlikely or not related to the study drug and were consistent with the age group studied. Intraocular pressure increases were recorded in more patients within the active treatment group, but the mean IOP did not exceed 21 mmHg in any treatment group up to POD 90. An IOP increase of 10 mmHg or more from baseline to any time point up to POD 90 was observed in 13% of placebo-treated patients, 21% of patients in the 342-mg group, and 29% of patients in the 517-mg group. Other treatment-emergent AEs were corneal edema, eye pain, inflammation in anterior eye chamber, and dry eye, all of which occurred in less than 15% of patients in any group (Table 2). Rates of inflammatory ocular AEs (anterior chamber inflammation, eye inflammation, and iritis) consistently were higher in the placebo group than in either of the active treatment groups (Tables 2 and 3).
63 (78.8) 48.8
117 (74.1) 47.5
115 (73.7) 44.2
Discussion
67 (83.8) 11 (13.6) 2 (2.6)
129 (81.6) 17 (10.8) 12 (7.6)
123 (78.8) 21 (13.5) 12 (7.6)
37 (46.3) 43 (53.8)
87 (55.1) 71 (44.9)
75 (48.1) 81 (51.9)
This phase III randomized, double-masked, multicenter trial was designed to evaluate the safety and efficacy of a novel intracameral dexamethasone drug-delivery suspension for treating postoperative inflammation associated with cataract surgery. In this trial, we found that a significantly greater percentage of patients treated with 342 or 517 mg IBI-10090 reached the primary and secondary end points compared with patients receiving placebo. Specifically, ACC clearing
The differences between IBI-10090 and placebo groups were statistically significant (P < 0.001).
Safety Fewer patients in either of the IBI-10090 treatment groups (50.0% and 46.2%) reported any treatment-emergent AEs up to POD 90 compared with patients in the placebo group (63.8%; Table 2). No ocular SAEs were reported up to POD 90 in any group. Nonocular SAEs were observed in 5% of patients receiving placebo, in no Table 1. Patient Demographics and Baseline Characteristics IBI-10090 Placebo IBI-10090 (n [ 80) 342 mg (n [ 158) 517 mg (n [ 156) Age (yrs), mean SD 65, no. (%) Male gender (%) Race, no. (%) White Black Other Study eye, no. (%) Right Left
SD ¼ standard deviation.
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Figure 2. Bar graph showing primary end point: percentage of patients with anterior chamber cell (ACC) grade of 0 at postoperative day (POD) 8.
at POD 8 was 63% and 66% in the 342- and 517-mg groups, respectively, both significantly greater compared with 25% of placebo-treated eyes; further, at POD 30, this significant relationship held. This complete ACC clearing rate was significantly more than the approximately 20% to 30% range typically observed for current eye drop treatments.15 Treatment with IBI-10090 was safe and well tolerated. No ocular SAEs were reported up to POD 90, and AEs among the 3 treatment groups were similar. The 5% to 15% of ocular AEs seen in the active drug groups were similar to those observed in the placebo group. Most of the AEs in the patients receiving IBI-10090 treatment may have been a consequence of the surgical procedure. Other studies have demonstrated efficacy and safety using intracameral dexamethasone injections in controlling postoperative inflammation. Gungor et al16 found that intracameral dexamethasone and intracameral triamcinolone acetonide were similarly effective in controlling postoperative inflammation after phacoemulsification; the authors concluded that intracameral dexamethasone may be a better alternative to apply at the end of surgery to suppress inflammation during the first 24 hours. Inflammation after cataract surgery, which can persist, remains an undesirable consequence despite many advances in surgical techniques and remains a common cause of patient discomfort, delayed recovery, and reduced visual outcomes.6,7 Although corticosteroids traditionally are the therapy of choice for inflammation,17 their long-term use for managing ocular inflammation can produce unwanted adverse events such as increased IOP. Nonsteroidal anti-inflammatory drugs are a common postoperative treatment, but their use is not without risk;
some patients have reported corneal melting and perforation after treatment with NSAIDs.18 The duration and degree of postoperative anti-inflammatory therapy also are debated, as improved surgical approaches have minimized the need to control more aggressive inflammation after cataract surgery compared with previous surgical techniques.17 It is clear, however, that there remains an unmet medical need for an effective anti-inflammatory treatment with an improved safety profile that does not elevate IOP significantly and reduces inflammationrelated complications significantly after cataract surgery. In this multicenter controlled trial, the IBI-10090 dexamethasone drug-delivery system was a safe and significantly effective treatment in patients undergoing cataract surgery and may be an alternative to corticosteroid drops and NSAIDs in this patient population. The delivery system, a one-time administration by physician-controlled injection after the completion of cataract surgery, eliminates the compliance problem in patients selfadministering eye drops. This formulation acts immediately to reduce inflammation compared with eye drops. A small dropletd5 mldinjected into the eye after cataract surgery forms a surface tensionebased sphere, and the drug is released into the eye as the droplet is absorbed, providing controlled delivery directly to the target tissue for up to 21 days, depending on the formulation. When the drug depot is fully absorbed, drug delivery stops. The concentration of drug delivered is highest on the day of application, and as the medication dissipates, the concentration in the anterior chamber should taper slowly at the same time as the need for anti-inflammatory therapy decreases.
