Post Approval Study of the CyPass System in Patients With Primary Open Angle Glaucoma Undergoing Cataract Surgery
Phase: NA
Conditions: Primary Open-angle Glaucoma, Cataract
Sponsor: Alcon Research



Page 2 of 83
1
PROTOCOL SYNOPSIS
Test Article(s) / 
Product(s):
CyPass System (Model 241-S) consisting of the CyPass Micro-Stent 
contained in a loading device (loader) and the CyPass applier
Objective(s):
To demonstrate that the rate of clinically relevant complications 
associated with CyPass Micro-Stent placement and stability using 
the CyPass 241-S applier, as determined at 36 months in the post-
market setting, is less than the pre-specified performance target, 
which is based on experience with the CyPass Model E applier in 
the COMPASS (TMI-09-01) Trial.
Clinical Trial Design: This is a prospective, multi-center, non-randomized, single-arm, 
safety and effectiveness clinical trial.
No. of Subjects:
It is estimated that 640 subjects will be enrolled.
Of these, it is estimated that 450 subjects will be successfully 
screened and implanted (30% screen failure rate).
Of these, it is estimated that 360 subjects will complete the study 
and provide 36-month data for statistical analyses (20% attrition 
rate).
Region(s):
US
Clinical Trial 
Duration:
a) The total expected duration of the clinical study is 60 months. 
b) Each subject’s expected participation in the study is up to 37.5
months which includes up to 42 days between the screening and
surgery visits, and 36 months of post-surgery follow-up.
c) A 22-month enrollment period is expected.
Clinical Trial 
Population:
Adults with Primary Open Angle Glaucoma (POAG) undergoing 
cataract surgery
Treatments:
Test Article:
CyPass Micro-Stent implanted with CyPass 
241-S applier
Administration:
The CyPass Micro-Stent is placed in the angle 
of the eye, with the proximal end extending 
from the angle into the anterior chamber (AC) 
and distal end residing in the supraciliary 
space.
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Page 8 of 83
Sample Size 
Justification (cont.)
Annex F of ANSI standard Z80.27-2014 refers to ensuring 
adequate sample size so that any adverse event of a given type that 
occurs in the population at a rate of 1% or greater is likely to be 
seen in the study. With 360 subjects, there is at least 97% 
probability that at least 1 adverse event will be detected, assuming 
a true rate of 1.0%. There is at least 95% probability if the true rate 
is 0.83%.
Interim Reports
Interim reports pertaining to the progress of the post-approval 
study will be submitted to the FDA for review every 6 months for 
the first two years, starting from the date of approval, and will 
continue to be submitted annually thereafter, until study 
completion.
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Page 9 of 83
2
TABLE OF CONTENTS
Table of Contents
Post Approval Study of the CyPass System in Patients with Primary Open Angle Glaucoma 
Undergoing Cataract Surgery .................................................................................1
1
PROTOCOL SYNOPSIS........................................................................................2
2
TABLE OF CONTENTS........................................................................................9
Table of Contents .......................................................................................................................9
List of Tables............................................................................................................................13
List of Figures..........................................................................................................................13
3
ABBREVIATIONS...............................................................................................14
4
GLOSSARY OF TERMS .....................................................................................16
6
SCHEDULE OF VISITS ......................................................................................24
7
INTRODUCTION ................................................................................................25
Background.......................................................................................................25
7.1
Clinical Trial Design.........................................................................................27
7.2
Study Milestones Timeline ...............................................................................27
7.3
8
CLINICAL TRIAL OBJECTIVES.......................................................................29
Primary Objective.............................................................................................29
8.1
Study Endpoints................................................................................................29
8.2
Effectiveness Endpoints ...............................................................................29
8.2.1
Primary Effectiveness Endpoint ...............................................................29
8.2.1.1
Secondary Effectiveness Endpoints..........................................................29
8.2.1.2
Safety Endpoints...........................................................................................30
8.2.2
Primary Safety Endpoint...........................................................................30
8.2.2.1
Secondary Safety Endpoints .....................................................................30
8.2.2.2
Other Safety Endpoints.............................................................................31
8.2.2.3
9
INVESTIGATIONAL PLAN ...............................................................................32
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Outline of Clinical Trial....................................................................................32
9.1
Study Design ....................................................................................................32
9.2
Rationale for Study Design ..............................................................................32
9.3
Risk Benefit Assessment ..................................................................................32
9.4
Study Entry.......................................................................................................33
9.5
Procedures Per Study Visit ...............................................................................34
9.6
Selection of the Study Eye ...............................................................................34
9.7
Ocular Hypotensive Medications at Screening ................................................34
9.8
10
SUBJECT POPULATION....................................................................................36
Inclusion Criteria..............................................................................................36
10.1
Intraoperative Inclusion Criteria.......................................................................37
