Abstract
Purpose
The XEN gel stent (XEN Glaucoma Treatment System®; AbbVie Inc., North Chicago, IL, USA) is a minimally invasive bleb-forming device implanted ab-interno to lower intraocular pressure. The gel stent is approved to treat refractory glaucoma in China since 2020, based on interim real-world study data from patients at Hainan Boao Super Hospital. Final study data on the gel stent’s effectiveness and safety in those patients are presented.
Patients and Methods
The single-center, single-arm, open-label, phase 3b Hainan study collected data from Chinese patients with refractory glaucoma (ie, failed surgical treatment or primary open-angle/pseudoexfoliative/pigmentary glaucoma unresponsive to medical therapy) who underwent ab-interno gel stent implantation. This study was designed for both retrospective and prospective collection of real-world data.
Primary Effectiveness Outcome
Proportion of study eyes at 12 months achieving ≥20% intraocular pressure (IOP) reduction from baseline without increasing the number of IOP-lowering medications and without secondary surgical intervention. Secondary effectiveness outcomes: mean IOP and mean number of IOP-lowering medications used over time. Safety outcomes: intraoperative complications and postoperative treatment-emergent adverse events (TEAEs), postoperative needling, and ophthalmic safety assessments.
Results
Fifty-nine patients were enrolled that composed the effectiveness (n=59 eyes) and safety (n=62 eyes) populations. Among the 59 study eyes, 53 (89.8%) completed the 12-month visit. Mean IOP decreased from 23.7 mmHg on 3.3 IOP-lowering medications at baseline (47.5% of patients requiring ≥4 medications; 59.3% with prior glaucoma surgery) to 17.4 mmHg on 1.0 IOP-lowering medication at month 12. 49.0% (95% CI: 34.8–63.4) of the study eyes achieved the primary effectiveness outcome based on observed data. Among study eyes with baseline IOP ≥20 mmHg (n=31/59; 52.5%), IOP decreased from 30.4 mmHg on 3.4 medications (baseline) to 17.2 mmHg on 0.6 medications (month 12), and 17/28 (60.7%) achieved the primary outcome. No intraoperative complications or ocular TEAEs leading to study discontinuation were reported. Excluding expected inflammatory TEAEs following filtration surgery, IOP decreased (8.1%) and IOP increased (33.9%) were the most common TEAEs ≤7 and >7 days after surgery, respectively.
Conclusions
The gel stent effectively lowered IOP and IOP-lowering medication burden in Chinese patients with refractory glaucoma, with no new unexpected safety findings, supporting its use as a minimally invasive bleb-forming surgical option in this population. Future considerations may include larger, prospective, comparative studies.
Keywords: glaucoma, glaucoma surgery, XEN gel stent, bleb, Chinese
Introduction
Over the last couple decades, surgical management of glaucoma has evolved considerably, with minimally invasive glaucoma surgery (MIGS) emerging as an alternative to conventional filtering procedures such as trabeculectomy and tube shunts. MIGS can be categorized into several broad areas: increasing trabecular outflow, increasing suprachoroidal outflow, targeting Schlemm’s canal and conjunctival bleb forming.1 The gel stent (XEN Glaucoma Treatment System®; AbbVie Inc., North Chicago, IL, USA) is a minimally invasive bleb-forming surgical (MIBS) device that is approved in several countries to lower intraocular pressure (IOP) following ab-interno implantation. In the European Union, the gel stent is indicated (since 2015) for the treatment of primary open-angle glaucoma (POAG) in which previous medical treatments have failed.2 In the United States, the gel stent is indicated (since 2016) for the management of refractory glaucoma, including cases in which prior surgical treatment has failed and cases of POAG, pseudoexfoliation glaucoma, or pigmentary glaucoma found unresponsive to maximum tolerated medical therapy.3
The clinical presentation of POAG can be subject to ethnic differences. East Asian individuals, including those of Chinese descent, have a higher prevalence of myopia compared to those of European descent,4 and myopia has been identified as a risk factor for primary open-angle glaucoma (POAG).5 Given that trabeculectomy can be technically more challenging in highly myopic eyes,6 the XEN45 gel stent, a minimally invasive ab-interno approach, may offer a procedural advantage in this patient subset by circumventing the anatomical difficulties associated with conventional filtering surgery. Furthermore, East Asian patients have been shown to have lower success rates and higher complication rates following trabeculectomy compared to other populations,7 providing additional rationale for evaluating minimally invasive alternatives such as the XEN gel stent in this demographic.
