The Hydrus Microstent for Refractory Open-Angle Glaucoma: A Prospective, Multicenter Clinical Trial (Hydrus VII Study)
Phase: NA
Conditions: Open-angle Glaucoma
Sponsor: Ivantis, Inc.

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Protocol NCT03267134
Page 1 
Hydrus Microstent For Refractory Glaucoma 
PROTOCOL NCT03267134 
THE HYDRUS MICROSTENT FOR REFRACTORY OPEN-ANGLE GLAUCOMA: 
A PROSPECTIVE, MULTICENTER CLINICAL TRIAL 
SUMMIT  
ZĞǀϬϴͲϮϬϮϬ

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
Table of Contents 
 
 
1.0 
DEVICE DESCRIPTION .................................................................................................3 
2.0 
SUMMARY OF NONCLINICAL STUDIES ..................................................................4 
2.1   BIOCOMPATIBILITY TESTING ......................................................................................4 
3.0 
 STUDY METHODS .........................................................................................................6 
3.1 SELECTION OF PATIENTS .............................................................................................6 
3.2 SCREENING INCLUSION CRITERIA ..............................................................................6 
3.3 SCREENING EXCLUSION CRITERIA .............................................................................7 
3.4 BASELINE INCLUSION CRITERIA .................................................................................8 
3.5 CONSENT ......................................................................................................................8 
3.6 ENROLLMENT ...............................................................................................................8 
4.0 
CLINICAL FOLLOW-UP SCHEDULE .........................................................................9 
5.0  
STATISTICAL METHODS  ..........................................................................................11 
5.1 GENERAL DATA HANDLING ......................................................................................11 
5.2  STUDY POPULATIONS .................................................................................................11 
5.3 EFFECTIVENESS ENDPOINTS ANALYSES ...................................................................11 
5.4 SAFETY ANALYSES .....................................................................................................12 
6.0 
ADVERSE EVENTS .......................................................................................................12 
6.1 ADVERSE EVENT DEFINITIONS ..................................................................................12 
6.2 ADVERSE EVENT ASSESSMENT AND DOCUMENTATION ...........................................13 
6.3 CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY ..............................................14 
6.4 ANTICIPATED OR UNANTICIPATED EVENTS ..............................................................15 
6.5 RELATIONSHIP OF THE EVENT TO THE DEVICE AND PROCEDURE ...........................15 
6.6 ONGOING ASSESSMENT AND OUTCOME ....................................................................16 
6.7 TREATMENT OR ACTION TAKEN ...............................................................................16 
6.8 SERIOUS ADVERSE EVENT AND UNANTICIPATED ADVERSE DEVICE EFFECT 
REPORTING ................................................................................................................16 
7.0 
DEFINITIONS .................................................................................................................20 
 
 
 

Protocol NCT03267134
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Hydrus Microstent For Refractory Glaucoma 
THE HYDRUS MICROSTENT FOR REFRACTORY OPEN-ANGLE GLAUCOMA: A 
PROSPECTIVE, MULTICENTER CLINICAL TRIAL 
1.0 
DEVICE DESCRIPTION 
The Hydrus Microstent is a crescent-shaped implantable device pre-loaded onto a hand-held 
delivery system.  
The Hydrus Microstent is composed of nitinol, a metal alloy of nickel (Ni) and titanium (Ti). 
Nitinol has been used extensively in a variety of implantable vascular and orthopedic devices 
for its proven properties of flexibility, strength and biocompatibility. As a shape memory alloy, 
nitinol has super elastic properties making it suitable as a support structure in Schlemm's 
canal. The Hydrus is approximately 8mm in overall length. The major and minor axes of the 
implant are 292μm and 185μm, respectively.  
The implant is laser cut to a proprietary design with alternating “spines” for structural support 
and “windows” to provide outflow pathways for aqueous humor.  After laser cutting, the shape 
of the implant is heat-set to a curvature that matches the curvature of Schlemm’s canal and is 
electro-polished to create a smooth biocompatible surface.  The length and curvature of the 
implant are designed to occupy approximately 90° or 3 clock hours of Schlemm’s canal. The 
implant is designed to have adequate structural thickness to support the tissue of the canal 
while providing maximum open flow areas through the canal, with the proximal portion of the 
implant exiting the canal through the trabecular meshwork to allow inflow of aqueous humor 
from the anterior chamber. 