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Figure 3. A, Graph showing secondary end point of percentage of patients with anterior chamber cell (ACC) grade of 0 over 30 postoperative days (PODs) of the study. B, Bar graph showing secondary end point of percentage of patients with anterior chamber flare (ACF) grade of 0 at POD 8. C, Bar graph showing secondary end point of percentage of patients with ACC plus ACF grades of 0 at POD 8. LOCF ¼ last observation carried forward.
Table 2. Treatment-Emergent Adverse Events to Postoperative Day 90 Preferred Term Any TEAE in study eye or both eyes Any ocular SAE* Any nonocular SAE* Study eye AEs occurring in 5% of at least 1 active treatment group IOP increase Patients with maximum increase in IOP 10 mmHg between PODs 1 and 90 Corneal edema Eye pain Anterior chamber inflammation Dry eye
Placebo (n [ 80)
IBI-10090 342 mg (n [ 158)
IBI-10090 517 mg (n [ 156)
51 (63.8) 0 (0.0) 4 (5.0)
79 (50.0) 0 (0.0) 0 (0.0)
72 (46.2) 0 (0.0) 4 (2.6)
7 (8.8) 7 (13.0)
18 (11.4) 29 (21.0)
21 (13.5) 38 (29.0)
10 16 2 12
12 4 8 6
8 7 10 0
(10.0) (8.8) (12.5) (0.0)
(6.3) (10.1) (1.3) (12.6)
(7.7) (2.6) (5.1) (3.8)
AE ¼ adverse event; IOP ¼ intraocular pressure; POD ¼ postoperative day; SAE ¼ serious adverse event; TEAE ¼ treatment-emergent adverse event. Data are no. (%). *An adverse event was classified as serious (SAE) if it caused or led to death, required prolonged hospitalization, resulted in persistent or significant disability, or was considered a significant medical event by the investigating physician.
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Table 3. Adverse Events Occurring in 2% or More of Any Treatment Group to Postoperative Day 90
Preferred Term Patients reporting any TEAE in study eye or both eyes Iritis Anterior chamber cells Cystoid macular edema* Eye inflammation Posterior capsule opacification Visual acuity reduced Foreign body sensation Vitreous floaters Photophobia Macular edema
Placebo (n [ 80)
IBI-10090 342 mg (n [ 158)
IBI-10090 517 mg (n [ 156)
51 (63.8)
79 (50.0)
72 (46.2)
11 8 3 6 2
(13.8) (10.0) (3.8) (7.5) (2.5)
4 6 6 4 3
(2.5) (3.8) (3.8) (2.5) (1.9)
5 2 5 3 6
(3.2) (1.2) (3.2) (1.9) (3.8)
2 0 0 3 2
(2.5) (0.0) (0.0) (2.8) (2.5)
4 3 3 3 2
(2.5) (1.9) (1.9) (1.9) (1.3)
4 4 4 0 1
(2.6) (2.6) (2.6) (0.0) (0.6)
TEAE ¼ treatment-emergent adverse event. Data are no. (%). *Cystoid macula edema was evaluated by OCT.
A strength of this trial was its large, randomized, doubleblind design and robust primary and secondary end points to evaluate the active drug’s effect in 2 dose groups. However, one limitation is that we did not compare active drug with current standard-of-care treatments. Future trials are planned to evaluate IBI-10090 versus standard treatments (eye drops) for inflammation occurring after cataract surgery. In conclusion, the IBI-10090 dexamethasone drugdelivery suspension at concentrations of 342 and 517 mg placed in the anterior chamber at the conclusion of cataract surgery was safe and effective in treating inflammation occurring after cataract surgery and may be an alternative to corticosteroid drop application in patients undergoing cataract surgery. Acknowledgments The authors thank the C13-04 study site principal investigators.
References 1. Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82:844e851.