In 2020, the gel stent was also approved in China to treat refractory glaucoma (ie, cases in which previous surgical treatment has failed and cases of POAG, pseudoexfoliative glaucoma, or pigmentary glaucoma unresponsive to maximum tolerated medical therapy).8 Approval of the gel stent in China was supported by interim data of the real-world study conducted at the Hainan Boao Super Hospital per requirement of the National Medical Products Administration (formerly known as the China Food and Drug Administration). The agency mandated that a study similar to the US pivotal registration study9 be conducted to inform on the real-world effectiveness and safety of the gel stent in Chinese patients with refractory glaucoma (defined above), relative to the Western population evaluated in the US pivotal study. As real-world evidence on the XEN gel stent in Chinese patients remains limited, this prospective and retrospective study represents an important contribution to the literature, providing comprehensive, real-world effectiveness and safety data for this device in a Chinese patient population.
Materials and Methods
Ethics and Study Design
This real-world, single-center, single-arm, open-label, phase 3b Hainan study (ClinicalTrials.gov registration number: NCT04303897) was conducted in China between December 19, 2019, and March 3, 2022. All procedures adhered to the Declaration of Helsinki and were conducted in accordance with the consensus ethical principles derived from international guidelines (including the Council for International Organizations of Medical Sciences International Ethical Guidelines), applicable International Council for Harmonisation Good Clinical Practice guidelines, International Organization for Standardization guidance, and all applicable laws/regulations. This study was designed for both retrospective and prospective collection of real-world data from Chinese patients with XEN implanted at Hainan Boao Super Hospital to evaluate the safety and effectiveness of the treatment. Patient data were de-identified in accordance with applicable data privacy regulations, including China’s Personal Information Protection Law (PIPL), and cross-border data sharing with the study sponsor was conducted in compliance with applicable laws and data transfer agreements.
The protocol, informed consent form, and other relevant documents (eg, recruitment flyers) were reviewed and approved by an institutional review board/independent ethics committee at Boao Super Hospital (CY-KY1912002) before initiation of the study. All eligible patients provided written informed consent before enrollment in the study.
Participants
The key inclusion criteria were age (≥18 years) at the time of signing the informed consent, and diagnosis of refractory glaucoma (ie, cases in which previous surgical treatment had failed and cases of POAG, pseudoexfoliative glaucoma, or pigmentary glaucoma that were unresponsive to maximum tolerated medical therapy).
Patients were excluded if they had angle closure glaucoma without an angle-widening procedure; a glaucoma shunt/valve in the target quadrant from a previous surgery; conjunctival scarring, a prior conjunctival surgery, or other conjunctival pathologies (eg, pterygium) in the target quadrant; active inflammation (eg, blepharitis, conjunctivitis, keratitis, or uveitis); iris neovascularization (active or within 6 months of the gel stent implantation date); an anterior chamber intraocular lens; intraocular silicone oil; or vitreous present in the anterior chamber.
The study eye was the implanted eye. For patients implanted bilaterally, the eye with higher IOP at baseline was the study eye; if baseline IOP was the same in both eyes, the first eye implanted was the study eye.
Study Visits and Treatment
Study visits were scheduled at screening/baseline (ideally ≤2 weeks before the surgery day), day 0 (implantation/surgery day), and postoperative day 1, week 1, month 1, month 3, month 6, and month 12. Although all implantations were performed at the Hainan Boao Super Hospital (the only hospital authorized to use the gel stent at the time the study started), the pre- and postoperative visits could be scheduled at the referring hospitals.
Per protocol, it was recommended that patients use ophthalmic solutions of preservative-free, broad-spectrum ophthalmic antibiotic (4 times daily on day −1) and corticosteroid (4 times daily for 5–7 days before surgery). MMC-soaked sponges (concentration: 0.2–0.4 mg/mL) were used at the surgeon’s discretion during the procedure. Topical (study eye only) and systemic IOP-lowering medications were suspended on surgery day.
XEN45 was used in this study. Gel stent placement was performed ab interno through a clear corneal incision, according to the directions for use.3 A secondary paracentesis was allowed if an injection of ophthalmic viscoelastic was needed to maintain the anterior chamber depth. The injector needle was then advanced through the peripheral cornea and across the anterior chamber toward the targeted quadrant. Corneal entry was to be at least 1‒2 mm anterior to the limbus to ensure proper angulation of the gel stent (up and away from the iris), and placement through the center of the angle.
After the patient’s eye was stabilized, the needle’s bevel was oriented upward, and the needle was pushed through the trabecular meshwork (under gonioscopy guidance) and sclera. When the needle was aligned with the desired entry point in the anterior chamber angle, the needle was advanced in the anterior chamber angle and sclera until the needle bevel became visible in the subconjunctival space. Small adjustments forward or backward could then be made to ensure that the entire bevel was visible in the subconjunctival space and the needle had relative freedom of movement within the sclera. At that point, any counterforce/countertraction was released to allow the eye to return to its natural position, and the gel stent was deployed by moving the injector slider forward.