Protocol NCT03267134
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Hydrus Microstent For Refractory Glaucoma 
The Hydrus Delivery System is a hand-held mechanical device that provides for manual 
delivery of the Hydrus Microstent through a stainless steel cannula into the target site in the 
eye.  The delivery system was designed for usability to provide smooth tracking and controlled 
delivery of the microstent into Schlemm's canal.  The hand piece is an ergonomic design for use 
in either the right or left hand, allowing for surgeon individual preference and hand position. To 
accommodate a wide range of hand positions, a rotatable sleeve at the distal end allows 
positioning and alignment of the cannula by the surgeon to direct the implant into Schlemm's 
canal.  The tracking wheel on the delivery system serves as the control mechanism to advance 
the implant into the canal or retract the implant into the cannula.  
To deliver the microstent into Schlemm’s canal, the cannula of the delivery system is inserted 
through a clear corneal incision (approximately 1.5mm in length). The cannula tip is then 
advanced through the trabecular meshwork until it enters Schlemm’s canal and the entry point 
into the meshwork is coincident with the end of the cannula bevel. The target tissue is 
visualized using a gonioscopic prism. After observing that the distal cannula tip is properly 
positioned through the trabecular meshwork into Schlemm's canal, the tracking wheel on the 
delivery system is used to advance and release the microstent. 
The Hydrus Microstent is packaged in sterile-barrier packaging and provided “STERILE” by 
gamma irradiation. 
2.0 
SUMMARY OF NONCLINICAL STUDIES 
2.1   
Biocompatibility Testing 
The selection of biocompatibility tests of the Hydrus Microstent was based on guidelines 
presented in EN ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and 
testing within a risk management process and ANSI Z80.27-2014- Aqueous Shunts for Glaucoma 

Protocol NCT03267134
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Hydrus Microstent For Refractory Glaucoma 
Applications (Section 4.2) with specific requirements applicable to metallic or non-polymeric 
implants as described in ANSI Z80.27, Section 6.3.  
The biocompatibility of the Hydrus Microstent and the Hydrus delivery system has been 
established through studies conducted by Wu-Xi AppTec, Inc. (St. Paul, MN) in accordance Good 
Laboratory Practices (GLP) and with EN ISO 10993-1 and parts 3, 5, 6, 10 and 11 for specific test 
requirements. For tests requiring extracts, coupons of nitinol were utilized rather than the 
Hydrus Microstent itself due to the very small mass and surface area of the Hydrus Microstent. 
The coupons were made of the same nitinol material and processed in a manner representative 
of production processes utilized to manufacture the implant, including laser cutting, 
electropolishing, cleaning and gamma irradiation.  
The delivery system is classified as having limited (<24 hours) ocular tissue contact. To 
demonstrate biocompatibility, cytotoxicity, delayed hypersensitivity, and intracutaneous 
irritation testing were performed. All results were negative for toxic effects. For the Hydrus 
Microstent, tested for permanent (>30 days) ocular tissue contact, the following studies were 
performed: cytotoxicity, material mediated pyrogen, acute systemic toxicity, delayed 
hypersensitivity, intracutaneous irritation, mutagenicity/genotoxicity, subacute toxicity, 
subchronic toxicity and muscle implantation (13 weeks). Additionally, a 6-month ocular 
implantation study was conducted in rabbits.  The results of testing on the Hydrus Microstent 
are summarized in Table 2 below. No biological toxicity was observed in any of the above test 
systems as identified in the test-specific ISO 10993 standards.  
Additionally, chemical characterization of extractables and leachables materials was performed 
by Legend Technical Services with review and a toxicological risk assessment performed by a 
qualified expert. These studies demonstrated negligible risk to health due to materials 
extracted or leached from nitinol samples representative of the implant. A follow-on longer-
term nickel elution study by WuXi Apptec using Hydrus Microstent as the test article confirmed 
the finding of negligible health risk from eluted nickel from the implant.  
TABLE 2 
RESULTS OF BIOCOMPATIBILITY TESTING ON HYDRUS MICROSTENT 
ISO 10993 
TEST 
RESULT 
Part 3 
Mutagenicity/Genotoxicity, Bacterial Reverse Mutation 
Study – saline and DMSO extracts 
Non-mutagenic 
Part 3 
In vitro Mouse Lymphoma Assay – 2 extracts 
Non-genotoxic 
Part 3 
In vivo Mouse Micronucleus Assay – 2 extracts 
Non-genotoxic 
Part 5 
Cytotoxicity Study using ISO Elution Method - MEM 
Non-toxic 
Part 5 
Cytotoxicity Study using ISO Agarose Overlay Method 
Non-toxic 
Part 6 
Muscle Implantation Study (13 weeks) 
Non-irritant 

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Hydrus Microstent For Refractory Glaucoma 
Part 6 
Chronic Ocular Implantation Study in Rabbits (6 months) 
Non-inflammatory 
Non-toxic 
Part 10 
Delayed Hypersensitivity (Maximization) Study -  saline 
and sesame oil extracts 
Non-sensitizing 
Part 10 
Intracutaneous  Irritation Study - saline and sesame oil 
extracts 
Non-irritant 
Part 11 
Acute systemic toxicity - saline and sesame oil extracts 
Non-toxic 
Part 11 
Subacute toxicity (intraperitoneal) - sesame oil extract 
Non-toxic 
Part 11 
Subchronic toxicity (intravenous) - saline extract 
Non-toxic 
Part 11 
Material mediated pyrogen (rabbit) 
Non-pyrogenic 
Part 18 
Chemical Hexane Extraction and Saline Leach Study 
Negligible risk from 
extracted/leached materials 
Part 18 
Nickel Elution Study 
Negligible risk from eluted 
nickel 
 
