A Prospective, Multicenter, Randomized Comparison of the Hydrus Microstent to the iStent for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery
Phase: NA
Conditions: Primary Open Angle Glaucoma, Pseudoexfoliative Glaucoma, Pigmentary Dispersion Glaucoma
Sponsor: Ivantis, Inc.

Ivantis, Inc. – Confidential 
THE HYDRUS III TRIAL: 
A PROSPECTIVE, MULTICENTER, RANDOMIZED COMPARISON OF THE HYDRUSTM AQUEOUS 
IMPLANT TO THE ISTENT FOR LOWERING INTRAOCULAR PRESSURE IN GLAUCOMA 
SUBJECTS UNDERGOING CATARACT SURGERY 
INVESTIGATIONAL PLAN 
NCT02024464
PROTOCOL #: CP-10-002 
REVISION: C 
PROTOCOL VERSION DATE: July 22, 2013 
SPONSOR: 
Ivantis, Inc. 
38 Discovery, Suite 150 
Irvine, CA 92618 
Telephone: +1 949-600-9650 
Facsimile: +1 949-600-9651 

Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
Table of Contents 
PERSONNEL AND FACILITIES .................................................................................................. 4 
PROTOCOL SIGNATURE PAGE ................................................................................................. 5 
STUDY OUTLINE . ........................................................................................................................ 6 
1.0 
INTRODUCTION AND RATIONALE ........................................................................... 11 
2.0 
NONCLINICAL AND PRIOR CLINICAL TESTING OF THE HYDRUS IMPLANT . 13 
2.1 
Clinical Trial Results ....................................................................................................... 13 
2.2 
Description of Device...................................................................................................... 14 
2.3 
Pre-Clinical Testing of Hydrus Aqueous Implant (ISO 10993) ...................................... 18 
3.0 
STUDY OBJECTIVE ....................................................................................................... 19 
4.0 
STUDY DESIGN ............................................................................................................. 19 
5.0 
STUDY ENDPOINTS ...................................................................................................... 21 
6.0 
STATISTICAL METHODS ............................................................................................. 21 
6.1 
Study Hypothesis ............................................................................................................ 21 
6.2 
Sample Size ..................................................................................................................... 21 
6.3 
Safety Analysis ................................................................................................................ 21 
7.0 
STUDY POPULATION ................................................................................................... 22 
7.1 
Inclusion Criteria ............................................................................................................. 22 
7.2 
Intraoperative Inclusion Criteria ..................................................................................... 22 
7.3 
Exclusion Criteria ............................................................................................................ 23 
8.0 
STUDY PROCEDURES .................................................................................................. 23 
8.1 
Subject Entry, Consent and Enrollment .......................................................................... 23 
8.2 
Cataract Extraction and IOL Replacement ...................................................................... 25 
8.3 
Surgical Procedure .......................................................................................................... 25 
8.4 
Perioperative Medication ................................................................................................ 26 
8.5 
Device Inventory ............................................................................................................. 27 
8.6 
Study Visits and Examination Schedule ......................................................................... 27 
8.7 
Postoperative Ocular Hypotensive Medications ............................................................. 32 
8.8 
Treatment of the Fellow Eye ........................................................................................... 32 
8.9 
Subject Disposition ......................................................................................................... 32 
9.0 
ADVERSE EVENTS (AES) ............................................................................................ 33 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
9.1 
Protocol-defined Adverse Events .................................................................................... 33 
9.2 
Anticipated Adverse Events ............................................................................................ 33 
9.3 
Intraoperative Adverse Events ........................................................................................ 33 
9.4 
Postoperative Adverse Events ......................................................................................... 33 
9.5 
Recording and Reporting Adverse Events ...................................................................... 34 
9.6 
Grading of AEs ............................................................................................................... 35 
9.7 
Adverse Events Requiring Expedited Reporting ............................................................. 35 
9.8 
Unanticipated Adverse Device Effect (UADE) Reporting ............................................. 36 
9.9 
Regulatory Reporting of Adverse Events ........................................................................ 36 
10.0 
DEVICE FAILURE MALFUNCTION ............................................................................ 36 
11.0 
SOURCE DOCUMENTATION ....................................................................................... 37 
12.0 
DATA COLLECTION AND ANALYSIS ....................................................................... 37 
13.0 
STUDY MONITORING .................................................................................................. 37 
14.0 
RECORDS RETENTION ................................................................................................. 37 
REFERENCES……. ..................................................................................................................... 38 
APPENDIX 1: SCHEDULE OF EVENTS AND PROCEDURES ............................................... 40 
APPENDIX 2:  INFORMED CONSENT ..................................................................................... 41 
APPENDIX 3:  SPONSOR’S COMMITMENTS ......................................................................... 48 
APPENDIX 4:  INVESTIGATOR’S QUALIFICATIONS AND RESPONSIBILITIES ............. 49 
APPENDIX 5:  DECLARATION OF HELSINKI ........................................................................ 51 
 
 
 
 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
PERSONNEL AND FACILITIES 
 
STUDY SPONSOR 
IVANTIS, INC 
38 DISCOVERY, SUITE 150 
IRVINE, CA 92618 
PHONE:  +1-949-600-9650 
 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
PROTOCOL SIGNATURE PAGE 
 
Protocol Number: CP-10-002-C  (HYDRUS III STUDY) 
 
 
A Prospective, Multicenter, Randomized Comparison of the HydrusTM Implant to the iStent for 
Lowering Intraocular Pressure in Glaucoma Subjects Undergoing Cataract Surgery. 
 
I have read this protocol and agree to adhere to the requirements outlined within.  I will review 
and discuss pertinent material with study personnel and ensure they are fully informed of the 
requirements of this protocol.  I will also ensure that this study is conducted in compliance with 
this protocol, Good Clinical Practice (GCP), and any applicable local or national regulatory 
agencies and their requirements. 
 
 
______________________________________________ 
Clinical Trial Site Name and Site Number 
 
 
 
 
___________________________________________ 
Printed Name of Clinical Investigator 
 
 
 
 
___________________________________________ 
 
________________ 
Clinical Investigator Signature  
 
 
 
Date
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
 
 
STUDY OUTLINE 
 
 
Study Title: 
A Prospective, Multicenter, Randomized Comparison of the 
HydrusTM Aqueous Implant to the iStent for Lowering Intraocular 
Pressure in Glaucoma Subjects Undergoing Cataract Surgery 
(HYDRUS III Trial) 
 
Study Device: 
The CE-marked HydrusTM Aqueous Implant (Ivantis, Inc., Irvine 
CA) 
 
Control Device: 
The iStent Trabecular Micro Bypass (Glaukos Inc., Laguna Hills, 
CA) -- a CE-marked device for the study indication. 
 