A properly placed gel stent had ~1 mm visible in the anterior chamber and ~2 mm in the subconjunctival space. Ideally, the exit from the sclera was ~3 mm from the limbus. If the gel stent was not correctly positioned, it could be removed by grasping it near its entry point in the angle and gently pulling it away from the angle in successive, repeated steps until the gel stent was completely within the anterior chamber and out via the corneal incision. The replacement stent was to be implanted in the same quadrant or as near as possible to the original location, using the same implantation technique.
After positioning was confirmed, the viscoelastic (if used) was irrigated and aspirated from the anterior chamber and replaced with new viscoelastic (if needed to maintain the anterior chamber depth). After closure of the corneal incision and visual confirmation of bleb formation, Seidel testing was performed to ensure that there was no leakage of aqueous humor.
After surgery, patients were advised to use ophthalmic solutions of preservative-free, broad-spectrum antibiotic for 1 week and corticosteroid 4 times daily on weeks 1 to 4, 3 times daily on week 5, twice daily on week 6, and once daily on weeks 7 to 12. IOP-lowering medications were reintroduced to manage high IOP if ≥1 of the following conditions was met: the patient’s IOP was not at target (per investigator judgement), progression of optic nerve cupping was noted, or progression of visual field loss was observed and confirmed with a second visual field test within 1 week.
If postoperative bleb needling was required, it was to be preferably performed in the operating room, using caution to avoid damaging/direct contact with the implant.
Assessments
The number of IOP-lowering medications was recorded at all study visits. IOP was assessed at all study visits except day 0, using Goldmann applanation tonometry per standard clinical practice; whenever possible, measurements were obtained at approximately the same time of day for each patient throughout the study, and preferably before the gonioscopy, pachymetry, and ophthalmoscopy evaluations were performed. Ideally, baseline IOP was determined before initiation of the preoperative steroid regimen (if applicable).
Best-corrected visual acuity (BCVA) was assessed at all study visits except day 0, per the decimal system/scale,10 and reported in logMAR units. Gonioscopy was performed at baseline to categorize the iridocorneal angle per the Shaffer scale, as well as week 1 (optional) and months 1, 3, 6, and 12 postimplantation to document any device displacement, malposition, movement, contact with the cornea and/or iris, and tip occlusion. Central corneal thickness was measured at baseline, month 3, and month 12 using ultrasound (contact) pachymetry. Slit lamp biomicroscopy was performed at all study visits (except day 0) to evaluate the condition of the eyelids, conjunctiva (including bleb characteristics), cornea (including corneal stromal edema at the implantation site), anterior chamber, iris/pupil, and lens, as well as the implant position. Unless pupil dilation put the patient at risk of acute angle closure (per investigator judgement), stereoscopic fundus assessments were obtained through a dilated pupil at baseline and months 1, 3, 6, and 12 to evaluate the macula, vitreous, and retina; determine the cup/disc ratio; and document the presence of optic disc pathology (if any). When dilation was used, ophthalmoscopy examinations were to be performed last.
Visual field assessments were performed at baseline (or up to 6 months before study entry) and month 12.
Treatment-emergent adverse events (TEAEs) were recorded at all study visits, in accordance with ISO 14155 and European Medical Device Regulation 2017/745 for clinical device research.
Outcomes
The primary effectiveness outcome was the proportion of study eyes achieving ≥20% IOP reduction from baseline at Month 12 without an increase in IOP-lowering medications and without secondary surgical intervention (SSI), representing a clinically meaningful improvement in IOP control for POAG patients requiring surgical intervention. For the primary analysis, this endpoint was evaluated in study eyes with month-12 data that had not undergone SSI.
Secondary effectiveness outcomes included mean IOP, mean change in IOP from baseline, and percent change in IOP from baseline at Month 12 among study eyes with evaluable baseline and month-12 IOP data; and mean number of IOP-lowering medications and mean change in IOP-lowering medications from baseline at Month 12. Proportion of patients using fewer IOP-lowering medications at 12 months than baseline, proportion of medication-free patients with IOP <20 mmHg at 12 months, and proportion of patients with IOP ≤15 mmHg without an increase in the number of IOP-lowering medications at 12 months were also evaluated.
Safety outcomes included the intraoperative complications, postoperative ocular TEAEs, device deficiency (including malfunctions, user errors, and improper labeling), and postoperative needling, as well as the changes from baseline in central corneal thickness, BCVA, and visual field, and biomicroscopy, gonioscopy, and ophthalmoscopy findings.
The effectiveness population included all implanted study eyes with postoperative effectiveness data. The safety population included all implanted eyes, including second eyes in bilaterally implanted patients.
Statistical Analysis
This study was designed as a single-arm, real-world observational study, and the statistical analyses were primarily descriptive. The objective was to estimate effectiveness and safety outcomes rather than to make causal or comparative inferences.
