The Safety and Effectiveness of the Hydrus Aqueous Implant for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery, A Prospective, Multicenter, Randomized, Controlled Clinical Trial
Phase: NA
Conditions: Primary Open Angle Glaucoma
Sponsor: Ivantis, Inc.

Page 1 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
 
 
 
 
PROTOCOL NCT01539239 
 
 
 
 
THE SAFETY AND EFFECTIVENESS OF THE HYDRUS AQUEOUS IMPLANT 
FOR LOWERING INTRAOCULAR PRESSURE IN 
GLAUCOMA PATIENTS UNDERGOING CATARACT SURGERY, 
A PROSPECTIVE, MULTICENTER, RANDOMIZED, 
CONTROLLED CLINICAL TRIAL 
 
 

Page 2 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
TABLE OF CONTENTS 
Contents 
 
 
1.0 
DEVICE DESCRIPTION............................................................................ 3 
2.0 
ALTERNATIVE PRACTICES AND PROCEDURES ........................................ 4 
3.0 
MARKETING HISTORY ........................................................................... 5 
4.0 
SUMMARY OF NONCLINICAL STUDIES .................................................. 5 
A. 
Biocompatibility Testing ................................................................................... 5 
B. 
Physicochemical Testing ................................................................................... 7 
C. 
Physical and Mechanical Testing ...................................................................... 8 
D. 
Sterilization, Package Integrity, Shelf Life, and Transport Stability ................ 10 
5.0 
STUDY METHODS ............................................................................... 12 
A. 
Selection of Patients ....................................................................................... 12 
B. 
Glaucoma Diagnosis ........................................................................................ 12 
C. 
Inclusion Criteria ............................................................................................. 12 
D. 
Intraoperative Eligibility Criteria ..................................................................... 13 
E. 
Exclusion Criteria............................................................................................. 13 
F. 
Consent ........................................................................................................... 15 
G. 
Enrollment ...................................................................................................... 15 
H. 
Wash Out ........................................................................................................ 15 
6.0 
CLINICAL FOLLOW-UP SCHEDULE ........................................................ 15 
7.0 
STATISTICAL ANALYSIS PLAN - STUDY ENDPOINTS .............................. 17 
A. 
The primary effectiveness endpoint for this study ......................................... 17 
B. 
The secondary effectiveness endpoint for the study ..................................... 17 
C. 
Accountability of PMA Cohort ........................................................................ 17 
8.0 
ADVERSE EVENTS ............................................................................... 18 
A. 
Adverse Event Definitions ............................................................................... 18 
B. 
Serious Adverse Events (SAEs) ........................................................................ 18 
C. 
Sight-Threatening Events ................................................................................ 19 
D. 
Unanticipated Adverse Device Effects ............................................................ 19 
E. 
Adverse Event Assessment and Documentation ............................................ 19 
F. 
Classification of Adverse Events by Severity................................................... 20 
G. 
Anticipated or Unanticipated Events .............................................................. 21 
H. 
Relationship of the Event to the Device and Procedure ................................ 21 
I. 
Outcome ......................................................................................................... 22 
J. 
Treatment or Action Taken ............................................................................. 22 
K. 
Serious Adverse Event and Unanticipated Adverse Device Effect Reporting 22 
L. 
Anticipated Adverse Events ............................................................................ 23 
9.0 
DEFINITIONS ....................................................................................... 25 
 
 
 

Page 3 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
1.0 
DEVICE DESCRIPTION 
The Hydrus Microstent is a crescent-shaped implantable microstent pre-loaded onto a 
hand-held delivery system. 
The microstent (Figure 1) is composed of nitinol, a metal alloy of nickel (Ni) and titanium 
(Ti).  Nitinol has been used extensively in a variety of implantable 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.  Its 
flexibility and small size allows delivery of the microstent through tortuous, restrictive 
passages with minimal force.  The implant is laser cut from nitinol tubing 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 microstent is approximately 8mm in overall length with 
major and minor axes of 292µm and 185µm, respectively.  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. 
 
