XEN-45 Gel Stent Versus Trabeculectomy in Glaucoma: Gold-Standard Pathway Study (GPS)

Study Overview
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Brief Summary
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The purpose of this study is to compare the safety and efficacy of XEN-45 to trabeculectomy in participants with open angle glaucoma refractory to topical medical therapy.

Detailed Description
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This is a multi-center, randomized, parallel group, prospective, open-label clinical trial to evaluate the ability of XEN-45 to reduce intraocular pressure (IOP) and reduce the amount of topical IOP-lowering medications in participants poorly controlled on topical therapy. The planned study duration is 12 months. Participants were to be screened for enrollment and eligible candidates were to be approached to ascertain interest in study participation. Eligible participants were to be randomized 2:1; resulting in approximately 95 eyes implanted with XEN-45 and 44 eyes received trabeculetomy by study end.

Official Title
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XEN-45 Gel Stent Versus Trabeculectomy in Glaucoma: Gold-Standard Pathway Study (GPS)

Conditions
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Glaucoma

Intervention / Treatment
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* Device: XEN-45 Gel Stent
* Procedure: Trabeculectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Open-angle glaucoma where the intraocular pressure (IOP) is not controlled when using topical IOP-lowering glaucoma medication Best-corrected baseline Snellen visual acuity of 20/100 or better Visual field mean deviation no worse than -18.0 decibels (dB) Medicated IOP ≥15 millimeter of mercury (mm Hg) and ≤44 mm Hg Participants not anticipated to require any ocular surgery (e.g., cataract surgery) in either eye up to 3 months from the time of inclusion Area of healthy, free, and mobile conjunctiva in the target area (superior bulbar conjunctiva) Trabecular meshwork must be visible (with Shaffer angle grade ≥2 in the target quadrant) Failed ab-interno canal or suprachoroidal micro invasive glaucoma surgery (MIGS) procedures (such as i-Stent, gonioscopy-assisted transluminal trabeculotomy [GATT], Ab-interno canaloplasty [ABiC], Kahook dual blade goniotomy, etc.) are allowed ≥3 months before enrollment. CyPass® Micro-Stents were not allowed. Exclusion Criteria: Participant has active neovascular, uveitic or angle recession glaucoma or any glaucoma associated with vascular disorders Participant has had prior ab externo incisional glaucoma surgery (such as trabeculectomy, viscocanalostomy, canaloplasty, tube shunts of any type, collagen implants, etc.), conjunctival filtering surgery, transscleral cycloablative procedures (such as cyclophotocoagulation, micro pulse cyclophotocoagulation, cryotherapy, ultrasound circular cyclocoagulation [UC3], etc.) or prior major conjunctival surgery (i.e., scleral buckle) Clinically significant inflammation or infection within 30 days before the preoperative visit (e.g., blepharitis, conjunctivitis, severe ocular surface disease, keratitis, uveitis, herpes simplex infection) Presence of conjunctival scarring or prior conjunctival surgery or other conjunctival pathologies (e.g., pterygium) in the target area History of corneal surgery, corneal opacities, or corneal disease Central corneal thickness ≤490 micrometer (μm) or ≥620μm Vitreous present in the anterior chamber Aphakic Participant has had prior intraocular surgery in either eye within ≤3 months before the preoperative visit (including phacoemulsification) History of complicated cataract surgery (e.g. with visual impairment, e.g. vitreous loss, anterior chamber intraocular lens [ACIOL], perhaps sutured intraocular lens [IOL] or scleral fixated IOL, prior cystoid macular edema [CME], etc.) Presence of intraocular silicone oil Active diabetic retinopathy, proliferative retinopathy, choroidal neovascularization, branch retinal vein occlusion, central retinal vein occlusion, geographic atrophy, or other ophthalmic disease or disorder that could confound study results or impaired episcleral venous drainage (e.g., Sturge-Weber or nanophthalmos, Axenfeld-Reiger, iridocorneal endothelial syndrome [ICE], etc.) Known or suspected allergy or sensitivity to drugs required for the protocol (including anesthesia), or any of the device components (e.g., bovine or porcine products, or glutaraldehyde) Pregnant or nursing women and those planning a pregnancy during the study period. Participation in another drug or device clinical trial concluding within 30 days before the preoperative visit