10.2
Exclusion Criteria.............................................................................................37
10.3
11
TREATMENT.......................................................................................................39
Investigational Products ...................................................................................39
11.1
Test Article....................................................................................................39
11.1.1
Control Article ..............................................................................................39
11.1.2
Package Contents..............................................................................................39
11.2
Usage ................................................................................................................40
11.3
Accountability Procedures................................................................................40
11.4
Procurement..................................................................................................40
11.4.1
Labeling........................................................................................................40
11.4.2
Handling .......................................................................................................40
11.4.3
Dispensing ....................................................................................................40
11.4.4
Returns of Damaged Products ......................................................................41
11.4.5
Final Disposition ..........................................................................................41
11.4.6
CyPass Post-implant Adjustment or Removal..................................................41
11.5
12
CLINICAL TRIAL PROCEDURES ....................................................................42
Clinical Trial Assessments................................................................................42
12.1
Study Visits.......................................................................................................42
12.2
Screening (Visit 0)........................................................................................42
12.2.1
Surgery (Visit 00) .........................................................................................44
12.2.2
Surgical Procedure....................................................................................45
12.2.2.1
1 Day Follow-up (Visit 1).............................................................................50
12.2.3
1 Week Follow-up (Visit 2) ..........................................................................50
12.2.4
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1 Month Follow-up (Visit 3).........................................................................51
12.2.5
3 Month Follow-up (Visit 4).........................................................................51
12.2.6
6 Month Follow-up (Visit 5).........................................................................52
12.2.7
12 Month Follow-up (Visit 6).......................................................................53
12.2.8
24 Month Follow-up (Visit 7).......................................................................54
12.2.9
36 Month Follow-up / Exit / Early Exit (Visit 8) .........................................54
12.2.10
Unscheduled Visits ...........................................................................................55
12.3
Discontinued Subjects ......................................................................................56
12.4
Clinical Trial Termination ................................................................................57
12.5
13
DEVICE DEFICIENCIES AND ADVERSE EVENTS.......................................58
General Information .........................................................................................58
13.1
Intraoperative Adverse Events......................................................................59
13.1.1
Postoperative Adverse Events ......................................................................60
13.1.2
Sight Threatening Adverse Events ...............................................................62
13.1.3
Other Postoperative Events/Findings ...........................................................62
13.1.4
Device Deficiencies......................................................................................63
13.1.5
Monitoring for Adverse Events ........................................................................63
13.2
Procedures for Recording and Reporting .........................................................63
13.3
Intensity and Causality Assessments ............................................................65
13.3.1
Return Product Analysis ...................................................................................65
13.4
Unmasking of the Study Information ...............................................................66
13.5
Follow-Up of Subjects with Adverse Events....................................................66
13.6
Pregnancy in the Clinical Study .......................................................................66
13.7
14
DATA REVIEW AND HANDLING ....................................................................67
Completion of Source Documents and Case Report Forms .............................67
14.1
Data Review and Clarifications........................................................................68
14.2
15
ANALYSIS PLAN ...............................................................................................69
Subject Evaluability..........................................................................................69
15.1
Analysis Data Sets............................................................................................69
15.2
Intention to Treat ..........................................................................................69
15.2.1
Demographics and Baseline Characteristics ....................................................69
15.3
Effectiveness Analyses .....................................................................................69
15.4
Primary Effectiveness...................................................................................69
15.4.1
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Secondary Effectiveness...............................................................................69
15.4.2
Statistical Hypotheses ...............................................................................70
15.4.2.1
Analysis Methods .....................................................................................70
15.4.2.2
Safety Analyses ................................................................................................70
15.5
Primary Safety..............................................................................................70