 
 
FIGURE 1: HYDRUS IMPLANT 
 
The microstent is implanted into the eye using a hand-held delivery system (Figure 2) that 
provides for manual delivery of the implant 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 delivery system 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.  
Spines 
Windows 
Distal Tip 
Inlet 

Page 4 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
 
 
FIGURE 2: HYDRUS DELIVERY SYSTEM 
 
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 
ALTERNATIVE PRACTICES AND PROCEDURES 
There are several alternatives for the correction of mild to moderate POAG.  These 
alternatives include:  
• Non-surgical treatment, such as IOP-lowering medications (topical eye drops or 
systemic IOP lowering drugs)  
• Laser treatment  
• Other incisional glaucoma surgery  
Each alternative has its own advantages and disadvantages.  A patient should fully discuss 
these alternatives with his/her physician to select the method that best meets expectations 
and lifestyle. 
 
 

Page 5 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
3.0 
MARKETING HISTORY 
The Hydrus Microstent is currently approved for commercial distribution in the European 
Union, Canada, Australia, New Zealand, Costa Rica and Columbia. 
The Hydrus Microstent has not been withdrawn from marketing for any reason relating to 
the safety and effectiveness of the device. 
4.0 
SUMMARY OF NONCLINICAL STUDIES 
A. 
BIOCOMPATIBILITY TESTING 
Biocompatibility testing was performed on the Hydrus implant or representative 
samples of the finished device (Table 1A) and on the patient-contacting components 
of the Hydrus delivery system (Table 1B).  The biocompatibility testing was 
performed in accordance with ISO 10993-1 - Biological evaluation of medical devices 
- Part 1: Evaluation and testing within a risk management process and relevant 
related sub-standards, including: 
• Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity 
• Part 5: Tests for in vitro cytotoxicity 
• Part 6: Tests for local effects after implantation 
• Part 10: Tests for irritation and skin sensitization 
• Part 11: Tests for systemic toxicity 
All biocompatibility testing was conducted in accordance with the provisions of 21 
CFR 58, Good Laboratory Practice for Nonclinical Laboratory Studies. 
 
 
 

Page 6 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
 
TABLE 1A: BIOCOMPATIBILITY TESTING OF THE HYDRUS IMPLANT 
 
Test 
Test Method 
Results 
Cytotoxicity 
MEM Elution 
ISO 10993-5 
Non-cytotoxic 
Cytotoxicity 
Agarose Overlay (Direct Contact) 
ISO 10993-5 
Non-cytotoxic 
Cytotoxicity 
Cell Growth Inhibition Assay 
ISO 10993-5 
Negative 
Sensitization 
Guinea Pig Maximization 
ISO 10993-10 
Non-sensitizer 
Intracutaneous Reactivity  
Rabbit Intracutaneous Reactivity  
ISO 10993-10 
Non-irritant 
Acute Systemic Toxicity 
Mouse USP Systemic Injection 
ISO 10993-11 
Non-toxic 
Material Mediated 
Pyrogenicity 
Rabbit Pyrogen  
ISO 10993-11:2006 
Non-pyrogenic 
Subacute Intraperitoneal 
Toxicity 
Mouse 14-Day Intraperitoneal Injection 
ISO 10993-11 
Non-toxic 
Subchronic Intravenous 
Toxicity 
Mouse 14-Day Intravenous Injection 
ISO 10993-11 
Non-toxic 
Mutagenicity 
Ames Reverse Mutation 
ISO10993-3 
Non-mutagenic 
Mutagenicity 
Mouse Micronucleus 
ISO10993-3:2003 
Non-genotoxic 
Mutagenicity 
Mouse Lymphoma  
ISO10993-3:2003 
Non-mutagenic 
Intramuscular 
Implantation 
Rabbit Muscle Implantation (13 weeks) 
ISO 10993-6:2007 
No different than 
control 
Chronic Toxicity 
6-Month Ocular Implantation Testing in 
Rabbits 
No different than 
control 
 
 
 

Page 7 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
TABLE 1B: BIOCOMPATIBILITY TESTING OF THE HYDRUS DELIVERY SYSTEM 
 
Test 
Test Method 
Results 
Cytotoxicity 
MEM Elution 
ISO 10993-5 
Non-cytotoxic 
Sensitization 
Guinea Pig Maximization 
ISO 10993-10 
Non-sensitizer 
Intraocular Irritation 
Intraocular Exposure in Rabbits 
Non-irritant 
Intracutaneous Irritation 
Rabbit Intracutaneous Reactivity  
ISO 10993-10 
Non-irritant 
Acute Systemic Toxicity 
Mouse USP Systemic Injection 
ISO 10993-11 
Non-toxic 
Material Mediated 
Pyrogenicity 
Rabbit Pyrogen 
ISO 10993-11 
Non-pyrogenic 
B. 
PHYSICOCHEMICAL TESTING 
Physicochemical testing was conducted to physically characterize and verify the 
stability of the microstent throughout the potential implant life span.  
Physicochemical testing (Table 2) was conducted on the Hydrus implant (or 
representative samples of the finished device) in accordance with ANSI Z80.27 - 
Ophthalmics - Implantable Glaucoma Devices and FDA Guidance Document - 
Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) 
Devices (December 15, 2015). 
 