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: XEN-45 Gel Stent<br>Participants underwent at least one preoperative visit and had XEN-45 gel stent implantation on Day 0 (The day of surgery). | Device: XEN-45 Gel Stent<br>* XEN-45 gel stent device implant<br>|
| Active Comparator: Trabeculectomy<br>Participants underwent at least one preoperative visit and had trabeculectomy as per standard of care in each investigative center on Day 0 (The day of surgery). | Procedure: Trabeculectomy<br>* Trabeculectomy surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving at Least 20% Intraocular Pressure (IOP) Reduction (Improvement) From Baseline at Month 12 With Prespecified Caveats | IOP is a measure of the fluid pressure inside the eye. In addition to achieving a 20% reduction of IOP from Baseline, the participants had to meet all of the following prespecified caveats at Month 12: no increase in the number of topical IOP-lowering medications compared to Baseline, no clinical hypotony, no loss of vision to count fingers or worse, and no secondary glaucoma surgical intervention. | Baseline (Preoperative) to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean IOP Over Time | IOP is a measurement of the fluid pressure inside the eye. | Baseline and Day 1, Weeks 1 and 2, Months 1, 3, 6, 9, and 12 | 
| Change From Baseline in Mean IOP Over Time | IOP is a measurement of the fluid pressure inside the eye. | Baseline and Day 1, Weeks 1 and 2, Months 1, 3, 6, 9, and 12 | 
| Mean Number of Topical IOP-Lowering Medications Over Time | IOP is a measurement of the fluid pressure inside the eye. Topical IOP-lowering medication classes included: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors,alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Baseline and Day 1, Weeks 1 and 2, Months 1, 3, 6, 9, and 12 | 
| Change From Baseline in Mean Number of Topical IOP-Lowering Medications Over Time | IOP is a measurement of the fluid pressure inside the eye. Topical IOP-lowering medication classes included: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors,alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Baseline and Day 1, Weeks 1 and 2, Months 1, 3, 6, 9, and 12 | 
| Change From Baseline in Mean IOP at Month 12 | IOP is a measurement of the fluid pressure inside the eye. | Baseline (Preoperative) and Month 12 | 
| Change From Baseline in Mean Number of Topical IOP-Lowering Medications at Month 12 | IOP is a measurement of the fluid pressure inside the eye. Topical IOP-lowering medication classes included: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors, alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Baseline (Preoperative) and Month 12 | 
| Change in Mean IOP From Preoperative Baseline Over Time in Participants With Eyes With Baseline IOP ≤18 mm Hg | IOP is a measurement of the fluid pressure inside the eye. | Baseline (Preoperative) and Month 12 | 
| Change in Number of Topical IOP-Lowering Medications From Preoperative Baseline to Month 12 in Participants With Eyes With Baseline IOP ≤18 mm Hg | Topical IOP-lowering medication classes included: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors, alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Baseline (Preoperative) and Month 12 | 
| Percentage of Participants Achieving Specific IOP Targets at Month 12 | IOP is a measurement of the fluid pressure inside the eye. Specific IOP targets included following IOP values (in mm Hg): ≤18, ≤17, ≤16, ≤15, ≤14, ≤13, ≤12 mm Hg. | Month 12 | 
| Percentage of Participants Achieving Specific Percentage IOP Lower Targets From Baseline at Month 12 | IOP is a measurement of fluid pressure inside the eye. Specific percentage IOP lower targets included ≥25%, ≥30%, ≥35%, ≥40% ≥45%, and ≥50% IOP reduction. | Baseline (Preoperative) to Month 12 | 
| Percentage of Participants Achieving at Least a 20% IOP Reduction and Specific IOP Targets on Same or Lower Number of Topical IOP-Lowering Medications at Month 12 | IOP is a measurement of fluid pressure inside the eye. Specific IOP targets included following IOP values (in mm Hg): ≤18, ≤17, ≤16, ≤15, ≤14, ≤13, ≤12 mm Hg. | Baseline (Preoperative) and Month 12 | 
| Percentage of Participants With Needlings Performed | Needling of eye involves breaking down the wall of the scar using a fine needle to improve the drainage of fluid inside the eye. | Up to Month 12 | 
| Mean Number of Needlings Per Eye | Needling of eye involves breaking down the wall of the scar using a fine needle to improve the drainage of fluid inside the eye. | Up to Month 12 | 