15.5.1
Statistical Hypothesis................................................................................70
15.5.1.1
Analysis Methods .....................................................................................70
15.5.1.2
Secondary Safety..........................................................................................71
15.5.2
Statistical Hypotheses...............................................................................71
15.5.2.1
Analysis Methods .....................................................................................71
15.5.2.2
Other Safety..................................................................................................71
15.5.3
Statistical Hypotheses ...............................................................................71
15.5.3.1
Analysis Methods .....................................................................................71
15.5.3.2
Ocular Adverse Events .................................................................................71
15.5.4
Non-Ocular Adverse Events .........................................................................72
15.5.5
Device Deficiencies......................................................................................72
15.5.6
Endothelial Cell Count .................................................................................72
15.5.7
Slit Lamp and Fundus Examinations............................................................72
15.5.8
Corneal Pachymetry .....................................................................................72
15.5.9
Visual Field Loss Mean Deviation Testing...................................................72
15.5.10
Manifest Refraction ......................................................................................72
15.5.11
Handling of Missing Data ................................................................................73
15.6
Interim Analyses...............................................................................................73
15.7
Sample Size Justification..................................................................................73
15.8
16
ADMINISTRATIVE PROCEDURES..................................................................75
Regulatory and Ethical Compliance.................................................................75
16.1
Informed Consent Procedures ..........................................................................75
16.2
Responsibilities of the Investigator and IRB/IEC ............................................75
16.3
Sponsor and Monitoring Responsibilities ........................................................76
16.4
Regulatory Documentation and Records Retention .........................................77
16.5
Clinical Trial Results ........................................................................................77
16.6
17
REFERENCES .....................................................................................................79
18
APPENDICES ......................................................................................................82
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List of Tables
Table 7-1
Study Milestones..............................................................................................28
Table 12–1
Medication Regimen........................................................................................49
List of Figures
Figure 7–1
Study Design....................................................................................................28
Figure 11–1
CyPass Micro-Stent .........................................................................................39
Figure 11–2
CyPass Applier with Guidewire Extended.......................................................39
Figure 12–1
CyPass Micro-Stent Packaged in the Loader...................................................46
Figure 12–2
CyPass Micro-Stent Loaded onto CyPass Applier Guidewire.........................46
Figure 12–3
CyPass Micro-Stent at Implant Site.................................................................47
Figure 13–1
Categorization of All Adverse Events..............................................................58
Figure 13–2
Categorization of All Serious Adverse Events.................................................59
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3
ABBREVIATIONS
Abbreviation
Definition
AC
Anterior chamber
ADE
Adverse device effect
AE
Adverse event
ANSI
American National Standards Institute
ASADE
Anticipated serious adverse device effect
BAT
Brightness acuity meter
BCDVA
Best corrected distance visual acuity
BID
Bis in die (two times a day)
C:D
Cup to disc (ratio)
CDE
Cumulative dissipated energy
CFR
Code of Federal Regulations
CJD
Creutzfeldt-Jacob disease
CRF
Case report form
CS
Clinically significant
CTM
Clinical trial management
CyPass
CyPass Micro-Stent
dB
Decibel
ECD
Endothelial cell density
ECL
Endothelial cell loss
EDC
Electronic data capture
EMR
Electronic medical record
EPT
Effective phacoemulsification time
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
US Food and Drug Administration
FL
Fixation losses
FP
False positive
GCP
Good Clinical Practice
GPCMS
Global Product Complaint Management System
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
I/A
Irrigation/aspiration
IB
Investigator brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFU
Instructions for use
IRB
Institutional review board
IOL
Intraocular lens
IOP
Intraocular pressure
ISO
International Organization for Standardization
ITT
Intention to treat
LCSM
Lead clinical site manager
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logMAR
Logarithm of the Minimum Angle of Resolution
MD
Mean deviation
MedDRA®
Medical Dictionary for Regulatory Activities
mmHg
Millimeters of mercury
MOP
Manual of procedures
NSAID
Non-steroidal anti-inflammatory drug
NCS
Not clinically significant
OCT
Optical coherence tomography
OVD
Ophthalmic viscoelastic device
PAS
Post approval study
POAG
Primary open angle glaucoma
PP
Per protocol
QID
Quater in die (four times a day)
SAE
Serious adverse event
SAS®
Statistical analysis software, SAS Institute Inc., Cary, NC
SITA
Swedish Interactive Thresholding Algorithm
SOP
Standard operating procedure
SSI
Secondary surgical intervention
TID
Ter in die (three times a day)
UBM
Ultrasound biomicroscopy
USV
Unscheduled visit
WHO
World Health Organization
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4
GLOSSARY OF TERMS
Adverse Device 
Effect (ADE)
Adverse event related to the use of an investigational medical device 
(test article) or control article. Note: This definition includes adverse 
events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation; any 
malfunction; and use error or intentional misuse of the 
investigational medical device or comparator, if applicable.