 
 

Page 8 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
TABLE 2: PHYSICOCHEMICAL TESTING OF THE HYDRUS IMPLANT 
 
Test 
Purpose 
Results 
Corrosion 
Resistance 
Determine susceptibility of 
microstent to galvanic corrosion 
per ASTM F 2129-08 
Microstent is considered 
corrosion resistant 
Exhaustive 
Extraction 
Determine identity and amount of 
extractable substances 
No extractable substances at 
levels that would affect the 
human eye 
Leachables 
Determine identity and amount of 
saline leachables 
No leachable substances at levels 
that would affect the human eye 
Nickel Elution 
Quantify amount of nickel ion 
released from microstent 
Risk of adverse effects resulting 
from nickel leaching is negligible 
Hydrolytic Stability 
Demonstrate 5 year accelerated 
hydrolytic stability of the 
microstent in situ 
Microstent is hydrolytically stable 
for 5 years; no detectable adverse 
effect on surface characteristics of 
finished microstents 
Insoluble Organics 
Evaluate microstent for evidence 
of inorganic compounds on the 
finished device at the end of the 
manufacturing process 
No significant levels of insoluble 
organics detected 
C. 
PHYSICAL AND MECHANICAL TESTING 
The Hydrus implant and delivery system were subjected to physical and mechanical 
testing in accordance with ANSI Z80.27 (Table 3). 
 
 
 

Page 9 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
TABLE 3: PHYSICAL AND MECHANICAL TESTING OF THE HYDRUS MICROSTENT 
 
Test 
Purpose 
Results 
Material Properties  
Nitinol (NiTi) Alloy 
Verify nitinol base material 
satisfies composition and 
mechanical characteristics 
for surgical implants per 
ASTM F2063-12 
Each lot of microstents is 
provided with a Certificate 
of Conformance to ASTM 
F2063-12 
Austinetic Finish Transition 
Temperature (Af) 
Verify Af  transition 
temperature of microstent  
following heat-set 
operation satisfies 
specification of 16±3º C 
Each lot of microstents is 
tested for Af transition 
temperature by differential 
scanning calorimetry 
testing per ASTM F2004 
Dimensions 
Verify overall dimensions 
are within specifications  
Each lot of microstents is 
inspected for nominal 
length, wall thickness and 
radius of curvature 
Edge and Surface Quality 
Verify edges and surface of 
microstent are smooth, 
free of cracks, protrusion, 
pits, dings, inclusions and 
stringers 
Each lot of microstents is 
subjected to surface/edge 
inspection by light 
microscopy and SEM 
Structural Integrity 
Verify microstent satisfies 
mechanical strength 
requirements per ANSI 
Z80.27-14 
Tensile force testing shows 
force at breakage > 0.5 N, 
satisfying requirements of 
ANSI Z80.27-2014 
Outflow Facility 
Verify microstent is able to 
increase outflow of 
aqueous humor sufficient 
to lower IOP in bench test 
model  
Benchtop testing 
demonstrates significant 
increase in outflow facility 
in cadaver eyes 
Magnetic Resonance 
Imaging Compatibility 
Evaluate the compatibility 
of the microstent with 
current standard magnetic 
resonance imaging 
techniques 
Microstent shown to be 
“MR-conditional” and 
labeled appropriately per 
ASTM F2503-13 
Delivery System 
Performance 
Verify delivery system 
consistently satisfies 
performance requirements 
for microstent delivery 
Performance testing 
demonstrates that the 
microstent is consistently 
delivered under conditions 
of in vitro bench testing and 
simulated in vivo use in 
cornea rim tissue 