3.0  
STUDY METHODS 
3.1 
Selection of Patients 
Only subjects who meet the inclusion and exclusion criteria will be eligible for surgery in this 
study.   
3.2 
Screening Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible.  Unless otherwise 
specified, all ocular criteria refer to the study eye only. 
x Male and female patients at least 45 years of age 
x A diagnosis of open-angle glaucoma (POAG, PXG, or PG), with optic nerve 
pathology described by one or more of the following: 
 Diffuse thinning, focal narrowing, or notching of the optic disc rim, 
especially at the inferior or superior poles with or without disc 
hemorrhage; 
 Localized abnormalities of the peripapillary retinal nerve fiber layer, 
especially at the inferior or superior poles; or 
 Optic disc neural rim asymmetry of the two eyes consistent with loss of 
neural tissue 
x BCVA of 20/80 or better in the study eye 
x Subject has refractory glaucoma, defined as: 
O Previously failed filtering or cilioablative procedure (i.e., includes incisional glaucoma 
surgery, cryotherapy, and cyclodiode therapy) and with uncontrolled IOP on medical 
therapy 
 

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
or 
 
O IOP is uncontrolled on maximum tolerable medical therapy (e.g., a minimum of four 
or more classes of topical glaucoma medications, or fewer if others are not tolerated 
or are not effective) 
x Subject has been on current glaucoma medication regimen for at least 30 days 
x A medicated /KWŽĨш20 mmHg ĂŶĚчϯϱmmHg by Goldmann applanation tonometry  
x Open anterior chamber angle anatomy (e.g., no peripheral anterior synechiae or iris 
processes) ǀŝƐƵĂůŝǌĞĚďǇŐŽŶŝŽƐĐŽƉǇǁŝƚŚĂ^ŚĂĨĨĞƌĂŶŐůĞŐƌĂĚĞŽĨш///ŝŶĂůůĨŽƵƌƋƵĂĚƌĂŶƚƐ 
x Visual field examination using Humphrey-Zeiss 24-2 SITA Std., with mean deviation (MD)  
of -3 dB or worse (conducted within 60 days of Screening is acceptable) 
x Visual field defects consistent with glaucomatous optic nerve damage, and with at least 
one of the following two findings: 
o A cluster of 3 or more points in an expected location of the visual field depressed 
below the 5% level, at least 1 of which is depressed below the 1% level on pattern 
deviation (PD) plot 
O Glaucoma hemi-field test “outside normal limits” 
x The subject is able to understand the requirements of the study and provide 
written informed consent 
x Subject is willing to follow study instructions, agrees to comply with all study 
procedures and attend all scheduled follow-up exams for 12 months 
postoperatively 
3.3 
Screening Exclusion Criteria 
Excluded from the study will be individuals with the following characteristics.  Unless specified 
otherwise, all ocular criteria refer to the study eye only. 
x Secondary glaucoma other than pseudoexfoliative and pigmentary (e.g., neovascular, 
uveitic, traumatic, steroid induced, lens induced, or glaucoma associated with increased 
episcleral venous pressure) 
x Diagnosis of acute angle closure, chronic angle closure, or congenital, malignant, or 
developmental glaucoma 
x Central visual field depression within 5 degrees of fixation with sensitivity < 15 dB in both 
hemifields on the numerical/dB plot  
x Pre-perimetric glaucoma 
x Ocular hypertension 
x Shallow or flat anterior chamber 
x Presence of peripheral anterior synechiae or iris processes obscuring angle visualization 
x Central corneal thickness greater than 620 or less than 480 microns 
x History of complicated intraocular surgery (e.g., vitreous in anterior chamber, zonular 
dehiscence) 
x History of failed Schlemm’s canal procedure (including but not limited to Glaukos iStent, 
Ellex ABiC, SightSciences Trab360, or New World Medical Kahook Dual Blade) 
x Epithelial or fibrous downgrowth 