Adverse Event 
(AE)
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device (test article). Note: For subjects, this 
definition includes events related to the test article, the control 
article, or the procedures involved. For users or other persons, this 
definition is restricted to events related to the test article.
Anticipated 
Serious Adverse 
Device Effect 
(ASADE)
Serious adverse device effect which by its nature, incidence, severity, 
or outcome has been identified in the risk management file.
Assessment
A procedure used to generate data required by the study.
Device Deficiency
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Note: This definition 
includes malfunctions, use errors, and inadequate labeling.
Malfunction
Failure of a medical device to meet its performance specifications or 
otherwise perform as intended. Performance specifications include all 
claims made in the labeling of the device. The intended performance 
of the device refers to the intended use for which the device is labeled 
or marketed.
Nonserious 
Adverse Event
Adverse event that does not meet the criteria for a serious adverse 
event.
Product 
Complaint
Any oral, electronic, or written communication that alleges 
deficiencies related to the identity (labeling), quality, durability, 
reliability, safety, effectiveness, or performance of a marketed 
product, including failure of the product, labeling or packaging to 
meet specifications, whether or not the product is related to or caused 
the alleged deficiency. A complaint may allege that an adverse event 
or medical device malfunction has occurred.
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Page 18 of 83
public health hazard, eg, human immunodeficiency virus (HIV) or 
Creutzfeldt-Jacob Disease (CJD).
Unanticipated 
Serious Adverse 
Device Effect 
(USADE)
Serious adverse device effect which by its nature, incidence, severity 
or outcome has not been identified in the risk analysis.
Use Error
Act or omission of an act that results in a different medical device 
response than intended by manufacturer or expected by user. 
Note: This definition includes slips, lapses, and mistakes. An 
unexpected physiological response of the subject does not in itself 
constitute a use error.
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7
INTRODUCTION
Background
7.1
Note: A summary of known and potential risks and benefits to humans, as identified in the 
literature or through preclinical testing and/or prior clinical evaluations, for the 
investigational product can be found in the Instructions for Use for the CyPass System.
As described in the American Academy of Ophthalmology Preferred Practice Pattern, POAG 
represents a significant public health problem. In the United States, the overall prevalence of 
open-angle glaucoma for adults 40 years old and older is estimated to be 1.86% (Friedman 
2004). Open-angle glaucoma (not including the major forms of secondary open-angle 
glaucoma, pseudoexfoliation glaucoma and pigmentary glaucoma) affects an estimated 2.22 
million people in the United States, and that number will increase to 3.3 million in 2020 as 
the population ages (Friedman 2004). Based on data extrapolated from the Baltimore Eye 
Survey, about half of those with glaucoma may be unaware that they have the disease 
(Tielsch 1991, Quigley 1997). In the United States, more than 7 million office visits occur per 
year for the primary purpose of monitoring patients with glaucoma and patients at risk for 
developing glaucoma (Javitt 1993, Schappert 1995). Glaucoma of all types is one of the 
leading causes of legal blindness in the United States (Congdon 2004, Sommer 1991, POAG 
Preferred Practice Patterns 2008). The findings of epidemiological investigations and risk 
factor analyses provide a framework for considering the cause and management of POAG. 
There are five important risk factors associated with glaucomatous optic neuropathy: 
1. Elevated IOP 
2. Older age 
3. Family history of glaucoma 
4. African or Hispanic/Latino descent 
5. Thinner central corneal thickness
While the relationship between IOP and loss of vision is fundamental to all current therapy 
for open-angle glaucoma, there are several other factors (eg, blood supply to the optic nerve, 
substances toxic to the optic nerve or retina, axonal or ganglion cell metabolism, and the 
lamina cribosa extracellular matrix) that may play a role in the progressive loss of vision due 
to glaucoma. Because elevated IOP is a treatable cause of glaucomatous optic nerve damage, 
one can expect to inhibit progression of glaucomatous optic neuropathy in many patients by 
lowering the IOP by means of medication, laser, filtering, implantation of aqueous drainage 
device, or cyclodestructive surgery. Results from randomized controlled trials and other 
studies reinforce this expectation and provide evidence that the more the IOP is lowered, the 
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Page 26 of 83
more likely it is that progressive loss of vision will be halted (Jay 1989, Migdal 1994, GLT 2 
1990, GLT and GLT Follow-up Study 1995, Kass 2002, Gordon 1999, Collaborative Normal-
Tension Glaucoma Study Group 1998, Heijl 2002, Leske 2003, Lichter 2001, AGIS 13 2004, 
EGPS 2005, EGPS 2002).