Page 10 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
D. 
STERILIZATION, PACKAGE INTEGRITY, SHELF LIFE, AND TRANSPORT STABILITY 
The Hydrus Microstent is supplied with the implant pre-loaded in the handheld 
delivery system.  The device is sealed in sterile-barrier (Tyvek®) packaging and 
packaged in a chipboard shelf box. 
The packaged device is sterilized by exposure to gamma radiation.  Microbiological 
studies have been conducted to demonstrate that the packaged device satisfies 
domestic and international requirements to be labeled ‘STERILE’ with a Sterility 
Assurance Level (SAL) of 10-6.  The sterilization cycle was validated in accordance 
with the provisions of ISO 11137-1:2006 - Sterilization of health care products – 
Radiation – Part 1: Requirements for development, validation and routine control of 
a sterilization process for medical devices and ISO 11137-2:2012 - Sterilization of 
health care products – Radiation - Part 2: Establishing the sterilization dose.  The 
methodology used was that applicable to substantiating 25 kGy as a minimum 
sterilization dose (Method VDmax25).  Successful completion of the sterilization 
validation qualifies dose monitoring as a means for routine lot release of the device. 
Sterilization, packaging, shipping, and shelf life studies were conducted to verify that 
the packaging for the device maintains a sterile barrier and that the device 
performance meets product specifications through the labeled shelf life.  The results 
of the sterilization, packaging, shelf life and transport stability studies are 
summarized in Table 4. 
 
 

Page 11 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
TABLE 4: STERILIZATION, PACKAGING, TRANSPORTATION AND SHELF LIFE TESTING 
 
Test 
Purpose 
Results 
Gamma Irradiation 
Sterilization 
Validation 
Demonstrate device is ‘STERILE’ to 
an SAL of 10-6 
Satisfies requirements of ISO 
11137-1 to be labeled ‘Sterile’ 
with an Sal of 10-6 
Bioburden 
Establish upper limit for product 
bioburden to establish sterility of 
(< 200 CFU/Device) 
Bioburden testing shows results  
< 200 CFU/Device 
Bacterial Endotoxin 
Verify bacterial endotoxin levels 
satisfy FDA Guidance for single-
use ophthalmic devices 
( < 0.2 EU/Device) 
 Bacterial endotoxin testing shows 
results < 0.2 EU/Device 
Package Evaluation 
– Bubble Leak  
Verify package seal integrity 
No bubble leak per ASTM F2096 
Package Evaluation 
– Seal Peel Test 
Verify package seal integrity 
Package seal peel strength 
 > 1.0 Lbf  
Transport Stability 
Verify package and device stability 
after transportation challenges 
Packaging and device satisfy 
specifications after transport 
challenges per ASTM D4169, 
distribution cycle 13 
Shelf Life Stability 
Verify sterile-barrier packaging 
and device satisfy specifications 
through labeled expiration date 
Sterile-barrier packaging and 
device satisfy specifications after 
aging to the labeled expiration 
date 
 
 
 
 

Page 12 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
5.0 
STUDY METHODS 
A. 
SELECTION OF PATIENTS 
Only subjects who meet the inclusion and exclusion criteria will be eligible for 
enrollment in this study. 
B. 
GLAUCOMA DIAGNOSIS 
Glaucoma is a progressive optic neuropathy that results in characteristic optic disc 
and visual field changes.  To qualify for the study, all subjects must have optic disc 
changes characteristic of glaucoma.  
C. 
INCLUSION CRITERIA 
Subjects must meet the following inclusion criteria to be eligible for the study eye: 
• Male and female patients, at least 45 years of age 
• An operable age-related cataract with BCVA of 20/40 or worse, eligible for 
phacoemulsification; if BCVA is better than 20/40, testing with a BAT meter 
on a medium setting must result in BCVA 20/40 or worse 
• A diagnosis of POAG treated with 1 to 4 hypotensive medications 
• Optic nerve appearance characteristic of glaucoma 
• Medicated IOP ≤ 31 mmHg 
• Diurnal IOP ≥ 22 mmHg and ≤ 34 mmHg after wash out of ocular hypotensive 
medications 
• IOP increase > 3 mmHg after wash out of ocular hypotensive medications 
• Visual field examination using Humphrey 24-2 SITA standard, meeting 
protocol specified minimum criteria for glaucoma defined as: 
1. 
Mild:  visual field loss on Humphrey visual field testing, with mean 
deviation (MD) between 0 and -6dB; fewer than 25% of points 
depressed below the 5% level and fewer than 15% of points 
depressed below the 1% level on pattern deviation plot; and no point 
within central 5° with sensitivity <15dB. 
2. 
Moderate: visual field loss on Humphrey visual field testing, with 
mean deviation worse than -6dB but no worse than -12dB; fewer than 
50% of points depressed below the 5% level, and fewer than 25% of 
points depressed below the 1% level on pattern deviation plot; no 
points within central 5° with sensitivity of ≤0dB; and only one 
hemifield containing a point with sensitivity <15dB within  
5° of fixation. 
 