For the primary effectiveness outcome, study eyes that required an SSI to control IOP (eg, trabeculectomy, cyclodialysis, additional shunt placement, and scleral suture to close the gel stent) were classified as /nonresponders. For such eyes, the highest IOP recorded during the study was used as the 12-month IOP in calculations of the mean IOP and mean change in IOP from baseline.
The primary endpoint analysis was based on observed data. To assess the impact of incomplete month-12 follow-up, prespecified sensitivity analyses were performed using the last observation carried forward (LOCF), worst IOP and medication count values, best IOP and medication count values, and extreme-case imputations in which all missing month-12 data were classified as failures/nonresponders or as responders. A subgroup analysis of the primary effectiveness outcome was also conducted in study eyes with baseline IOP ≥20 mmHg.
Kaplan–Meier analyses were performed to evaluate the time to failure (defined as the need for an SSI or more IOP-lowering medications at month 12 than baseline). For eyes requiring an SSI, the date of the SSI was used as the failure date. For eyes requiring additional IOP-lowering medications ≥1 month after implantation, the date of prescription was used. If additional IOP -lowering medication was prescribed before the Month 1 visit and persisted after the Month 1, then the Month 1 visit date was used as the failure date.
Continuous variables were summarized using mean, standard deviation (SD), median, quartiles (Q1, Q3), minimum (min), and maximum (max). Categorical variables were summarized using frequency counts and percentages. 95% confidence intervals (CIs) were provided for key effectiveness estimates to convey precision of estimation.
Statistical analyses were conducted using SAS software, Version 9.4 (SAS Institute, Cary, NC, USA). Two-sided hypothesis tests were performed at the 5% significance level. All 95% CIs were 2-sided, unless stated otherwise.
Sample Size Calculations
In the pivotal US registration study,9 analyses of observed data indicated that 75.4% of patients achieved the primary outcome (ie, ≥20% IOP reduction from baseline at 1 year without an increase in IOP-lowering medication count), and that the mean diurnal IOP reduction from baseline was 6.2 mmHg (standard error, 9.1). Assuming a similar responder rate and mean IOP reduction in Chinese patients, the estimated 95% CI for the primary effectiveness outcome in this study would be 3.8–8.8 with 50 patients, 4.2–8.4 with 70 patients, and 4.5–8.1 with 100 patients. Similar to the pivotal US registration study,4 enrollment of ~65 patients was thus planned for the Hainan study.
Results
Patient Disposition, Demographics, and Baseline Characteristics
In total, 59 patients (62 eyes) were enrolled and implanted with the gel stent. The effectiveness population comprised 59 study eyes, and the safety population comprised 62 implanted eyes. Among the 59 study eyes, 53 (89.8%) completed the 12-month visit. Across all implanted eyes, 55/62 (88.7%) completed the 12-month visit. Six (10.2%) patients (7 eyes; 11.3%) discontinued the study (Figure 1).
Figure 1.
Patient dispostion flow chart. *Death was not treatment-related, and the patient’s first eye/study eye completed the 12-month visit.
Overall, at baseline, mean age was 46.5 years and mean IOP was 23.7 mmHg on a mean of 3.3 IOP-lowering medications (Table 1). Most patients had POAG (74.6%), 47.5% required ≥4 IOP-lowering medications, and 59.3% had undergone prior glaucoma surgery. The visual field mean deviation was, on average, −17.7 dB (Table 1), indicating severe glaucoma.11
Table 1.