Medical and surgical therapies to treat elevated IOP are directed towards either reducing the 
rate of aqueous production, increasing the rate of aqueous outflow through the normal 
outflow channels, or a combination of both. For example, laser treatment of the trabecular 
meshwork works by increasing outflow. Surgical interventions are directed almost 
exclusively at increasing outflow, by creating an alternate or improved pathway to Schlemm’s 
canal or by directing aqueous outflow to alternative drainage sites outside of the interior of 
the eye. 
While filtering surgery such as trabeculectomy and implantation of an aqueous shunt to 
external reservoir directs aqueous outflow via drainage sites outside of the interior of the eye, 
there are significant risks of complication associated with this approach, including hypotony, 
infection, bleb fibrosis and erosion. Nevertheless, filtering surgery does provide an alternative 
path for the escape of aqueous humor and often reduces IOP and the need for medical 
treatment. The best estimate of the failure rate of filtering surgery alone or combined with 
medical therapy in a previously unoperated eye comes from the Advanced Glaucoma 
Intervention Study (AGIS 13 2004). The 10-year results indicate about 30% failure in African 
American patients and 20% failure in Caucasian American patients. While long-term control 
is often achieved, many patients will require further therapy or a re-operation, which carries a 
higher failure rate (Lichter 2001). Furthermore, filtering surgery increases the likelihood that 
phakic eyes will undergo cataract surgery. These limitations of filtering surgery have led to 
interest in devices which employ alternative approaches to increasing aqueous outflow, such 
as the CyPass Implant.
The CyPass Implant is a surgically implantable micro-device composed of the same 
polyimide material currently used for conventional intraocular lens haptics. This implant is 
inserted into the eye in the same general location as the tubes of conventional aqueous shunts. 
However, instead of shunting aqueous fluid to an external polymer plate, the CyPass Implant 
redirects aqueous fluid into the supraciliary space and the suprachoroidal space. 
The supraciliary space, which is continuous with the suprachoroidal space, has a negative 
hydrostatic fluid pressure relative to the anterior chamber (Jordan 2007, Ozdamar 2003).
When the normal anatomical barrier is crossed via the CyPass Implant, aqueous fluid drains 
away from the anterior chamber, thus reducing the IOP. In this fashion, the CyPass Implant 
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allows aqueous fluid to bypass a major site of resistance that has been associated with 
elevated IOP and the development of glaucoma. By guiding fluid directly into the 
supraciliary space rather than to the surface of the eye, complications such as hypotony, flat 
chamber and bleb fibrosis or erosion commonly encountered with conventional glaucoma 
surgery may be avoided. Shunting aqueous fluid flow directly into the supraciliary space and 
avoiding conjunctival and scleral incisions should minimize scarring since the angle region is 
populated with a single line of non-proliferating trabecular cells. Finally, shunting aqueous 
flow directly into the supraciliary space should also reduce long term complications such as 
endophthalmitis and external leaks since an external filtering bleb is not a characteristic of 
this surgery. 
Clinical Trial Design
7.2
This study is a prospective, non-randomized, multicenter, single arm, post approval study of 
the CyPass System. Approximately 640 subjects with POAG will be enrolled. Assuming a 
30% screen-fail rate, a total of up to 450 subjects will be implanted and followed for 36 
months. All subjects will receive the same treatment consisting of CyPass Micro-Stent 
implantation following uncomplicated cataract surgery in one eye. An attrition rate of 
approximately 20% is expected, leaving 360 subjects evaluable for statistical analyses with 
36-month data.
Interim reports pertaining to the progress of the post-approval study will be submitted to the 
FDA for review every 6 months for the first two years, starting from the date of FDA 
approval of the CyPass System, and will continue to be submitted annually thereafter, until 
study completion. 
Study Milestones Timeline
7.3
The study milestone timeline presented below is based on the expectation that, following the 
initiation of the first site, the remaining study sites will be activated at a rate of approximately 
3 per month, and the enrollment rate at activated sites will be approximately 2 subjects per 
month.