Page 13 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
• In subjects where the VF exam is not confirmatory for glaucomatous defect, 
retinal nerve fiber layer optical scanning laser imaging supporting 
ophthalmoscopy findings shall be performed 
• Shaffer grade ≥ III in all four quadrants 
• Cup:disc (c:d) ratio ≤ 0.8 
• Absence of peripheral anterior synechiae (PAS), rubeosis or other angle 
abnormalities that could impair placement of the implant 
• Subject is able and willing to attend scheduled follow-up exams for 2 years 
post-operatively (and up to 5 years postoperatively as part of a post-approval 
study) 
• Subject understands and signs the informed consent 
D. 
INTRAOPERATIVE ELIGIBILITY CRITERIA 
Individuals who meet the following intraoperative eligibility criteria in the study eye 
will be randomized into the treatment or control arms of this study. 
Subjects must have: 
• An intact and centered capsulorrhexis 
• An intact posterior capsular bag 
• A well-centered monofocal IOL placed in the capsular bag 
• A clear view of an open angle and visualization of the angle with direct 
gonioscopy following intracameral instillation of a miotic agent 
Subjects must not have: 
• Evidence of zonular dehiscence/rupture 
• Intraoperative floppy iris syndrome 
E. 
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. 
• Closed angle forms of glaucoma 
• Congenital or developmental glaucoma 
• Secondary glaucoma (such as neovascular, uveitic, pseudoexfoliative, 
pigmentary, lens-induced, steroid-induced, trauma induced, or glaucoma 
associated with increased episcleral venous pressure).  
• Use of more than 4 ocular hypotensive medications (combination 
medications count as two medications). 
• Previous argon laser trabeculoplasty, trabeculectomy, tube shunts, or any 
other prior filtration or cilioablative surgery. 

Page 14 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
• Prior surgery for an ab-interno or ab-externo device implanted in or through 
the Schlemm’s Canal. 
• Inability to complete a reliable 24-2 SITA Standard Humphrey visual field on 
the study eye at screening (fixation losses, false positive errors and false 
negative errors should not be greater than 33%).   
• Use of oral hypotensive medication for glaucoma for treatment of the fellow 
eye.  
• Subjects with advanced glaucoma or any subject who presents with an 
unacceptable risk to the subject of a washout of ocular hypotensive 
medications. 
• Best corrected visual acuity worse than 20/80 in the fellow eye. 
• A 24-2 SITA Standard Humphrey visual field mean deviation (MD) of worse 
than -12dB in the fellow eye. 
• Central corneal thickness > 620 microns and < 480 microns. 
• Proliferative diabetic retinopathy. 
• Previous surgery for retinal detachment. 
• Previous corneal surgery or clinically significant corneal dystrophy, e.g., 
Fuch’s dystrophy (>12 confluent guttae) 
• Unclear ocular media preventing visualization of the fundus or anterior 
chamber angle. 
• Degenerative visual disorders such as wet age-related macular degeneration. 
• Clinically significant ocular pathology, other than cataract and glaucoma. 
• Clinically significant ocular inflammation or infection within 6 months prior to 
screening. 
• Presence of extensive iris processes that obscure visualization of the 
trabecular meshwork. 
• Unable to discontinue use of blood thinners in accordance with surgeon’s 
standard postoperative instructions. 
• Known or suspected elevated episcleral venous pressure due to Sturge 
Weber, nanophthalmos, orbital congestive disease. 
• 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. 
• Current participation or participation in another investigational drug or 
device clinical trial (which includes the fellow eye) within the past 30 
calendar days.  
• Pregnant or nursing women; or women of child bearing age not using 
medically acceptable contraceptives. 
 
 

Page 15 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
       
 
 
 
 
 
            CONFIDENTIAL 
Protocol NCT01539239 
F. 
CONSENT 
Participation in the study is voluntary.  When it has been established that the subject 
is eligible for possible enrollment into the study, written informed consent (ICF) will 
be obtained. 
G. 
ENROLLMENT 
Patients who sign the informed consent form (ICF) are considered enrolled.  Only 
after ICF is obtained should study specific exams and wash out be initiated. 
H. 
WASH OUT  
After the subject has successfully completed the preoperative screening exam, the 
subject will be instructed to discontinue ocular hypotensive medications in the 
designated treatment eye for the appropriate washout period. 
6.0 
CLINICAL FOLLOW-UP SCHEDULE 
All subjects will be scheduled to return for follow-up examinations at defined intervals 
through 24 months.  Table 5 shows the schedule of events and procedures at each protocol-
required visit. 
 