| Percentage of Eyes Achieving at Least a 20% Reduction in IOP at Month 12 on the Same or Fewer Topical IOP-lowering Medications in Participants Who Had Needlings | IOP is a measurement of fluid pressure inside the eye. Topical IOP-lowering medication classes include: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors, alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Month 12 | 
| Percentage of Eyes Not Using Any Topical IOP-lowering Medications in Participants Who Had Needlings | Topical IOP-lowering medication classes included: prostaglandin analogues, beta adrenergic antagonists, carbonic anhydrase inhibitors, alpha adrenergic agonists, pilocarpine, and combinations of these treatments. | Month 12 | 
| Percentage of Participants With Antifibrotic Use During Needling | Antifibrotic use included mitomycin-C (MMC) which was standardized for both groups and administered according to physician training and practice. | Up to Month 12 | 
| Percentage of Participants Achieving Complete Success at Month 12 | Complete success was defined as IOP ≤18mm Hg, with 20% or greater IOP lowering from medicated Baseline, on no topical medications, and no clinical hypotony. The topical medication included any topical ophthalmic medication used on the study eye regardless of the indication and dosage. | Month 12 | 
| Percentage of Participants Achieving Qualified Success at Month 12 | Qualified success was defined as IOP ≤18 mm Hg, with 20% or greater IOP lowering from medicated Baseline, taking topical medications at Baseline Qualifying Visit, no clinical hypotony. The topical medication included any topical ophthalmic medication used on the study eye regardless of the indication and dosage. | Month12 | 
| Percentage of Participants Achieving Specific IOP Targets at Month 12 in Medication-free Eye | IOP is a measurement of the fluid pressure inside the eye. Specific IOP targets included following IOP values (in mm Hg): ≤18, ≤17, ≤16, ≤15, ≤14, ≤13, ≤12 mm Hg. Medication-free eye at Month 12 was defined as no IOP-lowering medication was used to the study eye at Month 12. | Month 12 | 
| Percentage of Participants Achieving Specific Percentage IOP Lower Targets From Baseline at Month 12 With Medication-free Eyes | IOP is a measurement of the fluid pressure inside the eye. Specific percentage IOP lower targets included ≥25%, ≥30%, ≥35%, ≥40% ≥45%, and ≥50% IOP reduction. Medication-free eye at Month 12 was defined as no IOP-lowering medication was used to the study eye at Month 12. | Month 12 | 
| Percentage of Participants With Intraoperative Adjunctive Antifibrotic Therapy Use | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. | Month 12 | 
| Percentage of Participants With Intraoperative Adjunctive Antifibrotic Therapy Based on Time of Administration | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. The time of administration was classified into two categories as: Before Procedure and After Procedure. | Month 12 | 
| Percentage of Participants With Different Modes of Administration of Intraoperative Adjunctive Antifibrotic Therapy | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. The mode of administration was classified into two categories as: Injection and Other. Other includes all other modes of administration apart from injection. | Month 12 | 
| Percentage of Participants With Different Volumes of Intraoperative Adjunctive Antifibrotic Therapy | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. The volume of administration measured in milliliters (mL) was classified into three categories as: 0.1, 0.2, and Other. Other includes all other volumes apart from 0.1 and 0.2. | Month 12 | 
| Percentage of Participants With Different Concentrations for Intraoperative Adjunctive Antifibrotic Therapy | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. The concentration of administration measured in milligram per milliliter (mg/mL) was classified into three categories as: 0.2, 0.4, and Other. Other includes all other concentrations apart from 0.2 and 0.4. | Month 12 | 
| Percentage of Participants With Different Absolute Dose for Intraoperative Adjunctive Antifibrotic Therapy | Antifibrotic use included MMC which was standardized for both groups and administered according to physician training and practice. The absolute dose of administration measured in microgram per milliliter (µg/mL) was classified into two categories as: 40, and Other. Other includes all other concentrations apart from 40. | Month 12 | 