Patient Demographics and Baseline Characteristics
| Variable | All Patients (N=59) | Patients with Baseline IOP ≥20 mmHg (n=31) |
|---|---|---|
| Age, mean (SD), years | 46.5 (15.8) | 45.8 (16.1) |
| Median (Q1, Q3) | 46.0 (33.0, 55.0) | 46.0 (31.0, 57.0) |
| Min, max | 23.0, 83.0 | 24.0, 83.0 |
| Sex, n (%) | ||
| Male | 45 (76.3) | 24 (77.4) |
| Female | 14 (23.7) | 7 (22.6) |
| Ethnicity, n (%) | ||
| Han | 59 (100) | 31 (100) |
| Study eye, n (%) | ||
| Left | 21 (35.6) | 13 (41.9) |
| Right | 38 (64.4) | 18 (58.1) |
| Glaucoma diagnosis, n (%) | ||
| POAG | 44 (74.6) | 21 (67.7) |
| Pigmentary glaucoma | 1 (1.7) | 1 (3.2) |
| Other* | 14 (23.7) | 9 (29.0) |
| Glaucoma duration, mean (SD), years | 4.5 (5.0) | 3.8 (4.2) |
| Median (Q1, Q3) | 3.0 (1.0, 6.0) | 3.0 (1.0, 5.0) |
| Min, max | 0, 21 | 0, 20 |
| History of glaucoma surgery, n (%) | 35 (59.3) | 19 (61.3) |
| IOP, mean (SD), mmHg | 23.7 (9.7) | 30.4 (8.8) |
| Median (Q1, Q3) | 20.3 (16.6, 29.7) | 29.6 (21.6, 37.9) |
| Min, max | 10.5, 47.5 | 20.0, 47.5 |
| IOP-lowering medications, mean (SD) | 3.3 (1.4) | 3.4 (1.5) |
| Median (Q1, Q3) | 3.0 (2.0, 4.0) | 4.0 (2.0, 4.0) |
| Min, max | 0, 6.0 | 0, 6.0 |
| Number of medications used, n (%) | ||
| ≤1 | 6 (10.2) | 3 (9.7) |
| 2 | 10 (17.0) | 5 (16.1) |
| 3 | 15 (25.4) | 5 (16.1) |
| ≥4 | 28 (47.5) | 18 (58.1) |
| BCVA, mean (SD), logMAR | 0.25 (0.32) | 0.22 (0.33) |
| Visual field mean deviation, mean (SD), dB | −17.7 (10.3) | −17.9 (9.8) |
| Central corneal thickness, mean (SD), µm | 547.0 (26.4) | 544.9 (26.6) |
| Vertical cup/disc ratio, mean (SD) | 0.86 (0.13) | 0.87 (0.11) |
Notes: *Included secondary open-angle glaucoma and steroid-induced glaucoma, but no cases of angle-closure glaucoma.
Abbreviations: BCVA, best-corrected visual acuity; IOP, intraocular pressure; logMAR, logarithm of the minimum angle of resolution; max, maximum; min, minimum; Q, quartile; SD, standard deviation.
Notably, 28/59 (47.5%) patients had a baseline IOP <20 mmHg and 31 (52.5%) had a baseline IOP ≥20 mmHg. In the latter subgroup, mean age was 45.8 years and mean baseline IOP was 30.4 mmHg on 3.4 medications; 67.7% of patients had POAG, 58.1% required ≥4 IOP-lowering medications, 61.3% had undergone prior glaucoma surgery, and the average visual field mean deviation was −17.9 dB.
Despite the lack of formal statistical comparisons, patient demographics and baseline characteristics generally appeared similar in the overall population and subgroup with baseline IOP ≥20 mmHg, except perhaps mean/median IOP (Table 1).
Implantation Site
Of the 62 eyes in total that received the gel stent, 23 (37.1%) underwent supratemporal implantation, and 39 (62.9%) underwent superonasal implantation.
Primary Effectiveness Outcome in All Study Eyes and Subgroup with Baseline IOP ≥20 mmHg
Per the primary analysis (53 eyes), 49.0% (95% CI: 34.8–63.4) of study eyes achieved ≥20% IOP reduction from baseline at 12 months post implantation, without IOP-lowering medication increase or SSI.
Findings were similar in the sensitivity analyses based on imputation of missing data at 12 months with the LOCF (49.2%; 95% CI: 35.9–62.5; N=59), worst IOP and medications count values (49.2%; 95% CI: 35.9–62.5; N=59), and best IOP and medications count values (52.5%; 95% CI: 39.1–65.7; N=59), as well as analyses in which all missing data were imputed as nonresponders/failures (42.4%; 95% CI: 29.6–55.9; N=59) and responders/successes (55.9%; 95% CI: 42.4–68.8; N=59).
Among study eyes with baseline IOP ≥20 mmHg, data available at 12 months, and no SSI (n=28), 60.7% (95% CI: 40.6–78.5) achieved the primary effectiveness outcome.
Secondary Effectiveness Outcomes in All Study Eyes
At month 12 in the study eyes overall, mean IOP was 17.4 mmHg (Figure 2), representing a mean reduction from baseline of 6.1 mmHg (95% CI: 2.7–9.5). Among study eyes with IOP data at both baseline and month 12, the mean percent change in IOP from baseline was −14.4%. Mean IOP reductions of at least 6.9 mmHg were observed at all other postoperative visits (Figure 2).
Figure 2.
Mean IOP and mean IOP-lowering medication count at each visit, and changes from baseline. *the analysis was for the worse eye (eye with higher IOP, or if equal IOP, the eye implanted first). †Analyzed in study eyes with IOP data at both baseline and month 12.
Abbreviations: CFB, change from baseline; CI, confidence interval; IOP, intraocular pressure; SD, standard deviation.
At month 12 in the study eyes overall, the mean number of IOP-lowering medications was 1.0 and the median number was 0 (Q1, 0; Q3, 2). Compared with baseline, the number of IOP-lowering medications was reduced by ≥1 in 82.4% (95% CI: 69.1–91.6) of study eyes; 3 (5.9%) study eyes needed 1 or 2 additional IOP-lowering medications, and 11.8% remained on the same number of IOP-lowering medications.