Study Population: 
Subjects with mild to moderate Primary Open Angle Glaucoma 
(POAG), pseudoexfoliative glaucoma, or pigmentary glaucoma 
undergoing cataract surgery. 
Study Objective: 
Compare the effectiveness of the HydrusTM Aqueous Implant to the 
iStent for lowering intraocular pressure in glaucoma subjects 
undergoing cataract removal and intraocular lens implantation in 
the indicated study population. 
 
Study Design 
And Methods: 
A post-market, prospective, multicenter, randomized clinical trial in 
which potential study participants with a positive diagnosis of 
POAG, pseudoexfoliative glaucoma, or pigmentary glaucoma and 
cataract will be screened for eligibility.  If eligible criteria are met, 
the study participants will undergo a screening washout phase 
during which all glaucoma medications (topical and oral) will be 
discontinued.  
 
Following wash-out, the subjects will return and be evaluated for a 
fully-washed-out baseline diurnal intraocular pressure (IOP).  If the 
baseline IOP criterion is met, the subjects will be scheduled for 
cataract surgery and Intraocular Lens (IOL) placement.   
 
After successful cataract extraction and IOL placement, subjects 
will be randomized to receive either a single HydrusTM Aqueous 
Implant or iStent.   
 
Interim follow up visits will be conducted at 1, 7, and 30 days, and 
then at 3, 6, 12, 18 and 24 months where each subject’s IOP will be 
measured and ocular health will be evaluated.  The primary 
endpoint will be diurnal IOP at 12 months as measured by 
Goldmann tonometry, after wash out of any hypotensive glaucoma 
medications.  There will be a visit at Month 18 and the final study 
visit will occur at 24 months. 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
Number of  Sites: 
Up to eight clinical sites in Europe and one in South America. 
Selection Criteria: 
 
Ocular criteria relates to the study eye only. 
 
Inclusion Criteria: 
 
• 
Male and female subjects, from 21 to 84 years of age. 
• 
A diagnosis of primary open angle glaucoma (POAG), 
pseudoexfoliative glaucoma (PXG), or pigmentary 
dispersion glaucoma (PDG). 
 
 
   
 
 
   
• 
An operable age-related cataract with BCVA of 20/40 or 
worse, eligible for phacoemulsification.   
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Protocol CP-10-002-C 
July 22, 2013 
 
 
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. 
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Protocol CP-10-002-C 
July 22, 2013 
 
 
• 
Closed angle forms of glaucoma 
• 
Diagnosis of acute angle closure, traumatic, congenital, 
malignant, uveitis, or neovascular glaucoma. 
• 
Secondary (such as neovascular, uveitic, traumatic, steroid 
induced, lens induced, or glaucoma associated with 
increased episcleral venuous pressure), congenital, or 
developmental glaucoma.  
• 
Previous argon laser trabeculoplasty (ALT).  Selective laser 
trabeculoplasty (SLT) is allowed.  
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
1.0 INTRODUCTION AND RATIONALE   
Glaucoma is a collection of disorders characterized by progressive loss of visual fields due to 
optic nerve damage, and is the leading cause of blindness in the U.S., affecting 1-2% of 
individuals aged 60 and over.  Research has determined that the rate of primary open-angle 
glaucoma (POAG) – the most common form of glaucoma -- in the United States is at 2.2 million 
people.1  Based on that figure, it is estimated that between three and six million people in Europe,  
and approximately 3 million people in South America have elevated intraocular pressure and are 
at an increased risk for developing POAG.  POAG accounts for 90% of all cases of glaucoma.  It 
is a slow, progressive disease that produces no symptoms in its early stages.  Although the 
drainage system of the eye remains open and functions properly, the eye is unable to remove the 
excess fluid at a pace sufficient to prevent a rise in intraocular pressure (IOP).  Progressive vision 
loss tends to be painless, and subjects often present with advanced disease.   
 
Although there are many risk factors associated with the development of glaucoma (age, race, 
myopia, family history, and injury), elevated intraocular pressure is the only risk factor that can 
be successfully treated and that is correlated with the reduction of glaucomatous optic 
neuropathy.  Management of glaucoma requires chronic, lifelong treatment with a spectrum of 
therapeutic options including medications, laser treatment and microsurgical devices / implants, 
all with the therapeutic goal of lowering intraocular pressure to target levels in order to prevent 
loss of visual fields from excessive pressure on the optic nerve.  
 
Historically, first-line treatment for elevated intraocular pressure consists of medical therapy.  
Results of the Early Manifest Glaucoma Trial (EMGT),2 the Advanced Glaucoma Intervention 
Study (AGIS),3, 4 the Collaborative Initial Glaucoma Treatment Study (CIGTS),5 the Normal 
Tension Glaucoma Study (NTG),6 and the Ocular Hypertension Treatment Study (OHTS) 
indicate that topical ocular hypotensive medication is effective in reducing intraocular pressure 
and thus delaying or preventing the progression of POAG.7 
 
Several major pharmacologic classes of therapeutic agents are used in the treatment of glaucoma.  
The mechanism of action consists of either decreasing aqueous fluid production in the ciliary 
epithelium, improving aqueous outflow via the trabecular meshwork (responsible for 80% of 
normal outflow) or the uveoscleral route (20%), or a combination of these methods.   
 
While currently available glaucoma medications are generally effective, these drugs are not 
without side effects.  Approximately 5% to 15% of subjects on prostaglandin analogues 
experience ocular side effects such as hypertrichosis, iris pigmentation, conjunctival hyperemia, 
and darkening of the periocular skin.  These side effects may serve to further discourage subjects 
from adhering to the dosing regimen.  Close to 60% of latanoprost monotherapy subjects 
experienced adverse events, at a rate of 1.7 events per subject, and 20% of subjects who 
discontinue latanoprost within first 24 months of treatment cite adverse events as the reason for 
discontinuation.8  This rate increased to 1.9 with addition of a beta-blocker and to 2.4 with 
brimonidine plus a beta-blocker. Adverse events associated with glaucoma medications included 
toxicity, allergic response, bronchospasm, cardiac failure, depression, impotence.  
 
In the face of the complexity of therapeutic regimens, the chronic use of multiple medications, the 
need for frequent daily administration, the presence of side effects and the chronic asymptomatic 
nature of POAG, subjects often do not take their medication consistently.  This presents the 
physician with a significant problem of subject non-compliance. 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
In a comprehensive review of 76 studies published between 1986-2000, mean drug compliance 
was found to be approximately 71% (S.D. 17%, range 34%-97%) and declined as the number of 
daily doses increased.9  Approximately 12% of glaucoma patients on once or twice daily dosing 
regimens reported missing a significant number of doses.10  Patients often underestimate their 
level of defaulting when questioned.  In a study using a pilocarpine eye drop monitor, on average, 
patients administered 76% of their eye drops, but reported taking 97% of the required dosage.11  
Patients often take their medication as prescribed on the day of a visit to the doctor, but when 
asked, admit to not taking their medication on a regular basis.  A study examining compliance 
with timolol found that non-complaint patients went a mean of 85 days per year without 
medication, with a maximum of 165 days.12    
 
The ability to administer eye drops, particularly in the elderly, and understanding of the disease 
and treatment are also important factors.  Brown et al (1984) found that even in patients 
experienced in the use of topical eye drops, 13% were unable to instill topical medications into 
both eyes successfully despite multiple attempts.13  Therefore, when combining all of the factors 
that can affect proper administration of glaucoma medication, the adherence to therapy factor is 
only 60.5% (79% prescription refilled, drops are instilled correctly 87% of the time, and patients 
administer the medication in a timely fashion 88% of the time).   
 