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
x Aphakia 
x Currently implanted anterior chamber IOL 
x Retinal laser within 90 days prior to screening 
x A need for additional ocular surgery (e.g., cataract surgery) or retinal laser procedure 
within the 12-month postoperative period 
x Proliferative diabetic retinopathy (PDR) 
x History of retinal detachment repair with silicone oil or scleral buckling procedure 
x Corneal dystrophy (e.g., Fuch’s Dystrophy, defined as > 12 confluent endothelial guttae) 
or corneal opacity 
x Previous corneal surgery, including lamellar or penetrating keratoplasty, LASIK or PRK 
x Fellow eye best-corrected visual acuity (BCVA) worse than 20/200 
x Inability to complete a reliable Humphrey-Zeiss 24-2 SITA Std visual field on the study eye 
(fixation losses, false positive, and false negative errors should not be greater than 33%) 
x Fellow eye visual field mean deviation worse than -18.00 dB 
x Exudative age-related macular degeneration (AMD) 
x History of intraocular inflammation or infection within 90 days prior to screening 
x Use of oral hypotensive medication (e.g., acetazolamide) for glaucoma treatment 
x Uncontrolled systemic disease that in the opinion of the Investigator would put the 
subject’s health at risk and/or prevent the subject from completing all study visits 
x Unable to suspend or temporarily discontinue use of blood thinners (e.g., warfarin, 
heparin, aspirin, etc.) in accordance with surgeon’s standard instructions 
x Pregnant or nursing women; or women of child bearing age not using medically 
acceptable birth control 
x Current participation or participation within the past 30 calendar days in another 
investigational drug or device clinical trial 
x Known or suspected allergy to nickel 
 
3.4 
Baseline Inclusion Criteria 
x Medicated diurnal IOP шϮϬŵŵ,ŐĂŶĚчϯϱmmHg 
3.5 
Consent 
Participation in the study is voluntary. When it has been established that the patient is eligible 
for possible enrollment into the study, written informed consent (ICF) will be obtained.   
3.6 
Enrollment 
Patients who sign the informed consent form (ICF) are considered enrolled.  Study specific 
exams should be initiated only after ICF is obtained.   

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
4.0 
CLINICAL FOLLOW-UP SCHEDULE 
All subjects will be scheduled to return for follow-up examinations at defined intervals through 
12 months. Table 5 shows the schedule of events and procedures at each protocol-required 
visit. 
 

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
SCHEDULE OF VISITS 
Procedure 
Screening1 
Baseline  
(30 days 
from Scr) 
Surgery  
(30 days 
from BL) 
1D 
Postop 
7D 
Postop 
(+/- 2D) 
1M 
Postop 
(30+/-
7D) 
2M 
Postop 
(60+/-
10D) 
3M 
Postop 
(90+/-
14D) 
6M 
Postop 
(183+/-
14D) 
9M Postop 
(274+/-
30D) 
12M 
Postop 
(365+/-
45D) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
Ophthalmic and Non-Ophthalmic 
X 
 
 
 
 
 
 
 
 
 
 
Medication Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Manifest Refraction 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
BCVA - Snellen 
X 
 
 
 
 
 
 
 
 
 
 
Visual Acuity-Pinhole 
 
 
 
X 
 
 
 
 
 
 
 
BCVA - ETDRS 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Intraocular Pressure 
Goldmann Applanation 
Tonometry 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Diurnal Intraocular Pressure 
Goldmann Applanation 
Tonometry 
 
X3 
 
 
 
 
 
 
 
 
X3 
Intraocular Pressure 
2 to 6 hours after surgery 
 
 
X4 
 
 
 
 
 
 
 
 
Pachymetry  CCT 
X 
 
 
 
 
 
 
 
 
 
X 
Gonioscopy  
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lenticular Opacity Grading 
X5 
 
 
 
 
X5 
 
 
X5 
 
X5 
Visual Field 
Humphrey 24-2 SITA Standard 
X 
 
 
 
 
 
 
X 
X 
 
X 
Fundus Exam/Disc Evaluation 
X 
 
 
 
 
X 
 
 
X 
 
X 
Optic Disc Photography 
 
X 
 
 
 
 
 
 
 
 
X 
Subject Questionnaire 
 
X 
 
 
 
 
 
X 
 
 
X 
Hydrus Implantation 
 
 
X6 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1  At the Screening Visit,  all assessments will be performed for both eyes. 
2  At the Baseline Visit, both eyes may be evaluated if eligibility confirmed after all Screening procedures completed. 
3  Daytime-Diurnal IOP measurements will be performed 3 times at 8:00 AM (± 1 hour), 12:00 PM (± 1 hour), and 4:00 PM (± 1 hour). 
4 Single reader method (no masking required) and only one measurement.  Goldmann or portable tonometer may be used. 
5  Phakic subjects only. 
6  Subjects who do not receive the microstent during surgery will be followed for safety for 1 month postoperatively or until the device-related adverse event, if applicable, has resolved or is stable. 

Protocol NCT03267134 
 
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Hydrus Microstent For Refractory Glaucoma 
 
5.0  STATISTICAL METHODS  
5.1 
General Data Handling 
Descriptive statistics on continuous variables will include mean, standard deviation, 
median, and range.  Confidence intervals will be included for selected endpoints. 
Categorical variables will be summarized using frequency counts and percentages.  A 
confidence level of 95% will be used for the confidence intervals.  Statistical testing will 
be two-sided with a significance level of 0.05 or one-sided with a significance level of 
0.025 unless specify otherwise.  Data listings of individual subject data may be provided. 
The baseline values are those that are obtained at the closest visit prior to the surgery.  The 
arithmetic difference between the baseline and the postoperative visit are defined as follows: 
Change from baseline = postoperative value – baseline value 
Percent change from baseline = change from baseline ÷ baseline X 100. 
The Safety Population includes all subjects for whom a Hydrus microstent was implanted or 
implantation was attempted. 
 