 

Page 16 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Protocol NCT01539239 
TABLE 5: SCHEDULE OF EVENTS AND PROCEDURES 
 
Procedure 
Screening 
(Both Eyes) 
(w/in 30d of 
washout 
start) 
Baseline 
(w/in 13d 
of 
minimum 
washout) 
Surgery 
(w/in 14d 
of 
minimum 
washout) 
1D 
Postop 
7D 
Postop 
(±2d) 
1M 
Postop 
(±7d) 
3M 
Postop 
(±14d) 
6M 
Postop 
(±21d) 
12M 
Postop 
(-28d/ +42d) 
18M 
Postop 
(±28d) 
24M 
Postop 
(-28d/ +42d) 
3Y, 4Y & 5Y 
Postop 
(±84d)  
Ophthalmic and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Ocular Medication Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Glaucoma Medication Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Manifest Refraction 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
BCVA  
X 
(Snellen) 
X 
(ETDRS) 
 
X 
(pinhol
e) 
(Snellen
) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(ETDRS) 
X 
(Snellen) 
IOP  
(Goldmann Applanation 
Tonometry) 
X 
 
 
X 
X 
X 
X 
X 
X2 
X 
X2 
X6 
Washed Out Diurnal IOP 
(Goldmann Applanation 
Tonometry) 
 
X1 
 
 
 
 
 
 
X1 
 
X1 
 
Pachymetry  CCT 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
Gonioscopy  
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Field  
(Humphrey 24-2 SITA-Std) 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
Fundus Exam/Disc evaluation 
X 
 
 
 
 
X 
 
X 
X 
 
X 
X 
Specular Microscopy  
X 
 
 
 
 
 
X 
X7 
X7 
X7 
X7 
X7 
Nerve Fiber Layer Imaging 
X3 
 
 
 
 
 
 
 
 
 
 
 
Ocular Symptom Questionnaire 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Adverse Event Assessment 
 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
1 Washed out diurnal IOP measurements will be performed after subject has washed out of any ocular hypotensive medications. All diurnal IOP measurement must be done PRIOR to the Gonioscopy, Fundus Exam and contact Pachymetry. An additional visit may be necessary to perform the diurnal IOP measurements.  
2 Only required for those subjects taking ocular hypotensive medications at the time of this visit. 
3 Only required for those subjects whose VF testing was not confirmatory for glaucomatous defect per the protocol defined criteria. 
4 Only adverse events associated with the ocular medication wash out.   
5 Study eye only for ocular medications other than hypotensive medications. 
6 Single operator tonometry may be conducted at 3, 4 and 5 year visits. 
7 Includes specular microscopy of the fellow eye for the central region only  
8 
Report all SAEs and only study eye ocular AEs. 
 

Page 17 of 26 
 
Ivantis, Inc. 
Hydrus® Microstent 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Protocol NCT01539239 
7.0 
STATISTICAL ANALYSIS PLAN - STUDY ENDPOINTS 
A. 
THE PRIMARY EFFECTIVENESS ENDPOINT FOR THIS STUDY 
Percentage of subjects with a reduction of at least 20% (i.e., ≥ 20%) in mean diurnal IOP 
from baseline in the study eye at 24 months following medication washout.  These 
subjects were defined as “IOP responders.” 
Subjects were defined as non-responders if they did not achieve the primary 
effectiveness endpoint, they were missing 24-month IOP assessment outcomes, if ocular 
hypotensive medications were not washed out at the 24-month visit, if they underwent 
an IOP-affecting secondary surgical procedure (i.e., iridotomy, iridectomy, 
trabeculectomy, glaucoma shunt implantation, argon laser trabeculoplasty, selective 
laser trabeculoplasty), or other surgery that would affect IOP. 
B. 
THE SECONDARY EFFECTIVENESS ENDPOINT FOR THE STUDY 
The mean diurnal unmedicated IOP change from baseline at 24 months was compared 
between the Hydrus group and control group. 
Each endpoint requires a comparison between the Hydrus and control groups.  The 
primary effectiveness analysis will be performed using the Intent to Treat (ITT) 
population, consisting of all randomized subjects grouped according to their 
randomization assignment.  
With regard to safety, anticipated and unanticipated AEs will be reported for all subjects 
randomized in the study.  Best corrected visual acuity (BCVA), central corneal 
pachymetry, slit lamp and fundus exams, gonioscopy and central corneal endothelial cell 
density (ECD) will also be used to assess safety. 
C. 
ACCOUNTABILITY OF PMA COHORT 
Subjects will be analyzed according to 3 separate population cohorts: 
ITT Population – all subjects randomized and grouped according to their 
randomization assignment (as randomized).  The ITT will be used for the analyses 
of the primary and secondary effectiveness endpoints. 
Per Protocol Population – ITT subjects that met the following conditions: 
• Met all protocol eligibility criteria 
• Had treatment consistent with randomization schedule 
• Completed the 24-month medication washout without secondary surgical 
intervention to control IOP or additional procedures that could affect IOP 
(such as cyclodialysis cleft) 