Finally, it is known that long-term topical therapy engenders local conditions which may 
adversely affect the outcome of possible future filtration surgery.  Because glaucoma requires 
lifelong management, there is a concern that prolonged use of medications may ultimately reduce 
sight saving therapeutic options.14  
 
These limitations of glaucoma medications, and the need for continuous long-term follow-up in 
order to prevent glaucoma progression of glaucoma and potential vision loss, have led to interest 
in the use of glaucoma implants.  Since open-angle glaucoma and cataracts are present with 
increasing frequency in older patients, and these conditions co-exist in an estimated 20% of 
cataract surgery patients (CMS published data), the ability to implant a glaucoma device during 
scheduled cataract surgery offers a unique opportunity for concurrent placement of a glaucoma 
implant without the risk of an additional intraocular surgical procedure.  Implantation of a 
glaucoma device designed to provide additional lowering of IOP can mitigate issues of drug 
compliance in elderly glaucoma patients with the continuous treatment offered by an implant.  An 
example of one such implant that has been CE marked and licensed (#80214) in Canada is the 
iStent® Trabecular Micro-Bypass Stent (Glaukos Corporation, Laguna Hills, CA. Model GTS 
100L/R).  The operating principle of this device is to provide a conduit for aqueous humor 
through the trabecular meshwork, thereby increasing aqueous flow. 
 
Ivantis has developed the HydrusTM Aqueous Implant for the purpose of decreasing IOP.  The 
Hydrus provides a conduit through the trabecular meshwork and also scaffolds Schlemm's canal, 
the aqueous collector channel that surrounds the eye.  The implanted Hydrus serves to both 
maintain or dilate Schlemm's canal and provide an opening through the trabecular meshwork to 
restore the natural outflow pathway of the eye. This dual function may improve IOP reduction 
compared to the iStent. 
 
On 26 May 2011, the HydrusTM Aqueous Implant was granted CE Mark by the National Standards 
of Authority of Ireland (CE 0050) for the reduction of IOP in POAG subjects. 
 
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Protocol CP-10-002-C 
July 22, 2013 
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Protocol CP-10-002-C 
July 22, 2013 
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Protocol CP-10-002-C 
July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
3.0 STUDY OBJECTIVE  
The objective of this clinical trial is to compare the effectiveness of the HydrusTM Implant to the 
iStent for lowering intraocular pressure (IOP) in glaucoma subjects undergoing cataract removal 
and intraocular lens implantation. 
4.0 STUDY DESIGN 
This study is a post-market prospective, randomized, controlled, multicenter clinical trial in 
which a total of approximately 150 subjects will be randomized after successful cataract surgery 
to receive either the Hydrus Implant or the iStent.  Potential study participants will be consented, 
at which time they will undergo screening criteria for eligibility.  If eligibility criteria are met 
after initial screening, the study participants will undergo a screening washout phase during 
which all glaucoma medications (topical and oral) will be discontinued; the duration of the wash-
out phase to be determined by the specific medication(s) used by the subjects.  Following wash-
out, the subjects will return for a baseline evaluation, and if found to continue to meet the 
eligibility requirements, and agree to participate, will be scheduled for cataract surgery, 
randomized, and followed up at specified intervals for a 2 year period. The study schema is 
presented in Figure 4. 
 
Of the two eye implants being used in this study, the HydrusTM Aqueous Implant (the test article) 
is currently CE marked for use in the EU countries.  It is intended for the reduction of intraocular 
pressure (IOP) in subjects with primary open angle glaucoma (POAG), pseudoexfoliative 
glaucoma, or pigmentary glaucoma as a stand-alone treatment or in conjunction with cataract 
surgery. The iStent (the control article) is currently CE marked for use in the EU countries.  It is 
intended for the reduction of IOP in POAG subjects with concurrent cataract or in stand-alone 
treatment, and is thus considered a suitable control.  
 
In the event a study subject does not respond to device therapy, hypotensive glaucoma 
medications may need to be prescribed during the follow up period to reduce IOP to a safe level, 
at the discretion of the attending physician.  To address the confounding effect of medications on 
the assessment of the devices’ ability to reduce IOP, a "wash-out" of all glaucoma medications 
will be conducted prior to the 12 and 24 month follow-up visits.  
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
      Figure 4: Study Schema
 
Screening & Consent 
Wash Out 
Safety Visit (optional) 
Baseline 
IOP 
22 - 36? 
Cataract Surgery 
Exit Study  
Hydrus N=75 
iStent N=75 
On  
Meds?
IOP Check & Wash Out 
Diurnal IOP  
(End of study at 24M) 
24 M Visit 
1d, 7d, 30d,  
3M & 6M Follow Up 
No 
Yes 
Yes 
No 
12 M Visit  
Randomize 1:1  
18 M Visit 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
7.3 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 
• 
Diagnosis of acute angle closure, traumatic, congenital, malignant, uveitis, or 
neovascular glaucoma. 
• 
Secondary (such as neovascular, uveitic, traumatic, steroid induced, lens induced, or 
glaucoma associated with increased episcleral venuous pressure), congenital, or 
developmental glaucoma.  
• 
Previous argon laser trabeculoplasty (ALT).  Selective laser trabeculoplasty (SLT) is 
allowed   
8.0 STUDY PROCEDURES 
8.1 Subject Entry, Consent and Enrollment  
Participants will be recruited from the Investigators’ subject population or referrals.  
Subjects that appear to be eligible subjects will be approached for study participation and 
sign a subject informed consent (PIC) prior to the commencement of study related 
procedures.  The investigator or designee will explain the study purpose, procedures, and 
subject responsibilities to the potential participant.  The subject shall be given the 
opportunity to ask questions and allowed time to consider the information provided.  The 
subject’s willingness and ability to meet the follow-up requirements will be determined.  
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
2. Place gonioprism lens on the eye to establish a view of the angle. Use ophthalmic 
viscosurgical device (OVD) as a coupling agent. Verify angle structures including 
scleral spur and trabecular meshwork to determine target location.  Remove 
gonioprism lens. 
3. The corneal incision must be located four clock hours clockwise from the target 
location for right-handed access (opposite for left-handed access).  If the corneal 
incision used for the cataract procedure is not viable for the introduction of the Hydrus 
Implant, make an additional 1.5mm incision in the corneal limbus.  Use an oblique 
incision angled toward the target location. 
4. Inject Healon GV or similar OVD into the anterior chamber unless similar OVD 
remains from cataract procedure.  Verify eye is firm but do not overinflate.   
5. Remove the Hydrus delivery device from the packaging and adjust the cannula 
orientation for proper hand position. 
6. Advance Hydrus Implant slightly out of the cannula, dip in OVD and retract implant 
back into cannula. 
7. Insert cannula through corneal incision, keeping needle curve parallel to iris to prevent 
touching iris, lens or cornea when passing across the anterior chamber.   
8. Replace gonioprism lens on cornea to establish view of anterior chamber angle and 
Hydrus cannula tip. 
9. Pierce the trabecular meshwork by aiming the cannula tip slightly uphill toward the 
pigment.  After piercing, the cannula tip should slide gently into Schlemm’s canal.  
10. Advance the device slowly by rolling the advancement wheel.  If resistance is felt, 
stop advancement, retract if necessary and readjust the cannula. 
11. Visually confirm Hydrus implant windows entering the canal.  The windows should 
be visible during advancement.  
12. When advancement is complete, roll wheel backwards to remove core. 
13. After core is removed, disengage the delivery system from the implant by slowly 
moving the cannula tip away from the canal and remove the cannula from the eye. 
14. Verify inlet placement and adjust if necessary using a Sinskey hook. 
15. Irrigate and aspirate the OVD from the anterior segment completely. 
16. Close the corneal incision per normal practice and verify eye is re-pressurized. 
8.4 Perioperative Medication 
A topical antibiotic and a topical steroid will be administered after surgery. The following 
dosing regimen is recommended: 
 