5.2  
Study Populations 
The Effectiveness Population will consist of all the subjects who undergo the Hydrus implantation 
surgery and are not discontinued early from the study due to unrelated reasons such as death or 
relocation. The primary analyses on the primary and secondary effectiveness endpoints will be 
based on the Effectiveness Population. The reasons for discontinuation will be reported.  
 
Intent to Treat. The ITT population will include all subjects undergoing Hydrus Microstent 
implantation surgery. For this study the ITT population is the safety population.  
 
Per Protocol. The Per Protocol (PP) population will include all implanted subjects who meet the 
following criteria:  
x 
Subject meets all protocol eligibility criteria.  
x 
Subject completes the 12-month visit.  
x 
Subject received secondary surgical intervention (SSI) for controlling IOP will be included 
and treated as non-responder  
x 
Subjects without adverse events that lower IOP such as cyclodialysis cleft.  
x 
Additional criteria, if any, will be established before the data review and database closure. 
5.3 
Effectiveness Endpoints Analyses 
5.3.1 
Primary Effectiveness Endpoint 
The primary effectiveness outcomes for this study is: 

Protocol CP 16-001 Rev 08-2020 
 
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Hydrus Microstent For Refractory Glaucoma 
 
x WƌŽƉŽƌƚŝŽŶŽĨƐƵďũĞĐƚƐǁŝƚŚшϮϬйĚĞĐƌĞĂƐĞŝŶŵĞĂŶĚŝƵƌŶĂů/KWĂƚϭϮŵŽŶƚŚƐ
while maintaining the same or fewer number of medications as at baseline 
 
The primary analyses of the primary endpoint will be based on the Effectiveness 
Population.  The exact 95% confidence interval of the response rate will be calculated 
based on binomial distribution.   
5.3.2 
Secondary Effectiveness Endpoint 
The secondary effectiveness endopoint for this study is: 
x Mean reduction in diurnal IOP at 12 months. 
The change in diurnal IOP from baseline at 12 months will be calculated for each 
subject, and the mean change in diurnal IOP and the corresponding 95% confidence 
interval will be calculated.  
5.3.3 
Other Effectiveness Analyses 
The following outcomes will be summarized descriptively at each scheduled visit based 
on the available data: 
x IOP, IOP change, and IOP percent change from baseline 
x Number of glaucoma medications and change in the number of glaucoma 
medications from baseline 
5.4 
Safety Analyses 
Adverse events (AEs) will be classified as intraoperative or postoperative.  The AEs will be 
summarized by counts and percentages.  They will also be summarized by severity (mild, 
moderate, severe) and relationship to the study device and implantation procedure.  
Additionally, the frequency and percentage of the serious adverse events will be presented.  
The summaries of the adverse events will be separated by ocular and non-ocular events.   
6.0 ADVERSE EVENTS 
6.1 
Adverse Event Definitions 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs in subjects, users or other persons, whether or not related to the 
microstent or delivery system.  Conditions or diseases that are chronic but stable (unchanged) 
should not be recorded as an AE.  Changes in a chronic condition or disease that are consistent 
with natural disease progression are NOT adverse events and also should not be recorded.  
Events that occur during the screening period should not be recorded.  AEs should be recorded 
starting with the Operative Visit. 
 
6.1.1 Serious Adverse Events (SAEs) 
An AE should be classified as an SAE and reported as such if it meets one or more of the 

Protocol CP 16-001 Rev 08-2020 
 
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Hydrus Microstent For Refractory Glaucoma 
 
following criteria: 
x Led to death  
x Led to serious deterioration in the health of the subject, that either resulted in  
o Life threatening illness or injury,  
o Permanent impairment of a body structure or a body function, or  
o Inpatient or prolonged hospitalization, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
x Led to fetal distress, fetal death, or a congenital abnormality or birth defect 
x Considered a significant medical event by the investigator based on medical judgment  
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
Hospitalizations for the following reasons will not be recorded as SAEs: 
x Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions. 
x Hospitalization or prolonged hospitalization required to allow outcome 
measurement for the study. 
x Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
6.1.2 Sight-Threatening Events 
A sight-threatening event should be reported as an SAE.  Sight-threatening events include, but 
are not limited to endophthalmitis, corneal decompensation, severe retinal detachment, severe 
choroidal hemorrhage, severe choroidal detachment, or aqueous misdirection.    
6.1.3 Unanticipated Adverse Device Effects 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity or degree of incidence in the 
investigational plan or application (including a supplementary plan or application). UADEs also 
include any unanticipated sight-threatening events and any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects.  
6.2 
Adverse Event Assessment and Documentation 
All subjects who undergo attempted implantation of the Hydrus will be evaluated for adverse 
events. All adverse events, regardless of severity and whether or not they are ascribed to the 
Hydrus implant or delivery system, will be recorded using standard medical terminology. All 
events for the study eye, fellow eye, and non-ocular are to be recorded. 
All adverse events will be evaluated beginning with onset, and evaluation will continue until 
resolution is noted, or until the investigator determines that the subject’s condition is stable.  