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9
INVESTIGATIONAL PLAN
Outline of Clinical Trial
9.1
This study is a prospective, non-randomized, multicenter, single arm, post approval study of 
the CyPass System. A total of 450 eyes from 450 subjects with POAG will be implanted to 
ensure 360 eyes of 360 subjects are available for analysis at 36 months. All subjects will 
receive the same treatment consisting of CyPass Micro-Stent implantation with cataract 
surgery in one eye.
Study Design
9.2
Subject participation in this study is expected to last up to 37.5 months and include 10 study 
visits. Approximately 640 subjects will be enrolled at the screening visit, to identify up to 450 
qualified subjects. Within 42 days of screening, qualified subjects will receive cataract 
surgery followed by implantation of the CyPass Micro-Stent in one eye (the study eye) at the 
surgery visit. Eight postoperative follow-up visits are planned to occur at 1 day, 1 week, 1 
month, 3 months, 6 months, 12 months, 24 months, and 36 months after surgery. Upon 
completion of the 36-month follow-up visit, subjects will be exited from the study.
Rationale for Study Design
9.3
This post-approval study is designed to provide continued reasonable assurance of the safety 
and effectiveness of the device. The safety and effectiveness endpoint was identified based on 
the findings from the pivotal clinical trial (COMPASS, TMI-09-01) for the CyPass Micro-
Stent. Since the safety and effectiveness in comparison with cataract surgery has been 
rigorously evaluated in the pivotal clinical trial, and another study (COMPASS-XT, 
GLD122b-C001) is ongoing to provide further long term follow up of the pivotal trial study 
population, there is no additional information that is necessary to be collected from a control 
arm of cataract surgery population; therefore, this study is a single arm study.
Risk Benefit Assessment
9.4
CyPass Micro-Stent is indicated for use in conjunction with cataract surgery for the reduction 
of IOP in adult patients with mild to moderate POAG. 
During the development of the CyPass Micro-Stent, the safety and performance aspects of 
the CyPass Micro-Stent have been evaluated using risk analysis techniques, and clinical 
hazards are addressed by the clinical study data. 
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In the pivotal clinical trial for the CyPass Micro-Stent, the COMPASS trial, the safety and 
effectiveness of CyPass implantation in conjunction with cataract surgery in subjects with 
mild to moderate POAG have been demonstrated. The study has shown that the additional 
reduction of IOP provided by the CyPass does not impact cataract surgery outcomes. The 
expected improvement in visual acuity has been shown to be nearly identical in each 
treatment group, while the reduction in IOP has been shown superior in subjects receiving the 
CyPass. Adverse events specifically related to the CyPass device were mostly transient in 
nature. There have been no reports of choroidal detachment, choroidal hemorrhage or flat 
anterior chamber. The COMPASS study has demonstrated that the benefit of CyPass 
implantation at the time of cataract surgery in patients with mild to moderate POAG 
outweighs its risks. Hence, FDA’s PMA approval was obtained for commercial distribution. 
Following FDA’s approval, in order to provide continued reasonable assurance of the safety 
and effectiveness of the device, a post-approval study (PAS) will be conducted. 
In the post-approval clinical study, a careful evaluation will be performed according to the 
inclusion/exclusion criteria to ensure that vulnerable or inappropriate subjects are not allowed 
to participate in the clinical study. Subject safety will be monitored closely via the collection 
of adverse events, safety parameter assessments, and postoperative visits (either planned or 
unplanned) throughout the course of the study. In addition, per IFU, the investigators will 
receive training by certified Alcon personnel prior to clinical study surgery.
Overall, the information that will be gained in the post-approval study will provide continued 
evidence with regard to safety and effectiveness of the device. With the mitigations that have 
been implemented to reduce the risk to subjects participating in the clinical study, the 
Sponsor concludes that the benefit/risk assessment for this clinical study is acceptable.  
Study Entry
9.5
Participants will be recruited from the Investigators’ patient population, referrals, or IRB 
approved materials. Patients that appear to be eligible subjects will be approached for study 
participation and sign an Informed Consent Form (ICF) 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 must 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. When it has been 
established that the subject is eligible for possible participation in the study, written informed 
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Page 35 of 83
Ocular hypotensive medication usage must be established at the beginning of the screening 
visit. If a potential subject has been using ocular hypotensive medications inconsistently over 
the past 28 days, or the prescribed regimen has changed during the past 28 days, the 
screening visit must be halted and rescheduled for a time when the subject’s status is either 
clearly ‘medicated’ or ‘unmedicated’.