1. Moxifloxacin 0.5% (Vigamox®), one drop four times per day commencing the 
day of the procedure and continued for one week postoperatively. 
2. Prednisolone acetate 1.0% (Pred Forte®), one drop four times per day for one 
week; followed by one drop three times per day for one week; followed by one 
drop two times per day for one week; followed by one drop once per day for one 
week, then discontinue.  
 
Medication to treat transient post-operative spikes in IOP resulting from the use of 
viscoelastic and surgical manipulation may be required in the immediate postoperative 
period.  
 
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Protocol CP-10-002-C 
July 22, 2013 
 
8.5 Device Inventory 
Each Hydrus Implant will be traceable via lot number. Lot numbers will be assigned 
according to date of manufacture and/or sterilization.  Records of device shipments will be 
maintained at the Ivantis, Inc. facility in accordance with Ivantis Inc.’s Quality System and 
internal procedures.  As only Hydrus Implant devices with CE mark clearance will be used 
in this study, device accountability records will not be required by the site.   
8.6 Study Visits and Examination Schedule 
All subjects will participate in defined follow-up visits through 24 months.  A Case Report 
Form (CRF) shall be completed for each scheduled exam.  Unscheduled or interim visits 
should also be recorded using the appropriate CRF.  
 
Screening Visit 
 
The subject must sign a subject informed consent prior to the commencement of any study 
related procedures.  Initial eligibility will be determined at the Screening Visit.  If the 
screening criteria are met, the subject will be considered enrolled in the study and will be 
instructed to discontinue the use of ocular hypotensive medications, according to Table 2, 
prior to returning for the Baseline Exam.  Subjects not using an ocular hypotensive 
medication may be scheduled for the Baseline Exam up to 45 days after completing the 
Screening Exam.  Ineligible subjects will be exited from the study.  The reason for exit 
will be documented on the Study Summary Form for each enrolled subject.  
 
The following information will be captured at this visit: 
• 
Signed subject informed consent (if not done previously) 
• 
Demographic information, medical history and ocular medications  
• 
Bilateral best corrected visual acuity (Snellen) 
• 
Bilateral manifest refraction 
• 
Bilateral Humphrey 24-2 SITA standard visual field (All required visual fields 
will be obtained with a Humphrey automated perimeter using the 24-2 SITA 
standard threshold strategy.)   
• 
Bilateral slit lamp biomicroscopy  
• 
Bilateral IOP with Goldmann tonometer  
NOTE: Any time IOP is performed, two measurements should be obtained for 
each IOP measurement; if these values are within ± 2 mmHg of one another, the 
mean of these two readings will be recorded on the CRF. If the first two 
measurements differ by more than 2 mmHg, a third measurement will be 
performed, and the median of the three measurements will be used. 
• 
Bilateral dilated fundus examination and C:D ratio assessment Gonioscopy in the 
study eye (including Shaffer grading for all 4 quadrants)  
• 
Bilateral central corneal pachymetry 
Safety Visit 
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Protocol CP-10-002-C 
July 22, 2013 
 
Between the screening visit and the baseline visit, the subject’s IOP status may be checked 
at the discretion of the investigator.  Data from this visit will not be collected unless an 
adverse event occurs. If during the washout period, the subject experiences an IOP spike 
of > 36 mmHg requiring the use of hypotensive medication or surgical intervention, the 
subject will be exited from the study. 
 
Baseline 
 
The Baseline visit is performed following glaucoma medication wash-out, to confirm 
subject eligibility after medications are discontinued.  The following information will be 
captured at this visit: 
 
• 
Bilateral assessment of any changes in ocular medical history and medications 
• 
Bilateral manifest refraction  
• 
Bilateral ETDRS best-corrected visual acuity  
• 
Bilateral slit lamp biomicroscopyNon-diurnal Goldmann tonometry, fellow eye 
only 
• 
Diurnal Goldmann tonometry, study eye only, taken at 3 time points:   
o Time 1:  8:00 AM (± 1 hour) 
o Time 2:  4 hours later (± 1 hour) than Time 1  
o Time 3:  4 hours later (± 1 hour) than Time 2.   
Mean diurnal IOP will be computed from the three IOP time points.  The mean diurnal 
IOP must be ≥ 22 and ≤ 36 mmHg in order to qualify for the study. 
 
Operative 
 
Surgery will be scheduled after the subject successfully completes the baseline exam, but 
not more than 60 days after the date of the baseline exam.  In the period between the 
baseline visit and the surgery date, the patient may be re-started on hypotensive 
medications after determination of the washed out diurnal IOP.   
The following information will be collected at this visit: 
 
• 
Randomization assignment 
• 
Type of anesthesia  
• 
 
• 
Clock hour location of Hydrus insertion  
• 
Viscoelastic used  
• 
Surgical complications  
• 
Intraoperative adverse events (AEs)  
 
1 Day Postoperative 
 
This visit must occur on the first day postoperatively. The following information will be 
captured at this visit: 
• 
Ocular medications   
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Protocol CP-10-002-C 
July 22, 2013 
 
• 
Pinhole visual acuity  
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry at 8:00 AM ± 1 hour 
• 
Adverse events. 
 