Protocol CP 16-001 Rev 08-2020 
 
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Hydrus Microstent For Refractory Glaucoma 
 
The investigator will take appropriate and necessary therapeutic measures required for 
resolution of the adverse event. Any medication necessary for the treatment of an adverse 
event must be recorded.  
All AEs will be characterized by the following criteria: 
x Event term 
x Severity 
x Expectedness 
x Relationship to study device or procedure 
x Outcome 
x Treatment or action taken. 
 
Whenever possible, recognized medical terms should be used when recording AEs. Colloquialisms 
and/or abbreviations should not be used.  Only one medical concept, preferably a diagnosis 
instead of individual symptoms, should be recorded as the event. 
If more than one distinct adverse event occurs, each event should be recorded separately.  
However, if known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be 
recorded rather than individual signs and symptoms (e.g., record congestive heart failure rather 
than dyspnea, rales, and cyanosis).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as a separate AE.  A diagnosis that is subsequently 
established should be reported as follow-up information.  However, signs and symptoms that 
are considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs (e.g., if congestive heart failure and severe headache are observed at the same 
time, each event should be recorded as an individual AE). 
Events occurring secondary to other events should be recorded as sequelae to the primary 
cause; a "primary" event, if clearly identifiable, should represent the most accurate clinical term 
to record as the AE.  Treatment for an adverse event should not be recorded as the adverse 
event.  Instead, the reason for the treatment or procedure should be assessed as the potential 
adverse event. 
6.3 
Classification of Adverse Events by Severity 
All adverse events should be graded on a three-point scale (mild, moderate, severe) for 
severity.  The definitions are as follows: 
 
Mild:  
Transient discomfort; no medical intervention/therapy required and does not 
interfere with daily activities. 
Moderate:   Low level of discomfort or concern with mild to moderate limitation in daily 
activities; some assistance may be needed; minimal or no medical 
intervention/therapy required. 
Severe:  
 Extreme discomfort and limitation in daily activities, significant assistance 
required; significant medical intervention/therapy required. 

Protocol CP 16-001 Rev 08-2020 
 
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Hydrus Microstent For Refractory Glaucoma 
 
 
There is a distinction between the severity and the seriousness of an adverse event. Severity is 
a measurement of intensity; thus, a severe reaction is not necessarily a serious adverse event 
(SAE).  For example, a headache may be severe in intensity, but would not be serious unless it 
met one of the criteria for serious adverse events listed in the protocol. 
 
6.4 
Anticipated or Unanticipated Events 
All AEs will be evaluated as to whether they are anticipated or unanticipated. 
  
Anticipated: 
An adverse event is anticipated (i.e., expected) when the nature, severity, 
or degree of incidence was previously described.  Expected adverse 
events are listed in 8.8.1. 
Unanticipated: 
An adverse event is unanticipated (i.e., unexpected) when the nature, 
severity, or degree of incidence was not previously described.  
6.5 
Relationship of the Event to the Device and Procedure 
The study investigator will evaluate if the AE is related to the Hydrus device or the Hydrus 
procedure. Relationship is defined in the following manner: 
  
Not related: Evidence indicates no plausible direct relationship to the study device or 
procedure, such that: 
x A clinically plausible temporal sequence is inconsistent with the onset of the AE 
and device or procedure; and/or 
x A causal relationship is considered biologically implausible; and/or 
x The AE can be attributed to concurrent/underlying illness, other drugs, or 
procedures. 
 
Related: Evidence indicates a reasonable temporal sequence of the event with the study device 
or procedure exists, or that the association of the event with study device administration is 
unknown and the event is not reasonably supported by other conditions, such that: 
x There is a clinically plausible time sequence between onset of the AE and study 
device or procedure; and/or 
x There is a biologically plausible mechanism for study device or procedure causing or 
contributing to the AE; and 
x The AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, 
or procedures. 
Remote: Exposure to the device/procedure and the occurrence of adverse event cannot be 
reasonably determined to be unrelated to the device or the procedure.   

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Hydrus Microstent For Refractory Glaucoma 
 
6.6 
Ongoing Assessment and Outcome 
Adverse events will be assessed at all postop visits until resolution or stabilization occurs.  
Changes in severity and intervention will be recorded.    
 