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) With Current Glasses | BCVA was performed using a Snellen eye chart with glasses, and the BCVA data collected in the visual acuity electronic case report form (eCRF) page was analyzed. The number of lines read correctly was assessed as the line change from baseline at each follow-up evaluation and were log transformed. A logMAR value of 0 equates to 20/20 Snellen visual acuity (normal distance eyesight), with a lower and negative logMAR value indicating better visual acuity. | Baseline and Day 1, Weeks 1 and 2, and Months 1, 3, 6, 9, and 12 | 
| Mean Change From Baseline in Manifest Refraction - Mean Visual Acuity Using Snellen Eye Chart in LogMAR Scale | Manifest Refraction - Mean Visual Acuity was performed using a Snellen eye chart with glasses. The line change from baseline at each follow-up evaluation in logarithm of the minimum angle of resolution (logMAR) was calculated. A logMAR value of 0 equates to 20/20 Snellen visual acuity (normal distance eyesight), with a lower logMAR value indicating better visual acuity. | Baseline (Preoperative) and postoperative Months 1, 3, 6, and 12 | 
| Mean Surgically Induced Astigmatism - Autorefractor Reading |  | Month 12 | 
| Mean Change From Baseline in Surgically Induced Astigmatism - Autorefractor Reading |  | Baseline (Preoperative) and Month 12 | 
| Mean Change From Baseline in Surgically Induced Astigmatism - Topography at Selected Sites |  | Baseline (Preoperative), Week 1, and Months 1 and 12 | 
| Mean Change From Baseline in Optical Biometry - Anterior Chamber Depth |  | Baseline, Day 1 and Week 2 | 
| Mean Change in From Baseline Optical Biometry - Keratometry (K)1, K2, Delta D | The keratometric values for keratometry (K) measured in 2 meridians (i.e., flat keratometry [K1] and steep keratometry [K2]) along with Delta (D) were determined. | Baseline, Day 1 and Week 2 | 
| Bleb Morphology - Anterior Segment Optical Coherence Tomography (AS-OCT) at Selected Sites |  | Up to Month 12 | 
| Bleb Morphology - Slit Lamp Photography at Selected Sites |  | Up to Month 12 | 
| Percentage of Participants With Clinical Hypotony | Clinical hypotony was defined as vision reduction (2 lines or more) related to macular changes consistent with hypotony maculopathy (macular folds), optic disc edema, and/or serous choroidal detachments because of low IOP. | Month 12 | 
| Percentage of Eyes With IOP 6 mm Hg or Less at Any Time Point and Relevant Clinical Assessment | Eyes with IOP 6 mm Hg or less at any time point and relevant clinical assessment (vision reduction [2 lines or more] related to macular changes consistent with hypotony maculopathy [macular folds], optic disc edema, anterior chamber status, and/or serous choroidal detachments because of low IOP) of these eyes at those time points were assessed. Only data from study eyes are included. The worse eye was selected as the study eye if both eyes met the inclusion criteria. The worse eye was defined using the visual field MD at Baseline, with the worse eye having the most negative MD. In cases where the MD was the same in both eyes to two decimal places, the worse eye was defined as the eye with the higher IOP. | Up to Month 12 | 
| Percentage of Participants With Specific Intraoperative Adverse Events of Special Interest (AESIs) | An adverse event(AE)is any untoward medical occurrence in a clinical investigation participant administered drug; it does not necessarily have to have a causal relationship with the treatment. Intraoperative AESIs included- Detached Descemet's membrane,iris damage,lens contact,vitreous bulge or loss,anterior chamber bleeding,retrobulbar hemorrhage,conjunctival perforation,conjunctival or scleral flap tearing,shallow anterior chamber with peripheral iridocorneal touch,flat anterior chamber with iridocorneal touch extending to the pupil,device malfunction identified prior to implantation,and choroidal hemorrhage of effusion. Only categories with at least one participant with event in the study eye are reported. The worse eye was selected as the study eye if both eyes met inclusion criteria. The worse eye was defined using visual field MD at Baseline, with the worse eye having the most negative MD. If MD was same in both eyes to two decimal places, the worse eye=eye with higher IOP. | Median follow-up of 366.0 days | 
| Percentage of Participants With Postoperative Treatment-Emergent Adverse Events of Special Interest (AESIs) | AE=any untoward medical occurrence in a clinical investigation participant administered drug;it does not necessarily have to have a causal relationship with the treatment. TEAE is an AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug. Postoperative AEs included but were not limited to: angle recession, anterior chamber changes, BCVA loss,bleb leak, blebitis, cataract, choroidal effusion, chronic pain, corneal edema, cyclodialysis, Dellen, device malfunction, endophthalmitis, fixed dilated pupil, hyphema, hypotony, implant issues, increase in corneal thickness/IOP, explant, iridodialysis, iritis, loss of eye, etc.Worse eye=eye if both eyes met inclusion criteria. Worse eye was defined using visual field MD at Baseline, with worse eye having the most negative MD. In cases where MD was the same in both eyes to two decimal places, worse eye was defined as eye with higher IOP. | Median follow-up of 366.0 days | 