1 Week Postoperative (7 ± 2 days) 
  
The following information will be captured for the study eye, unless otherwise noted, at 
this visit: 
 
• 
Ocular medications 
• 
Manifest refraction  
• 
ETDRS BCVA 
• 
Slit lamp biomicroscopy 
• 
Goldmann tonometry at 8:00 AM ± 1 hour 
• 
Gonioscopy 
• 
Adverse events. 
 
1 Month Postoperative (30 ± 7 days) 
 
The following information will be captured for the study eye, unless otherwise noted, at 
this visit: 
 
• 
Ocular medications 
• 
Manifest refraction  
• 
ETDRS BCVA 
• 
Goldmann tonometry at 8:00 AM ± 1 hour 
• 
Slit lamp biomicroscopy 
• 
Gonioscopy  
• 
Adverse events. 
 
3 Months Postoperative (90 ± 14 days) 
 
The following information will be captured for the study eye at this visit: 
 
• 
Ocular medications 
• 
Manifest refraction  
• 
ETDRS BCVA 
• 
Humphrey 24-2 SITA standard visual field  
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry at 8:00 AM ± 1 hour 
• 
Fundus examination and C:D ratio assessment 
• 
Gonioscopy  
• 
Adverse events 
 
6 Months Postoperative (180 ± 21 days) 
 
 
The following information will be captured for the study eye, unless otherwise noted, at 
this visit: 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
 
• 
Ocular medications 
• 
Manifest refraction  
• 
ETDRS BCVA 
• 
Humphrey 24-2 SITA standard visual field  
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry at 8:00 AM ± 1 hour 
• 
Fundus examination and C:D ratio assessment 
• 
Gonioscopy  
• 
Adverse events. 
 
12 Months Postoperative (365 ± 45 days) 
 
The following information will be captured at this visit: 
 
• 
Ocular medications 
• 
Bilateral manifest refraction  
• 
Bilateral ETDRS BCVA 
• 
Bilateral Humphrey 24-2 SITA standard visual field   
• 
Bilateral slit lamp biomicroscopy Non-diurnal Goldmann tonometry, fellow eye 
only, at 8:00 AM ± 1 hour 
• 
Diurnal Goldmann tonometry, study eye only, – taken at 3 intervals:   
o Time 1:  8:00 AM (± 1 hour) 
o Time 2:  4 hours later (± 1 hour) from Time 1  
o Time 3:  4 hours later (± 1 hour) from Time 2   
NOTE:   
 If the subject is not on medications in the study eye, then a diurnal 
measurement may be taken for the study eye at this visit.   
 If the subject is on medications in the study eye, the subject’s IOP 
should be checked at a single time period, and if appropriate, begin 
wash out of medications in the study eye according to Table 2.  After 
the appropriate time period, a diurnal IOP should be obtained for the 
study eye.    
 All IOP measurements must be performed within the Month 12 
protocol specified window.  
 If the principal investigator deems wash out inappropriate due to safety 
reasons, a clinical justification must be documented on the appropriate 
case report form. 
• 
Bilateral dilated fundus examination and C:D ratio assessment 
• 
Gonioscopy for study eye  
• 
Bilateral central corneal pachymetry 
• 
Adverse events 
 
18 Months Postoperative (540 ± 28 days) 
 
 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
The following information will be captured for the study eye, unless otherwise noted, at 
this visit: 
 
• 
Ocular medications 
• 
Manifest refraction  
• 
ETDRS BCVA 
• 
Slit lamp biomicroscopy  
• 
Goldmann tonometry 
• 
Dilated fundus examination and C:D ratio assessment 
• 
Gonioscopy  
• 
Adverse events. 
 
24 Months Postoperative (730 ± 45 days) 
 
The following information will be captured at this visit: 
 
• 
Ocular medications 
• 
Bilateral manifest refraction  
• 
Bilateral ETDRS BCVA 
• 
Bilateral Humphrey 24-2 SITA standard visual field  
• 
Bilateral slit lamp biomicroscopy 
• 
Non-diurnal Goldmann tonometry, fellow eye only, at 8:00 AM ± 1 hour 
• 
Diurnal Goldmann tonometry, study eye only, taken at 3 intervals:   
o Time 1:  8:00 AM (± 1 hour) 
o Time 2:  4 hours later (± 1 hour) from Time 1  
o Time 3:  4 hours later (± 1 hour) from Time 2   
NOTE:   
 If the subject is not on medications in the study eye, then a diurnal 
measurement may be taken for the study eye at this visit.   
 If the subject is on medications in the study eye, the subject’s IOP 
should be checked at a single time period, and if appropriate, begin 
wash out of medications in the study eye according to Table 2.  After 
the appropriate time period, a diurnal IOP should be obtained for the 
study eye.    
 All IOP measurements must be performed within the Month 24 
protocol specified window.  
 If the principal investigator deems wash out inappropriate due to safety 
reasons, a clinical justification must be documented on the appropriate 
case report form. 
• 
Bilateral dilated fundus examination and C:D ratio assessment 
• 
Gonioscopy for study eye  
• 
Bilateral central corneal pachymetry  
• 
Adverse events. 
  
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
The procedures associated with each study visit are outlined and summarized in Appendix 
1 (Schedule of Events and Procedures).  
 
Unscheduled Visits 
Any visit to the clinical site, other than those specified in the protocol, will be documented 
as an unscheduled visit.  Examples of unscheduled visits may include a subject complaint 
regarding the study eye and/or treatment to the study eye is required or changed, or any 
other visit deemed necessary at the discretion of the clinician.  The Investigator and/or 
qualified investigational staff will perform the procedures necessary to evaluate the study 
participant at these visits, and will record the visit in the subject’s chart and on an interim 
CRF.  No specific testing is required at interim visit.   
8.7 Postoperative Ocular Hypotensive Medications 
Since the study population is undergoing cataract surgery involving use of an ophthalmic 
viscoelastic agent and post-operative steroids, both of which are known to cause IOP 
elevation, use of glaucoma medications in the first month after surgery is expected in some 
cases. In these cases, additional visits may be performed to assess IOP, and medications 
discontinued if the subject’s condition allows. 
 
Long-term medical therapy may be implemented or additional surgical measures may be 
performed at any time during the study at the Investigator’s discretion in the event it is 
required.  The primary concern of the Investigator and Sponsor at all times is the health 
and safety of the subjects.   
 
A record of all medications added, discontinued or changed will be documented on the 
appropriate Case Report Form for each scheduled visit or on a Case Report Form for an 
Unscheduled (Interim) Visit, if necessary. 
8.8 Treatment of the Fellow Eye 
The fellow eye should be treated within the site’s standard of care.  Any enrolled subject – 
regardless of randomization assignment – may receive CE-marked Hydrus Implant 
treatment as part of the standard of care to the fellow eye in conjunction with planned IOL 
implantation – following initial randomization and treatment of the assigned eye in the 
study.     
8.9 Subject Disposition  
Subjects may be terminated (exited) from the study early due to: 
• Screening failure, 
• A threat to the subject’s health emerges in the course of following study 
procedures, 
• Inability to continue with the study, and 
• Voluntary withdrawal. 
 