2. Centers for Disease Control and Prevention. Eye disorders. http:// www.cdc.gov/visionhealth/basic_information/eye_disorders.htm; 2015. Accessed December 18, 2017. 3. Congdon N, Vingerling JR, Klein BE, et al. Prevalence of cataract and pseudophakia/aphakia among adults in the United States. Arch Ophthalmol. 2004;122:487e494. 4. American Academy of Ophthalmology. Preferred Practice Pattern: cataract in the adult eye. American Academy of Ophthalmology; 2008. 5. Donnenfeld E. Current use of non-steroidal anti-inflammatory drugs in the treatment of ocular inflammation related to cataract surgery. Eur Ophthal Rev. 2012;6(3):173e177. 6. McColgin AZ, Heier JS. Control of intraocular inflammation associated with cataract surgery. Curr Opin Ophthalmol. 2000;11:3e6. 7. Mentes J, Erakgun T, Afrashi F, Kerci G. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Int J Ophthalmol. 2003;217:408e412. 8. Alcon. Vexol package insert. http://www.drugs.com/pro/vexol. html; 2015. Accessed December 18, 2017. 9. Alcon. Durezol package insert. Fort Worth, TX: Alcon Pharmaceuticals; 2013. 10. Grob SR, Gonzalez-Gonzalez LA, Daly MK. Management of mydriasis and pain in cataract and intraocular lens surgery: review of current medications and future directions. Clin Ophthalmol. 2014;8:1281e1289. 11. Cable M. Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. Clin Ophthalmol. 2012;6:997e1004. 12. Tsai T, Robin AL, Smith 3rd JP. An evaluation of how glaucoma patients use topical medications: a pilot study. Trans Am Ophthalmol Soc. 2007;105:29e33; discussion 35. 13. Schwartz GF, Hollander DA, Williams JM. Evaluation of eye drop administration technique in patients with glaucoma or ocular hypertension. Curr Med Res Opin. 2013;29:1515e1522. 14. Dietlein TS, Jordan JF, Luke C, et al. Self-application of single-use eyedrop containers in an elderly population: comparisons with standard eyedrop bottle and with younger patients. Acta Ophthalmol. 2008;86:856e859. 15. Kurt E, Mayali H. Early post-operative complications in cataract surgery. Cataract Surg. 2012;39:247e258. 16. Gungor SG, Bulam B, Akman A, Colak M. Comparison of intracameral dexamethasone and intracameral triamcinolone acetonide injection at the end of phacoemulsification surgery. Indian J Ophthalmol. 2014;62:861e864. 17. DeCroos FC, Afshari NA. Perioperative antibiotics and antiinflammatory agents in cataract surgery. Curr Opin Ophthalmol. 2008;19:22e26. 18. Miyanaga M, Miyai T, Nejima R, et al. Effect of bromfenac ophthalmic solution on ocular inflammation following cataract surgery. Acta Ophthalmol. 2009;87:300e305.
Footnotes and Financial Disclosures Originally received: June 12, 2017. Final revision: December 1, 2017. Accepted: December 20, 2017. Available online: ---.
Presented at: American Society of Cataract and Refractive Surgeons Annual Meeting, April 2015, San Diego, CA. Manuscript no. 2017-1256.
1
Ophthalmic Consultants of Long Island, Garden City, New York, and Department of Ophthalmology, New York University, New York, New York.
2
Cornea Services, Cincinnati Eye Institute, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio.
Financial Disclosure(s): The author(s) have made the following disclosure(s): E.H.: Consultant e Alcon Laboratories, Inc., Allergan, Kala Corporation, Mati Therapeutics, Omeros, PRN, Senju Pharmaceuticals, Shire, TearLab, TearScience; Financial support e Alcon Laboratories, Inc., Allergan, Mati Therapeutics, Omeros, PRN, Senju Pharmaceuticals; Lecturer e Alcon Laboratories, Inc., Allergan, Omeros, Senju Pharmaceuticals, Shire, TearScience
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Ophthalmology Volume -, Number -, Month 2018 Icon Bioscience participated in the design of the study, conduct of the study, data collection, data management, data analysis, interpretation of the data, and preparation, review, and approval of the manuscript. HUMAN SUBJECTS: Human subjects were included in this study. The institutional review board approved the study, and informed consent to participate in the study was obtained from all patients. The study complied with the Health Insurance Portability and Accountability Act of 1996. Author Contributions: Conception and design: Donnenfeld Analysis and interpretation: Donnenfeld Data collection: Donnenfeld
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Obtained funding: none Overall responsibility: Donnenfeld, Holland Abbreviations and Acronyms: ACC ¼ anterior chamber cell; ACF ¼ anterior chamber flare; AE ¼ adverse event; IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; POD ¼ postoperative day; SAE ¼ serious adverse event. Correspondence: Eric Donnenfeld, MD, Ophthalmic Consultants of Long Island, 2000 North Village Avenue, Suite 402, Rockville Centre, NY 11570. E-mail: [email protected].