The proportion of study eyes with an IOP <20 mmHg at 12 months while being medication-free was 58.8% (95% CI: 44.2–72.4). The proportion of study eyes with an IOP ≤15 mmHg at 12 months while requiring the same number or fewer IOP-lowering medications (vs baseline) was 43.1% (95% CI: 29.4–57.8).
In total, 7 (11.9%) study eyes were classified as failures as they needed an SSI (n=5) and/or additional IOP-lowering medications (n=3), compared with baseline. Patients had an approximately 90% probability of not having failed treatment at 1 year (Figure 3).
Figure 3.
Kaplan–Meier curve of time to treatment failure. Treatment failure was defined as the need for additional secondary surgical intervention (ie, trabeculectomy, cyclodialysis, additional shunt placement, scleral suture closure of the gel stent, or removal of the gel stent), or use (at 12 months) of more intraocular pressure-lowering medications than at baseline. The date of the secondary surgical intervention or date of prescription of the additional medication(s) constituted the time to the failure. If the additional IOP-lowering medication(s) was/were prescribed before the 1-month visit and used continuously after the 1-month visit, then the 1-month visit date was used as time to the failure.
Safety Outcomes
There were no intraoperative complications. Postoperatively, overall, 21 serious ocular TEAEs were reported in 17 implanted eyes (Table 2): IOP increased (n=8, 12.9%), cataract (n=2, 3.2%), device displacement (n=2, 3.2%), and poor healing (n=2, 3.2%), as well as flat anterior chamber, vitreous hemorrhage, primary open-angle glaucoma (ie, development of POAG in the fellow eye), ocular hypertension, keratoconjunctivitis, device exposure, and Tenon’s cyst (n=1 each, 1.6%). At study end, all eyes were resolved without sequelae or recovering (poor healing), except 2: 1 in a patient with a serious TEAE of cataract declined treatment and 1 in a patient with a serious TEAE of implant displacement required follow-up but no treatment (per investigator judgement). One patient died due to a serious nonocular TEAE of pneumonia unrelated to the study treatment. No serious TEAEs of endophthalmitis or choroidal detachment occurred. No ocular TEAEs led to study discontinuation and 93.6% (n=247/264) of ocular TEAEs reported were mild or moderate in severity (Table 2). With the exception of TEAEs expected as part of the inflammatory response following filtration surgery in general (eg, conjunctival hyperemia, corneal edema, anterior chamber inflammation, and anterior chamber flare), IOP decreased/low IOP (8.1% of eyes) and IOP increased (33.9% of eyes) were the most common TEAEs occurring ≤7 and >7 days after surgery, respectively (Table 3).
Table 2.
Summary of Postoperative TEAEs
| Events, No. | Eyes, n | % of Eyes | |
|---|---|---|---|
| Ocular TEAEs (62 implanted eyes) | |||
| All | 264 | 62 | 100 |
| Mild | 209 | 62 | 100 |
| Moderate | 38 | 30 | 48.4 |
| Severe | 13 | 10 | 16.1 |
| Information missing | 4 | 3 | – |
| Serious*,† | 21 | 17 | 27.4 |
| Device related | 40 | 27 | 43.6 |
| Serious and device related | 10 | 8 | 12.9 |
| Leading to discontinuation | 0 | 0 | 0 |
| Nonocular TEAEs (N=59 patients) | |||
| All | 3 | 3 | 5.1 |
| Mild | 1 | 1 | 1.7 |
| Moderate | 1 | 1 | 1.7 |
| Severe | 1 | 1 | 1.7 |
| Serious‡ | 1 | 1 | 1.7 |
| Leading to discontinuation‡ | 1 | 1 | 1.7 |
Notes: *Requiring hospitalization or resulting in death. †Included intraocular pressure increased (n=8, 12.9%), cataract (n=2, 3.2%), device displacement (n=2, 3.2%), and poor healing (n=2, 3.2%), as well as flat anterior chamber, vitreous hemorrhage, POAG (ie, development of POAG in the fellow eye), ocular hypertension, keratoconjunctivitis, device exposure, and Tenon’s cyst (n=1 each, 1.6%). One patient with a serious TEAE of cataract declined treatment. One case of implant displacement required follow-up but no treatment. All other serious TEAEs were resolved without sequelae at study end or recovering (poor healing). ‡Pneumonia (not treatment-related) that resulted in death.
Abbreviations: POAG, primary open-angle glaucoma; TEAE, treatment-emergent adverse event.
Table 3.