Subjects who are terminated due to screen failure will not be followed beyond the date of 
screen failure.  For safety reasons, randomized subjects who are terminated shall be 
followed until the planned end of study period.  Terminated subjects will not be replaced.   
Notification of a subject’s early termination should be made immediately to the sponsor 
and documented on the appropriate CRF.    
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
 
Completed subjects are those subjects who have not been terminated from the study prior 
to completion of follow up. 
 
9.0 ADVERSE EVENTS (AE) 
All medical events, treatments and outcomes will be recorded in the subject’s chart as per the 
site’s routine medical practice but not all untoward medical events will be collected on the CRFs.  
9.1 Protocol-defined Adverse Events 
Adverse events as defined in this protocol include all ocular adverse events (AE) in the study eye.  
These events must be reported on the adverse event CRF.  The Investigator must categorize each 
AE by degree of harm to the subject (mild, moderate, or severe), and the relationship to study 
device and implantation procedure (not related, possibly, probably, or definitely).  Since there are 
no aspects of the study that can affect both eyes, only serious adverse events observed in the 
fellow eye will be captured on the case report form throughout the course of the study.   
 
Ocular conditions or diseases that are chronic but stable and meet the inclusion and exclusion 
criteria should be recorded on the screening CRF under Ocular History.  Changes in any chronic 
condition or disease that are consistent with natural disease progression are not considered AEs 
and will not be recorded on an AE CRF. 
 
9.2 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: 
 
9.3 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 
• 
Significant iris injury or trauma 
• 
Corneal edema 
• 
Zonular dialysis 
 
9.4 Postoperative Adverse Events 
Postoperative adverse events include: 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
• 
Chronic pain in the study eye >3 months postoperative 
• 
Flat anterior chamber with lens/cornea touch or with iridocorneal apposition without 
lens/cornea touch >1 month postoperative 
• 
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 
• 
Device obstructed by iris, vitreous, lens, fibrous overgrowth, fibrin, or blood 
• 
Device explantation 
• 
Device malposition, dislodgement or movement 
• 
Wound dehiscence (persistent aqueous leak or fistula formation) 
• 
Inflammation (defined as any inflammation requiring treatment with topical, sub-
Tenon’s or systemic anti-inflammatory medication) lasting longer than 1 month 
• 
Endophthalmitis 
• 
Persistent hyphema of  > 2 mm present > 1 week postoperative 
• 
Corneal opacification 
• 
Corneal decompensation 
• 
Corneal edema persisting > 1 month (mild to moderate corneal edema prior to 1 
month postoperative is not considered an adverse event) 
• 
Retinal complications (flap tears, retinal detachment, or proliferative 
vitreoretinopathy) 
• 
Elevated mean IOP ≥ 10 mmHg than the qualifying baseline mean IOP > 1 month 
postoperative 
• 
Events resulting in an unplanned ocular surgical reintervention (other than 
paracentesis to relieve pressure prior to 1 week postoperative)   
• 
Phthisis 
• 
Significant foreign body sensation at or after 3 months postoperative 
• 
A change in C/D ratio of ≥ 0.3 units on slit lamp biomicroscopic examination 
• 
Peripheral anterior synechia  
• 
A 2-point worsening to 4+ anterior chamber cells or flare at or after 3 months 
postoperative, not associated with a pre-existing condition 
• 
A 2-point worsening to severe on the slit lamp examination findings (other than cells 
and flare) at or after 3 months postoperative not associated with a pre-existing 
condition 
• 
A 2-point worsening of ocular symptoms to severe or very severe at or after 3 months 
postoperative not associated with a pre-existing condition 
9.5 Recording and Reporting Adverse Events 
To improve the quality and precision of acquired AE data, Investigators should observe the 
following guidelines: 
 
• 
Whenever possible, use recognized medical terms when recording AEs on the AE 
CRF.   Do not use colloquialisms and/or abbreviations. 
• 
For the purposes of reporting infection/inflammation, the following terms and 
definitions should be used: 
 
Iritis: 
Presence of inflammatory cells in the anterior chamber, with or 
without anterior vitreous inflammation.   
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
• 
The presence of aqueous flare alone will not be considered 
to constitute iritis.   
• 
For the purposes of this protocol, the term "iritis" will 
encompass both cases of iritis without anterior vitreous 
inflammation (iritis) and those with anterior vitreous 
inflammation (iridocyclitis). 
 
Iridocyclitis: 
Presence of inflammatory cells in both the aqueous and vitreous. 
 
Vitritis:   
Presence of active inflammation in the vitreous, as demonstrated 
by the presence of inflammatory cells (trace or greater) involving the 
mid-vitreous cavity. 
• 
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. 
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. 
 
 
 
9.6 Grading of AEs 
AEs are to be graded on a three-point scale (mild, moderate, severe) and reported in detail 
on the appropriate AE CRF.  The definitions are as follows: 
• 
Mild:  Discomfort noticed but no disruption of normal daily activity 
• 
Moderate:  Discomfort sufficient to reduce or affect normal daily activity 
• 
Severe:  Incapacitating with inability to work or perform normal daily activity, 
and any event resulting in death or requiring rehospitalization. 
 
9.7 Adverse Events Requiring Expedited Reporting 
Investigators must report any events that meet any one of the following criteria to Ivantis within 48 
hours of observing or learning of the event: 
• 
Any adverse event with an outcome of death or blindness. 
• 
Any Serious Adverse Event (SAE) that is device or procedure related. 
• 
Any unanticipated adverse device effect (UADE), also called an unanticipated device-
related adverse event. 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
For these expedited event reports, investigators should record all case details that can be gathered 
within 48 hours on the SAE page of the CRF.   
 
An AE should be classified as an SAE and reported as such if it meets one or more of the following 
criteria: 
• 
Caused or led to death 
• 
Life threatening 
• 
Required or prolonged inpatient hospitalization 
• 
Site threatening 
• 
Disabling (i.e., the AE resulted in substantial disruption of the subject’s ability to carry out 
normal life functions) 
• 
Resulted in congenital anomaly/birth defect 
• 
Does not meet any of the above serious criteria but may jeopardize the subject or requires   
medical or surgical intervention to prevent one of the outcomes listed above. 
 
9.8 Unanticipated Adverse Device Effect (UADE) Reporting 
An Unanticipated Adverse Device Effect (UADE) means any serious adverse effect (as 
defined above) 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), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects. 
 
Any UADE must be reported by phone or fax to the Sponsor within 24 hours of 
knowledge of that event. The Sponsor will be responsible for informing regulatory 
authorities and all other IRBs and Investigators participating in the study of the UADE.    
 