The clinical outcome of an AE will be characterized as follows: 
x Resolved without sequelae 
x Resolved with sequelae (specify) 
x Stabilization; no possible resolution 
x Ongoing (i.e. continuing at time of study discontinuation) 
x Death. 
After exit from the study, ongoing AEs should be followed until resolution (with or without 
sequelae), stabilization, or it is determined that there is no possible resolution.  Subjects who 
present or report with a significant, ocular (study eye only) adverse event at the exit visit, 
should be followed by the physician after exit for AE resolution/stabilization. 
6.7 
Treatment or Action Taken 
x None 
x Medical Intervention  
x Surgical Intervention (includes device explant) 
x Other. 
 
6.8 
Serious Adverse Event and Unanticipated Adverse Device Effect Reporting 
Serious Adverse Events (SAE) and unanticipated adverse device effects (UADE) must be reported 
to the study sponsor as soon as possible and no later than 10 working days after the investigator 
first learns of the event.  
 
For initial reports, investigators should record all case details that can be gathered within the 
reporting timeframe. Relevant follow-up information should be submitted to the Sponsor as 
soon as it becomes available and/or upon request.  For some events, the sponsor or its 
designee or the medical monitor may follow up with the site by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the event (e.g., hospital discharge summary, consultant report, or autopsy report).  
Reports relating to the subject’s subsequent medical course must be submitted to the study 
sponsor until the event has subsided or, in case of permanent impairment, until the event 
stabilizes and the overall clinical outcome has been ascertained. 
The Sponsor will be responsible for informing regulatory authorities and all other IRBs/ECs and 
Investigators participating in the study of the UADE within 10 working days after notice of the 
event. 
6.8.1 Anticipated Adverse Events 

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Hydrus Microstent For Refractory Glaucoma 
 
Anticipated AEs associated with glaucoma surgical procedures that might reasonably be 
expected to occur in this study are listed below.  These specific examples of anticipated AEs 
include, but are not limited to: 
Intraoperative Adverse Events 
x Choroidal hemorrhage or effusion  
x Corneal abrasion 
x Corneal edema 
x Cyclodialysis cleft 
x Hyphema obscuring the surgeon’s view  
x Inadvertent perforation of the sclera 
x Iridodialysis 
x Lens / capsular bag damage (crystalline or IOL) 
x Microstent malposition  
x Significant iris injury or trauma 
x Vitreous loss 
x Zonular dialysis 
 
Postoperative adverse events include 
x Angle closure 
x Angle recession 
x Anterior chamber cell or flare requiring either an increase in the standard postoperative 
steroid regimen or re-initiation of steroid use following completion of the standard 
postoperative steroid regimen.    
x Aqueous misdirection 
x Atrophy, phthisis 
x Best-corrected visual acuity loss of 2 lines (10 letters) or more compared to baseline on 
the ETDRS chart measured before or at 1-month postoperative  
x Best-corrected visual acuity loss of 2 lines (10 letters) or more compared to baseline on 
the ETDRS chart measured after 1-month postoperative 
x Blebitis 
x Choroidal detachment 
x Choroidal hemorrhage or effusion (detachment with at least a partially hemorrhagic 
component that obstructs or causes pain, including both peripheral and “kissing” 
choroidal detachments) lasting 30 days or less 
x Choroidal hemorrhage or effusion (detachment with at least a partially hemorrhagic 
component that obstructs or causes pain, including both peripheral and “kissing” 
choroidal detachments) lasting longer than 30 days 
x Chronic anterior uveitis defined as inflammation of grade 1+ or worse persisting for more 
than 90 days postoperatively or that recurs less than 90 days after discontinuing standard 
medication regimen  
x Chronic pain in the study eye onset ³ 3-months postoperative 
x Corneal decompensation 

Protocol CP 16-001 Rev 08-2020 
 
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Hydrus Microstent For Refractory Glaucoma 
 