All-Causality Postoperative Ocular TEAEs Reported in ≥2% of Implanted Eyes, by Day of Onset
| Preferred Term | ≤7 Days After Surgery Day | >7 Days After Surgery Day | ||||
|---|---|---|---|---|---|---|
| Events, No. | Eyes, n (N=62) |
Eyes, % | Events, No. | Eyes, n (N=62) |
Eyes, % | |
| Conjunctival hyperemia* | 58 | 57 | 91.9 | 9 | 8 | 12.9 |
| Corneal edema* | 56 | 56 | 90.3 | 1 | 1 | 1.6 |
| Anterior chamber inflammation* | 51 | 51 | 82.3 | 1 | 1 | 1.6 |
| Intraocular pressure decreased | 5 | 5 | 8.1 | 0 | 0 | 0 |
| Anterior chamber flare* | 4 | 4 | 6.5 | 1 | 1 | 1.6 |
| Intraocular pressure increased† | 3 | 3 | 4.8 | 31 | 21 | 33.9 |
| Flat anterior chamber | 2 | 2 | 3.2 | 0 | 0 | 0 |
| Hyphema | 2 | 2 | 3.2 | 0 | 0 | 0 |
| Ocular hypertension | 1 | 1 | 1.6 | 2 | 2 | 3.2 |
| Device displacement | 0 | 0 | 0 | 3 | 3 | 4.8 |
| Cataract | 0 | 0 | 0 | 2 | 2 | 3.2 |
| Conjunctival hemorrhage | 0 | 0 | 0 | 2 | 2 | 3.2 |
| Corneal epithelium defect | 0 | 0 | 0 | 2 | 2 | 3.2 |
| Iris synechiae | 0 | 0 | 0 | 2 | 2 | 3.2 |
| Keratic precipitates | 0 | 0 | 0 | 2 | 2 | 3.2 |
Notes: *Expected as part of the inflammatory response following glaucoma filtration surgery in general. †Based on investigator judgment. All events were mild in severity and resolved without treatment.
Abbreviations: TEAE, treatment-emergent adverse event.
Two (3.2%) device deficiencies, not caused by manufacturing defects, were recorded on surgery day; those implants were replaced, and the events did not lead to study discontinuation.
At study end, 18 (29.0%) eyes had required 24 needlings following gel stent implantation, ie, ~1.3 needling per eye on average. Of those 24 needlings, 10 (41.7%) and 7 (29.2%) were performed in postoperative months 1 and 3, respectively.
The mean (SD) change in central corneal thickness from baseline (mean [SD], 547.1 [25.8] μm; n=58) was −9.5 (16.3) μm at 12 months (n=32). The mean (SD) change in BCVA from baseline (mean [SD], 0.25 [0.32] LogMAR; n=51) was 0.05 (0.28) LogMAR at 12 months (n=36). The average (SD) visual field mean deviation was −17.6 (10.2) dB at baseline (n=49) and −16.2 (12.8) dB at 12 months (n=36). The biomicroscopy examinations did not reveal any clinically meaningful differences between the baseline and 12-month visit in terms of corneal findings and anterior chamber/iris/lens condition. Among the 38 patients with gonioscopy data at 12 months, 4 (10.5%), 3 (7.9%), and 2 (5.3%) exhibited angle abnormality, peripheral iris synechiae, and device displacement, respectively. The mean (SD) change in eyes’ vertical cup/disc ratio from baseline (mean [SD], 0.86 [0.13]; n=58) was 0.03 (0.13) at 12 months (n=45) and dilated fundus examinations showed a decrease in the proportion of eyes with abnormal findings (at least numerically) between the baseline (≤80.0%; n=60 or 61) and month-12 (≤58.5%; n=41) visits.
Discussion
The US pivotal registration study previously demonstrated that, compared with baseline, the gel stent effectively reduced both IOP and the number of IOP-lowering medications in patients with refractory glaucoma (defined in the Introduction), with an acceptable safety profile.9 At 12 months, 75.4% (46/61; observed data) reported ±20% IOP lowering from baseline on the same or fewer medications,9 and the mean IOP reduction from baseline was 9.1 mmHg (95% CI: 7.5–10.7) excluding patients with missing data (n=4) and those requiring a glaucoma-related secondary surgical intervention (n=9).9 In addition, the mean IOP-lowering medication count decreased from 3.5 (baseline; N=65) to 1.7 (month 12; n=52), and 69.2% (n=36/52) of patients required fewer medications at month 12 than baseline.9 No intraoperative complications were reported; postoperative TEAEs were mostly mild or moderate, resolved without sequelae, and not unexpected in a population of patients with refractory glaucoma; and the needling rate was 32.3% (n=21/65).9 Since then, multiple studies supporting the effectiveness and safety of the gel stent have been published, including a prospective, randomized, controlled study of the gel stent vs trabeculectomy in open-angle glaucoma12, and peer-reviewed publication of studies conducted in China.13,14
The current study’s findings indicate the gel stent also effectively reduced both IOP and the medication burden in Chinese patients with refractory glaucoma (defined as in the US pivotal registration study).9 49.0% of study eyes and 60.7% of study eyes with baseline IOP ≥20 mmHg achieved ≥20% IOP reduction from baseline at 12 months without an increase in the number of IOP-lowering medications used, and the mean IOP reduction from baseline was 6.1 mmHg (95% CI: 2.7–9.5).