9.9 
Regulatory Reporting of Adverse Events 
Clinical sites are responsible for the reporting of adverse events to their Ethics 
Committee (EC) in alignment with local EC requirements.  As the study sponsor, Ivantis, 
Inc. will be responsible for required adverse event reporting to all appropriate Regulatory 
Authorities within reporting requirements. 
 
10.0 
DEVICE FAILURE MALFUNCTION 
The following definitions clarify device failure and device malfunction: 
 
Device Failure:  a device failure has occurred when the cannula is withdrawn without 
implantation after an attempted deployment (advancement wheel utilized). 
 
Device Malfunction: a device malfunction has occurred if the device does not operate 
according to the Instructions for Use (IFU). 
 
Should there be a serious adverse event associated with a device failure/malfunction, notify the 
Sponsor within 48 hours. 
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Ivantis, Inc. – Confidential 
 
Protocol CP-10-002-C 
July 22, 2013 
 
 
Product complaints should be reported to Ivantis, Inc. through the usual Product Complaint 
Handling system, and the suspect device should be returned to Ivantis, Inc. 
 
11.0 
SOURCE DOCUMENTATION 
Any information collected at the time of the subject visit is considered source documentation.  In 
order for information to be considered as a source document (e.g., chart notes, visual field 
printouts Nerve Fiber Imaging printouts, etc.), it should be part of the subject’s permanent 
medical record.   
12.0 
DATA COLLECTION AND ANALYSIS  
13.0 
CASE REPORT FORMS WILL BE PROVIDED TO THE CLINICAL SITES BY 
THE SPONSOR.  SITE CLINICAL RESEARCH COORDINATORS OR 
INVESTIGATORS WILL TRANSFER DATA FROM SOURCE DOCUMENTS 
TO THE CASE REPORT FORMS.  IVANTIS WILL PROVIDE EACH STUDY 
SITE WITH A STUDY MANUAL AND TRAINING ON DATA COLLECTION.  
STUDY MONITORING  
Ivantis personnel (or their representative/designee) will monitor this clinical study in a manner 
consistent with applicable health authority regulations. 
 
1. 
Ivantis personnel/designee may meet with investigator(s) prior to the initiation of the 
study in order to review the adequacy of the subject population, facilities, and 
equipment with respect to the needs of the study, and to familiarize the investigator 
with the study protocol. 
2. 
Ivantis personnel/designee may meet with the investigator(s) to perform a site 
initiation visit in which this visit may be at the time study subjects begin to be 
enrolled.  This visit is to ensure that study is ready to begin, subjects are being 
properly selected, and that study data are being correctly recorded. 
3. 
Interim monitoring visits and telephone consultation will occur as necessary during 
the course of the study to ensure the proper progress and documentation of the study 
findings 
4. 
Ivantis personnel/designee may visit the clinical site when all subjects have 
completed the final visit of the study to collect the Case Report Forms, source 
documents, and any other required documents in order to closing out the site. 
 
14.0 
RECORDS RETENTION 
Investigational sites must keep all records (case report forms, regulatory binder, subject records, 
source documentation) pertaining to the Ivantis clinical investigation for either a period of at least 
two years after the trial is complete, or as long as local regulatory requirements dictate.  Ivantis 
will make arrangements for storage of records at the request of the investigator.
Protocol #: CP-10-002, Rev. C July 22, 2013 
 
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Protocol CP-10-002-C 
July 22, 2013 
 
 
 
 
 
 
 
 
REFERENCES 
 
1. 
Friedman DS, Wolfs RC, O'Colmain BJ, et al.  Prevalence of open-angle glaucoma among 
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Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Reduction of intraocular 
pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch 
Ophthalmol 2002; 120:1268-1279. 
 
3. 
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of 
intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol 
2000; 130:429-440. 
 
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The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison of glaucoma outcomes in 
black and white subjects within treatment groups. Am J Ophthalmol 2001; 132:311-320. 
 
5. 
Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative 
Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or 
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6. 
Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous 
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therapeutically reduced intraocular pressures. Am J Ophthalmol 1998; 126:487-497. 
 
7. 
Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a 
randomized trial determines that topical ocular hypotensive medication delays or prevents the 
onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120:701-713. 
 
8. 
Hedman K, Watson PG, Alm A. The effect of latanoprost on intraocular pressure during 2 years 
of treatment. Surv Ophthalmol 2002; 47 (Suppl 1):S65-S76. 
 
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Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose 
regimens and medication compliance. Clin Ther 2001; 23:1296-1310. 
 
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Konstas AGP, Maskaleris G, Gratsonidis S, Sardelli C. Compliance and viewpoint of glaucoma 
subjects in Greece. Eye 2000; 5:752-6. 
 
11. 
The Glaucomas. In: Ritch R SM, Krupin T, ed. St. Louis, MO: CV Mosby and Co., 1989:199-
218, 827. 
 
12. 
Rotchford AP, Murphy KM. Compliance with timolol treatment in glaucoma. 1998; 12:234-6. 
 
13. 
Brown MM, Brown GC, Spaeth GL. Improper topical self-administration of ocular medication 
among subjects with glaucoma. Canadian Journal of Ophthalmology 1984; 19:2-5. 
 
14. 
Hejkal TW, Camras CB. Prostaglandin analogs in the treatment of glaucoma. Semin 
Ophthalmol 1999; 14:114-123. 
 
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July 22, 2013 
 
 
 
 
 
 
 
 
 
15.  
Cutright DE, Bhaskar SN, Perez B, et al.  Tissue Reaction to Nitinol Wire Alloy.  Oral Surg 
Oral Med Oral Pathol 1973; 35:578-584 
 
16. 
Castleman LS, Motzkin SM, Alicandri FP, et al.  Biocompatibility of Nitinol Alloy as an 
Implant Material.  J Biomed Mater Res 1976; 10:695-731. 
 
17. 
Kapanen A, Ryhanen J, Danilov A, et al.  Effect of Nickel-Titanium Shape Memory Metal 
Alloy on Bone Formation.  Biomaterials 2001; 22:2475-2480. 
 
18.  
Cho L, Roffi M, Mukherjee D, et al.  Superficial Femoral Artery Occlusion:  Nitinol Stents 
Achieve Better Flow and Reduce the Need for Medications Than Balloon Angioplasty Alone.  J 
Invasive Cardiol 2003;15:198-200. 
 
19. 
Riccioni ME, Shah SK, Tringali A, et al.  Endoscopic Palliation of Unresectable Malignant 
Oesophageal Strictures with Self-Expanding Metal Stents:  Comparing Ultraflex and 
Esophacoil Stents.  Digest Liver Dis 2002;34:356-363. 
 
20. 
Bezzi M, Zolovkins A, Cantisani V, et al.  New ePTFE/FEB-covered Stent in the Palliative 
Treatment of Malignant Biliary Obstruction.  J Vasc Interv Radiol 2002; 13:581-589. 
 
21. 
Kang SG, Jung GS, Cho SG, et al.  The Efficacy of Metallic Stent Placement in the Treatment 
of Colorectal Obstruction.  Korean J Radiol 2002; 3:79-86. 
 