The inclusion requirements for baseline IOP at screening are different for medicated and 
unmedicated subjects (refer to inclusion criterion #4 in Section 10.1).
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10
SUBJECT POPULATION
The study population includes approximately 450 qualified subjects to be enrolled and 
implanted at approximately 20 sites (approximately 22 subjects implanted per site). To 
participate in the clinical trial, subjects must have primary open angle glaucoma in the study 
eye and also be undergoing cataract surgery in that eye. The study enrollment period is 
expected to last approximately 22 months. No single site is permitted to implant more than 
25% of the total subjects.
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11
TREATMENT
In this single arm study, all subjects will receive the same treatment: implantation of one 
CyPass Micro-Stent in one eye per subject.
Investigational Products
11.1
Test Article 
11.1.1
The test article in this clinical study is the CyPass System (Model 241-S) which consists of 
the CyPass Micro-Stent contained in a loading device (loader) and the CyPass applier. The 
CyPass System is manufactured by Alcon Laboratories.
Figure 11–1
CyPass Micro-Stent
Figure 11–2
CyPass Applier with Guidewire Extended
Control Article
11.1.2
There is no control article in this clinical study.
Package Contents
11.2
The CyPass System (Model 241-S) consists of the CyPass Micro-Stent, which is contained in 
a loading device (loader), and the CyPass applier. The device is supplied sterile and non-
pyrogenic in a sealed tray. The sealed tray is placed in a unit box containing product labeling 
and product information. The CyPass System has been sterilized using radiation.
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Usage
11.3
The CyPass Micro-Stent is placed in the angle of the eye, with the proximal end extending 
from the angle into the anterior chamber and the distal end residing in the supraciliary space. 
It is implanted through the primary corneal incision made for cataract extraction / IOL 
implantation, following routine cataract surgery. One CyPass Micro-Stent will be implanted 
into one study eye of each qualified subject. CyPass implantation will be performed by a 
licensed physician who is a study Investigator.
Accountability Procedures
11.4
Details related to the procurement, labeling, handling, dispensing, and final disposition are 
outlined below. Throughout the clinical study, the Investigator is responsible for accounting 
for all investigational product and must ensure that the clinical study investigational product 
is not used in any unauthorized manner.
Procurement
11.4.1
The CyPass System is the sole study investigational product and will be procured by each 
investigative site through their usual commercial channels. A device accountability log will 
be maintained for all CyPass devices used in the study eyes of enrolled subjects. 
Labeling
11.4.2
The CyPass System is commercially available and will be supplied with commercial labeling.
Handling
11.4.3
Investigational product provided for use in this clinical study must be stored in a safe, secure 
location with limited access, separated from general stock. Daily temperature of test article 
storage conditions will be monitored and recorded. Transportation or transfer of product from 
one location to another must be documented, utilizing a Transportation Log (or similar 
documentation) for appropriate accountability.
Dispensing
11.4.4
The Investigator must keep a current record of the dispensing of all investigational products. 
This record must be made available to the Sponsor’s monitor to account for all 
investigational product. Any discrepancy and/or deficiency must be recorded, with an 
explanation.
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Returns of Damaged Products
11.4.5
Refer to the MOP for the procedures for returning damaged investigational product.
Final Disposition
11.4.6
It is the Investigator’s responsibility to return any and all unused investigational product to 
the Sponsor, as directed.
CyPass Post-implant Adjustment or Removal
11.5
Refer to the MOP for the procedures for CyPass repositioning, CyPass trimming, CyPass 
lumen occlusion, and CyPass explant.
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12
CLINICAL TRIAL PROCEDURES
Clinical Trial Assessments
12.1
The following section outlines the assessments to be performed in this clinical study. 
Assessments are described in detail in the GLD122c-C001 MOP, and are outlined in tabular 
format in Section 6 of this protocol.
Study Visits
12.2
All subjects will participate in defined follow-up visits through 36 months. A follow-up 
electronic Case Report Form (eCRF) shall be completed for each scheduled exam. 
Unscheduled visits must also be recorded using the appropriate eCRF. 