x Corneal edema persisting > 30 days ;ŵŝůĚƚŽŵŽĚĞƌĂƚĞͿŽƌƐĞǀĞƌĞĐŽƌŶĞĂůĞĚĞŵĂшϭĚĂǇ͘ 
x Corneal opacification 
x Descemet’s membrane detachment 
x Device migration (dislodgement or movement) 
x Device obstruction  
x ůĞǀĂƚĞĚŵĞĂŶ/KWшϭϬŵŵ,ŐƚŚĂŶƚŚĞƋƵĂůŝĨǇŝŶŐďĂƐĞůŝŶĞŵĞĂŶ/KWonset before or at 
1-month postoperative  
x ůĞǀĂƚĞĚŵĞĂŶ/KWшϭϬŵŵ,ŐƚŚĂŶƚŚĞƋƵĂůŝĨǇŝŶŐďĂƐĞůŝŶĞŵĞĂŶ/KWonset after 1-month 
postoperative 
x Endophthalmitis 
x Flat anterior chamber with lens/cornea touch or shallow anterior chamber with peripheral 
iridocorneal apposition  
x Hyphema > 2 mm in height (layered) at any time  
x Hyphema present or arising > 30 days postoperative 
x Hypotony (defined as IOP < 6 mmHg) onset before 1-month postoperative  
x Hypotony (defined as IOP < 6 mmHg) onset at or after 1-month postoperative 
x Implant corneal touch 
x Implant-iris touch associated with intraocular inflammation, pigment dispersion, or other 
sequelae  
x Inadvertent bleb 
x /ŶĐƌĞĂƐĞŝŶǀĞƌƚŝĐĂůͬƌĂƚŝŽŽĨшϬ͘ϯƵŶŝƚƐĨƌŽŵƐĐƌĞĞŶŝŶŐŽŶĨƵŶĚƵƐĞǆĂŵŝŶĂƚŝŽŶ 
x Iris prolapse/wound incarceration 
x Maculopathy including hypotonic maculopathy 
x Persistent diplopia 
x Pupil block 
x Retinal complications (e.g., flap tears, retinal break, retinal detachment, age related 
macular degeneration, diabetic retinopathy, macular edema, epiretinal membrane, 
central serous retinopathy, or proliferative vitreoretinopathy) 
x Scleral ectasia 
x Surgical re-intervention in the study eye (other than paracentesis to relieve pressure 
within the 1 week visit)   
x Toxic anterior segment syndrome (TASS) 
x Vitreous haze 
x Vitreous hemorrhage 
x Vitritis 
x Worsening of 2-points (from screening) to “severe” on the slit lamp examination findings 
(other than cells and flare) onset at or after 3-months postoperative not associated with a 
pre-existing condition 
x Worsening of lens opacities (defined as a 2.0 or more score change on at least one 
category of the LOCS III grading system, at 2 or more consecutive visits) 
x Worsening of visual field (mean deviation worsening by 3.0 dB or more, confirmed by 2 
repeat measurements) 
x Wound dehiscence (persistent aqueous leak or fistula formation) 

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Hydrus Microstent For Refractory Glaucoma 
 
For any adverse event that may be due to incorrect device positioning (i.e. vitreous hemorrhage, 
hyphema, hypotony), gonioscopy should be performed to assess the device position. If the 
position cannot be adequately evaluated by gonioscopy, ultrasound biomicroscopy (UBM) should 
be performed. 
For slit lamp examination, gonioscopy and fundus findings for which there is no grading scale, 
any finding considered by the study investigator to be marked or severe, i.e., clinically 
significant, should be recorded as an Adverse Event.  
 
 

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Hydrus Microstent For Refractory Glaucoma 
 
7.0 DEFINITIONS 
Device Obstruction 
No obstruction:  Tissue located around the inlet (portion of device in anterior chamber), 
however the flow path from the anterior chamber into Schlemm’s canal is not obstructed. 
Device obstruction:  Inlet (portion of device in anterior chamber) is filled with tissue 
resulting in an obstructed flow path from the anterior chamber into Schlemm’s canal. 
Endophthalmitis: Diffuse intraocular inflammation predominantly involving the vitreous cavity 
but also involving the anterior chamber, implying a suspected underlying infectious cause; if 
known; record the diagnosis (i.e., disease or syndrome) rather than component signs and 
symptoms on AE pages of the CRF. 
Peripheral anterior synechia (PAS):  Iris adhesions that cross the scleral spur and adhere to the 
peripheral cornea, not including iris processes. 
Malposition:  Gonioscopic evidence that all windows of the microstent and/or distal end are 
not in Schlemm’s canal. 
Uveitis: Inflammation in the uveal tract (iris, ciliary body, and choroid), either primary or 
secondary to keratitis or systemic diseases.  Includes iritis (presence of inflammatory cells in the 
anterior chamber; aqueous flare alone is not considered to constitute iritis) and iridocyclitis 
(presence of inflammatory cells in both the aqueous and vitreous). 
Vitreous Haze:  A worsening of inflammation by 2 grades or a finding of Grade 3 (optic nerve 
head is visible but the borders are blurry and cannot see vessels) or Grade 4 (optic nerve head is 
obscured) on the grading scale provided in Appendix 2. 
Vitreous Hemorrhage:  A worsening of density by 2 grades or a finding of Grade 3 (Red reflex is 
visible but no central retinal detail is seen posterior to the equator by ophthalmoscopy) or 
Grade 4 (No red reflex on ophthalmoscopy) on the grading scale provided in Appendix 2. 
Vitritis: Presence of active inflammation in the vitreous, as demonstrated by the 
presence of inflammatory cells (trace or greater).  
x The presence of inflammation involving only the anterior vitreous will not be 
considered to constitute vitritis because it may result from iridocyclitis (see above). 
x Active inflammation in the vitreous should be clinically differentiated from cellular 
debris from prior episodes of inflammation, hemorrhage, or other causes. 
x The presence of vitreous flare alone in the absence of active inflammatory cells will 
not be considered to constitute vitritis. 
Active inflammation in the vitreous should be clinically differentiated from cellular debris from 
prior episodes of inflammation, hemorrhage, or other causes.