22. 
Song HY, Park, H, Suh TS, et al.  Recurrent Traumatic Urethral Strictures Near the External 
Sphincter:  Treatment With a Covered, Retrievable, Expandable Nitinal Stent - Initial Results.  
Radiology 2003; 226:433-440. 
 
23. 
Prasad M, Bent JP, Ward RF, et al.  Endoscopically Placed Nitinol Stents for Pediatric Tracheal 
Obstruction.  Int J Pediatr Otorhinolaryngol 2002; 66:155-160. 
 
24. 
Ko GY, Song HY, Seo TS, et al.  Obstruction of the Lacrimal System:  Treatment with a 
Covered, Retrievable, Expandable Nitinol Stent versus a Lacrimal Polyurethane Stent.  
Radiology 2003;227:270-276. 
 
25. 
Simon M, Kaplow R, Salzman E, et al.  A Vena Cava Filter Using Thermal Shape Memory 
Alloy:  Experimental Aspects.  Radiology 1977;125:87-94. 
 
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Himpens JM.  Laproscopic Inguinal Hernioplasty.  Surg Endosc 1993; 7:315-318. 
 
 
27. 
Ryhanen J, Niemela E, Kaarela O, et al.  Stabilization of Acute, Complete Acromioclavicular 
Joint Dislocations with a New C Hook Implant.  J Shoulder Elbow Surg 2003; 12:442-445 
 
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APPENDIX 3:  SPONSOR’S COMMITMENTS 
 
Ivantis, Inc. is committed to: 
1. 
Complying with the Declaration of Helsinki, and all applicable health authority regulations 
governing the conduct of clinical research studies. 
2. 
Protecting the rights, health, safety and welfare of study subjects. 
3. 
Informing the clinical investigators of any new information about the study, which may affect the 
health, safety or welfare of the subjects, or may influence their decision to continue participation 
in the study. 
4. 
Providing the clinical investigators with the study protocol, and a full set of Case Report Forms on 
which to document the study evaluation variables for each subject entered into the study. 
5. 
Certifying that IRB/EC approval of the protocol and Investigator’s Agreement will be completed 
prior to treatment at an investigational site. 
6. Complying with ISO 14155-1:2003/(R) 2008. 
 
 
Protocol #: CP-10-002, Rev. C 
 
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July 22, 2013 
 

 
 
APPENDIX 4:  INVESTIGATOR’S QUALIFICATIONS AND RESPONSIBILITIES 
 
Each investigator must be a licensed physician who has completed a residency or preceptorship in 
ophthalmology.  The investigators have the following responsibilities: 
 
A. Subject Selection 
The investigator is responsible for assuring that all subjects entering the study conform to the 
subject selection criteria. 
 
B. Informed Consent 
The investigator is responsible for fully reviewing the nature of the study, the possible risks, and 
alternative treatments with prospective subjects prior to their enrollment in the study.  The 
investigator is responsible for obtaining written Informed Consent for each subject, prior to 
enrollment in the trial.  A copy of the signed Informed Consent Form will be maintained in the 
subject's medical record, a copy of the signed Informed Consent Form will become an integral part 
of each Case Report file provided to the Sponsor, and a copy will be provided to the subject. 
 
C. Institutional Review Board (IRB) / Ethics Committee (EC) Approval 
The investigator must obtain approval for his/her participation in this protocol from the IRB/EC for 
the institution at which the procedure will be performed, prior to entering any subjects in the study.  
The Informed Consent document to be used will also be submitted by the Investigator to the 
IRB/EC for approval prior to initiation of the study.  Assurance that the IRB/EC approval of the 
study protocol and Informed Consent has been obtained will be provided to the Sponsor prior to 
initiation of the study. 
The Investigator must keep the IRB/EC informed of the progress of the study at least annually. 
 
D. Subject Evaluations and Data Reporting 
The investigator is responsible for performing the subject evaluations as described in the study 
protocol.  All information generated by the subject evaluation will be recorded on the Case Report 
Forms provided by the Sponsor, and a copy of supporting source documents will be filed with the 
CRFs.  Case Report Forms will be filled out in ink.  Any corrections will be made by lining out, 
dating and initialing.  Correction fluid will not be used.  The Enrollment, AE, and Exit CRF pages 
will be signed and dated by the investigator when each subject completes the study confirming that 
he or she has reviewed and agrees with all data recorded in the CRF booklet.  Upon monitoring 
visits, each original form will be returned to IVANTIS or its designee along with a copy of the 
associated source documents.  Copies of all Case Report Forms will be retained at the study site in 
order to be available for monitoring by IVANTIS or its designee.   
Investigator(s) will not deviate from the study protocol without prior approval of IVANTIS unless 
protection of the health, safety or welfare of study subjects requires prompt action. 
 
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E. Clinical Trial Material Accountability 
The investigator must maintain accurate records of the receipt of all investigational material 
provided by IVANTIS or its designee.  In addition, accurate records must be kept on the amount 
and date that investigational material was used or returned for each subject in the trial.  In addition, 
a separate area on the Case Report Form for each subject will be provided for the purpose of 
maintaining this record. 
Only Hydrus Implant devices with CE mark clearance will be used in this study.  Device 
accountability records will not be required by the site as the device is non-investigational. 
 
 
 
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APPENDIX 5:  DECLARATION OF HELSINKI 
 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
 
A. 
INTRODUCTION 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs.  
2. 
Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles. 
3. 
It is the duty of the physician to promote and safeguard the health of subjects, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
4. 
The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my subject will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act in the subject's best interest when providing 
medical care." 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. 
In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. 
In medical practice and in medical research, most interventions involve risks and 
burdens. 
9. 
Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
10. 
Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
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requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration.  
 
B.  
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
 
11. 
It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.  
13. 
Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. 
The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
15. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee. 
16. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on subjects or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent. 
17. 
Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
18. 
Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals 
or communities affected by the condition under investigation. 
19. 
Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
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20. 
Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
21. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. 
Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. 
In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject's freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
25. 
For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
26. 
When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. 
For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is 
intended to promote the health of the population represented by the potential subject, the 
research cannot instead be performed with competent persons, and the research entails 
only minimal risk and minimal burden. 
28. 
When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject's dissent 
should be respected. 
29. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious subjects, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
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specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
30. 
Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication.  
 
C.  
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
 
31. 
The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the subjects who serve as research subjects. 
32. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists; or 
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
subjects who receive placebo or no treatment will not be subject to any risk of 
serious or irreversible harm. Extreme care must be taken to avoid abuse of this 
option. 
33. 
At the conclusion of the study, subjects entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. 
The physician must fully inform the subject which aspects of the care are related to the 
research. The refusal of a subject to participate in a study or the subject's decision to 
withdraw from the study must never interfere with the subject-physician relationship. 
35. 
In the treatment of a subject, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
subject or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 
 
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