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• Had preoperative visual field mean deviation (MD) of <0 
• Without major protocol deviation established before the data review and 
database closure 
Safety Population – all subjects who were randomized and treated. Subjects in 
the Hydrus group will be grouped according to whether the implantation 
procedure was attempted (as treated) and includes those subjects for whom 
implantation was not successful. 
8.0 
ADVERSE EVENTS 
A. 
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 investigational medical device.  Conditions or diseases that are chronic 
but stable (unchanged) should not be recorded on AE pages of the CRF.  Changes in a 
chronic condition or disease that are consistent with natural disease progression are 
NOT adverse events and also should not be recorded on the AE pages of the CRF. 
B. 
SERIOUS ADVERSE EVENTS (SAES) 
An AE should be classified as an SAE and reported as such if it meets one or more of the following 
criteria: 
• Led to death  
• 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, 
• Led to fetal distress, fetal death or a congenital abnormality or birth defect 
• 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: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions. 
• Hospitalization or prolonged hospitalization required to allow outcome 
measurement for the study. 

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• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
C. 
SIGHT-THREATENING EVENTS 
An event considered sight-threatening, e.g., endophthalmitis, corneal decompensation, 
severe retinal detachment, severe choroidal hemorrhage, severe choroidal detachment, 
aqueous misdirection, etc., should be reported as an SAE if it meets one or more of the 
following criteria: 
• Resulted in permanent loss of sight and did not require medical or surgical 
intervention.  
• Required surgical intervention to prevent permanent loss of sight. 
• In the opinion of the investigator it may require medical intervention to prevent 
permanent loss of sight. 
D. 
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.  
E. 
ADVERSE EVENT ASSESSMENT AND DOCUMENTATION 
All subjects who have been exposed to the study treatment will be evaluated for 
adverse events.  All adverse events, regardless of severity and whether or not they are 
ascribed to the study treatment, will be recorded in the source documents and CRF 
using standard medical terminology.  During the post 24 month period (annual visits at 
3, 4 and 5 years), AEs will be reported in accordance with Table 5. 
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.  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 on the concomitant medication case 
report form.  
All AEs will be characterized by the following criteria: 
• Event term 

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• Severity 
• Expectedness 
• Relationship to study device or procedure 
• Outcome 
• 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 on the CRF 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). 
Adverse events occurring secondary to other events (e.g., sequelae) should be identified 
by the primary cause; a "primary" event, if clearly identifiable, should represent the 
most accurate clinical term to record as the AE event term. 
For example: 
Orthostatic hypotension  ⇒fainting and fall to floor ⇒head trauma ⇒neck pain 
The primary event is orthostatic hypotension and the sequelae are head trauma and neck 
pain. 
F. 
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. 

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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. 
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 
Section VIII.L. 
G. 
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 VIII.L. 
Unanticipated: 
An adverse event is unanticipated (i.e., unexpected) when 
the nature, severity, or degree of incidence was not 
previously described.  
H. 
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: 
• A clinically plausible temporal sequence is inconsistent with the onset of 
the AE and device or procedure; and/or 
• A causal relationship is considered biologically implausible; and 
• 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: 
• There is a clinically plausible time sequence between onset of the AE and 
study device or procedure; and/or 

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• There is a biologically plausible mechanism for study device or procedure 
causing or contributing to the AE; and 
• 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. 
I. 
OUTCOME 
The clinical outcome of an AE will be characterized as follows: 
• 
Resolved without sequelae 
• 
Resolved with sequelae (specify) 
• 
Ongoing (i.e. continuing at time of study discontinuation) 
• 
Death 
J. 
TREATMENT OR ACTION TAKEN 
• None 
• Medical Intervention  
• Surgical Intervention (includes device explantation) 
• Other 
K. 
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. 