| Percentage of Participants With BCVA Worst Line Change From Baseline Across Follow-Up | The categories = Worsening (<-2), No Change (≥-2 and ≥2), Improving (>2) and Missing were used for determining BCVA worst line change from Baseline. Only categories with at least one participant with event are reported. | Baseline up to Month 12 | 
| Pachymetry Based on Change From Baseline In Average Central Corneal Thickness | Pachymetry was measured as average central corneal thickness (microns/micrometer) change from Baseline. | Baseline (Preoperative) and Month 12 | 
| Change From Baseline in Visual Field Examinations Analyzed by Machine Type | All visual field examination data were collected and reported as mean deviation by Humphrey machine. | Baseline and Month 12 | 
| Percentage of Participants With at Least One Adverse Event (AE), Serious Adverse Events (SAEs), Adverse Device Effects (ADEs) and Serious ADEs (SADEs) | AE=any untoward medical occurrence in a clinical investigation participant administered drug; it does not necessarily have to have a causal relationship with the treatment. An SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is a medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. ADEs and SADEs are AEs and SAEs that are caused by the device | Median follow-up of 366.0 days | 
| Patient-reported Outcomes (PRO): Change From Baseline in Symptom and Health Problem Checklist (SHPC-18) Scores | The SHPC-18 is an 18-item questionnaire that asks participants being treated for glaucoma questions about eye symptoms or problems they may experience. There are two domains: Local Eye Symptoms (7 items) subscale score 0 to 700 divided by 7 and Visual Function Problem (11 items) subscale score 0 to 1100 divided by 11. The scores of each subscale ranges from from 0 (not at all) to 100 (a lot); higher scores indicate more bother. A frequency score was calculated by summing the individual response scores of each item, and ranges from 0 to 7 for Local Eye Symptom and from 0 to 11 for Visual Function. A total bothersome score for the SHPC-18 is calculated by summing all 18 items scores, resulting in a range from 0 to 1800, then dividing the sum by 18, to create a total bothersome score ranging from 0 (not at all) to 100 (a lot); higher scores indicate more bother. A negative change from Baseline for all scales and subscales indicates improvement. | Baseline (Preoperative) to Month 6 | 
| PRO: Percentage of Participants With Post-Surgical Resumption of Activities and Daily Routine | Participants answered the question, Since your glaucoma surgery, would you consider that you have resumed your usual activities and daily routine? using the following categories: Not at all, Somewhat, Moderately so, Mostly, Completely. | Month 3 | 
| PRO: Percent Change From Baseline in Work Productivity and Activity Impairment (WPAI): Percent Overall Work Impairment Due to Health | WPAI-General Health (GH) is 6-question participant rated questionnaire to determine the amount of absenteeism, presenteeism, work productivity loss and daily activity impairment attributable to general health. It yields 5 sub-scores: hours actually worked, work time missed due to health impairment while working, impairment while working due to health, overall work impairment due to health, activity impairment due to health. These sub-scores are transformed to impairment percentages (range from 0 to 100), with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement. | Baseline (Preoperative) and Month 12 | 
| PRO: Percent Change From Baseline in WPAI: Percent Activity Impairment Due to Health | WPAI-General Health (GH) is 6-question participant rated questionnaire to determine the amount of absenteeism, presenteeism, work productivity loss and daily activity impairment attributable to general health. It yields 5 sub-scores: hours actually worked, work time missed due to health impairment while working, impairment while working due to health, overall work impairment due to health, activity impairment due to health. These sub-scores are transformed to impairment percentages (range from 0 to 100), with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement. | Baseline (Preoperative) and Month 12 |