Observed differences in patients’ baseline characteristics between the current vs US pivotal9 studies include ethnicity (100% Han Chinese vs 4.6% Nonspecified asian), gender (76.3% male vs 46.2%), POAG diagnosis (74.6% vs 87.7%), IOP requirement at baseline (none vs 20–35 mmHg), and average visual field mean deviation (−17.7 dB vs −15.8 dB). These differences in baseline characteristics may explain the lower efficacy observed in this study compared with the US pivotal study, particularly the baseline IOP. When the analysis was performed using baseline IOP ≥20 mmHg, a larger proportion (60.7%) of patients achieved ≥ 20% reduction in IOP at month 12. It is also notable that the mean IOP reduction from baseline observed in this study is in line with that in other published studies (6.1–6.7 mmHg).15–17 Moreover, the mean number of IOP-lowering medications was reduced by ~2.3 herein, with 82.4% of study eyes requiring fewer medications at month 12 than at baseline compared with 1.8 and 69.2% in the US pivotal study.9 The differences in IOP-related effectiveness between the US pivotal study and Hainan study warrant further investigation.
The current Chinese cohort fills a gap in evidence regarding XEN gel stent use in Asian patients. In predominantly Caucasian populations, 12-month stand-alone XEN studies report IOP reductions of approximately 28–35%,18,19 success rates of 70–80%,18,19 and medication-free rates around 54%18,20 with needling rates of 26–35%.18,19 The IOP and medication reductions observed in the Hainan study are broadly consistent with these Western studies, though the overall responder rate (49.0%) is lower, likely reflecting baseline differences such as the high proportion of patients with prior glaucoma surgery (59.3%) and baseline IOP <20 mmHg (47.5%). Asian cohort data from Taiwan, Korea, and China similarly demonstrate effective IOP and medication reductions at 12 months, while also highlighting that East Asian eyes may benefit from closer postoperative bleb surveillance and more frequent needling interventions (reported rates of 32–56%) compared with Western eyes,21–24 consistent with a more active fibroproliferative healing response in this population.7 International registry data further confirm that Asian ethnicity is an independent clinical variable warranting consideration in postoperative management planning.25 The Hainan study, with a 29.0% needling rate, is at the low range of, or comparable to, these Asian studies but supports the value of proactive, bleb management to optimize outcomes with the XEN gel stent in Chinese patients.
Potential limitations of the study include that it is based on real-world evidence and the less stringent eligibility criteria inherent to such designs may introduce selection bias. Higher rigor data could have been collected prospectively and/or retrospectively by the surgeon and referring ophthalmologist. Additional limitations include a single-center design which may limit the generalizability of findings to broader Chinese patient populations and diverse clinical settings, no comparator arm which precludes direct conclusions about the relative efficacy or safety of the gel stent vs other surgical options and small sample size not designed or powered to identify independent predictors of response or failure. Furthermore, the follow-up duration may be insufficient to fully evaluate the long-term durability of IOP reduction or the occurrence of late-onset complications. Larger, prospective, comparative studies with longer follow‑up may be valuable to further characterize the stability of these parameters in Chinese patients. Nonetheless, considering the limited number of studies of the gel stent conducted in China, the study met the objective of describing the real-world effectiveness and safety of the gel stent in Chinese patients with refractory glaucoma, and supports use of this MIBS device in China.
Conclusion
This real-world study showed that, at month 12, the mean IOP reduction from baseline was 6.1 mmHg and 82.4% of patients had lowered their IOP-lowering medication count by at least 1 (vs baseline), supporting effectiveness of the gel stent as a treatment option for Chinese patients with refractory glaucoma. The gel stent also had an acceptable safety profile in this patient population, consistent with the established safety and effectiveness profile of the device, without unexpected or new safety concerns.
Funding Statement
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. AbbVie and the authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Michele Jacob, PhD, of Evidence Scientific Solutions (Philadelphia, PA, USA), and funded by AbbVie (North Chicago, IL, USA).
Data Sharing Statement
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Use Agreement (DSUA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ and then select “Home”.
Disclosure
YL, YZ, NW, HZ, HL, and JQ: nothing to disclose. ZC, BB, SZ, DY, SSL, and MRR are employees of AbbVie and may hold AbbVie stock. Authors affiliated with AbbVie (the study sponsor) were not involved in the direct clinical management or examination of patients; all clinical assessments and patient care decisions were made by the independent site investigators. The authors report no other conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Use Agreement (DSUA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ and then select “Home”.