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The Sponsor will be responsible for informing regulatory authorities and all other 
IRBs/ECs and Investigators participating in the study of the UADE. 
L. 
ANTICIPATED ADVERSE EVENTS 
Anticipated AEs associated with glaucoma and/or cataract 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 
Complications of cataract surgery 
• Anterior capsule tear 
• Posterior capsular rupture 
• Vitreous in the anterior chamber 
• Choroidal detachment 
Other complications 
• Hyphema obscuring the surgeon’s view 
• 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 1 month) 
• Choroidal detachment 
• Significant iris injury or trauma 
• Corneal abrasion 
• Corneal edema 
• Zonular dialysis 
• Cyclodialysis 
• Cyclodialysis cleft 
• Iridodialysis 
• Vitreous loss not associated with the cataract procedure 
• Inadvertent perforation of the sclera 
Postoperative adverse events include 
• Angle recession 
• Chronic pain in the study eye ≥ 3 months postoperative 
• Flat anterior chamber with lens/cornea touch or shallow anterior chamber with 
peripheral iridocorneal apposition 

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• Best-corrected visual acuity loss of 2 lines (10 letters) or more on the ETDRS 
chart measured at or after 3 months postoperative 
• Hypotony (defined as IOP < 6 mmHg) at or after 1 month postoperative 
• Maculopathy including hypotonic maculopathy 
• Descemet’s membrane detachment 
• Device migration (dislodgement or movement) 
• Device obstruction, partial or complete 
• Implant corneal touch 
• Inadvertent bleb 
• Scleral ectasia 
• Wound dehiscence (persistent aqueous leak or fistula formation) 
• Anterior chamber cell and 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 
• Peripheral anterior synechia (PAS) with device obstruction 
• Peripheral anterior synechia (PAS) without device obstruction 
• Endophthalmitis 
• Layered hyphema 
• Circulating blood in the AC and/or vitreous cavity  
• Corneal opacification 
• Corneal decompensation 
• Corneal edema persisting > 1 month (mild to moderate) or severe corneal edema 
≥ 1 day 
• Retinal complications (flap tears, retinal detachment, or proliferative 
vitreoretinopathy) 
• Elevated mean IOP ≥ 10 mmHg than the qualifying baseline mean IOP  
> 1 month postoperative 
• Surgical re-intervention in the study eye (other than paracentesis to relieve 
pressure prior to 1 week postoperative) 
• Atrophy, phthisis 
• Iris prolapse/wound incarceration 
• Significant foreign body sensation at or after 3 months postoperative 
• Increase in C/D ratio of ≥ 0.3 units on fundus examination 
• Worsening of visual field (mean deviation worsening by 2.5 dB or more, 
confirmed by 2 repeat measurements) 
• 2-point worsening to 4+ anterior chamber cells or flare at or after  
3 months postoperative, not associated with a pre-existing condition 

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• 2-point worsening to severe on the slit lamp or fundus examination findings 
(other than cells and flare) at or after 3 months postoperative not associated 
with a pre-existing condition 
• 2-point worsening of ocular symptoms to severe or very severe at or after 3 
months postoperative not associated with a pre-existing condition 
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, an ultrasound 
biomicroscope (UBM) should be performed. 
For slit lamp 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. 
9.0 
DEFINITIONS 
Iritis:  Presence of inflammatory cells in the anterior chamber.  The presence of aqueous 
flare alone is not considered to constitute iritis. 
Iridocyclitis:  Presence of inflammatory cells in both the aqueous and vitreous. 
Uveitis:  Inflammation in the uveal tract (iris, ciliary body, and choroid), either primary 
or secondary to keratitis or systemic diseases. 
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.  
Vitritis:  Presence of active inflammation in the vitreous, as demonstrated by the 
presence of inflammatory cells (trace or greater).  
• The presence of inflammation involving only the anterior vitreous will not be 
considered to constitute vitritis because it may result from iridocyclitis (see above). 
• Active inflammation in the vitreous should be clinically differentiated from cellular 
debris from prior episodes of inflammation, hemorrhage, or other causes. 
• 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. 

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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. 
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.