Informed consent MUST be properly completed and documented prior to performing any 
study-specific testing. Upon signing informed consent, subjects are considered enrolled in the 
study. All subjects will be assigned a single subject identifier at the screening visit. The 
subject identifier consists of a combination of a 4-digit investigator number and a 5-digit 
subject number. The number is automatically generated sequentially by the electronic data 
capture (EDC) system. As an example: “1234.00001” (the investigator number and the 
subject number are separated by a “.” character). This number will be used throughout the 
clinical study.
It is recommended that ocular assessments be performed in the order presented below. All 
assessments must be recorded in source documentation, and also in the eCRF, if applicable. 
Adverse events are collected and reported for both the study eye and the fellow eye (refer to 
Section 13 DEVICE DEFICIENCIES AND ADVERSE EVENTS).
Screening (Visit 0)
12.2.1
Below is a list of study procedures to be undertaken at screening (Visit 0) which must take 
place from 42 days to 1 day before surgery. Data collected at screening (Visit 0) are 
considered baseline data. Conduct ocular assessments in both eyes. 
1. Upon identification of a possible study participant, carry out the informed consent 
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process. Refer to Section 16.2 Informed Consent Procedures.
NOTE: Subjects must formally consent to participate in the study prior to undergoing any 
study specific testing.
2. Document demographics, child bearing potential, ocular and non-ocular medical history, 
and ocular and non-ocular concomitant medications, including the number of ocular 
hypotensive medications being used. 
3. Perform a urine pregnancy test if the subject is a female of child bearing potential.
4. Perform manifest refraction and record monocular best corrected distance visual acuity 
(BCDVA) using an ETDRS chart at 4 meters.
5. Perform specular microscopy.
6. If a reliable visual field has not been obtained in the past 6 months with a Humphrey 
automated perimeter using the 24-2 SITA standard threshold strategy, then conduct a 
visual field assessment in accordance with these requirements and confirm its reliability.
If needed, this test may be repeated up until 1 day before surgery in order to obtain a 
reliable result.
7. Measure IOP with Goldmann tonometer between 8:00 am and 10:00 am (refer to MOP, 
Measuring IOP).
NOTE: At this and all subsequent visits, if the first two measurements are within ±2 
mmHg of one another, use the mean of these two readings. If the first two measurements 
differ by more than 2 mmHg, perform a third measurement and use the median of the 
three measurements.
8. Conduct slit lamp examination (refer to MOP for grading scales).
9. Perform Gonioscopy (including Shaffer grading for all 4 quadrants).
10. Conduct dilated fundus examination (including C:D assessment).
11. Conduct central corneal pachymetry.
NOTE: Collect three measurements and use the median value.
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Page 47 of 83
14. Examine the AC angle with the gonio lens under the microscope. Take note of angle 
anatomy to identify the best implantation site. Avoiding the area of the anterior ciliary 
arteries at 3, 6, 9 and 12 o’clock may help reduce the possibility of significant bleeding.
15. Fill the AC with ophthalmic viscoelastic (OVD) and use additional OVD as necessary to 
maintain a deep, stable AC during the CyPass Micro-Stent implantation process. 
16. Introduce the loaded CyPass applier guidewire tube through the cataract incision and 
advance towards the intended site of implantation until the guidewire tube and sleeve 
have cleared the incision. When crossing the AC, rotate the CyPass applier guidewire 
such that its curvature is parallel to the iris plane.
17. Position the CyPass applier guidewire radially toward the scleral spur/ciliary body 
interface. Care should be taken to align the curvature of the CyPass on the guidewire with 
the curvature of the sclera bordering the supraciliary space to reduce the possibility of 
encountering resistance during insertion. To gain access, place the distal end of the 
guidewire at the scleral spur/ciliary body interface and smoothly advance the guidewire 
through the tissue plane between the ciliary body and adjacent sclera to separate the 
ciliary body from the scleral spur at the point of implantation. 
18. Continue to advance the guidewire until only the most proximal retention ring and the 
collar of the CyPass Micro-Stent are located in the AC (Figure 12-3). An additional 
confirmatory placement landmark is when the top of the CyPass Micro-Stent collar is 
even with Schwalbe’s line. In this position, the distal tip of the CyPass Micro-Stent 
should be resting against the sclera in the supraciliary space anterior to both retinal and 
choroidal tissues.
Figure 12–3
CyPass Micro-Stent at Implant Site
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19. Hold the CyPass applier stationary and carefully press the front button on the CyPass 
applier to retract the guidewire into the guidewire tube, leaving the Micro-Stent anchored 
between the sclera and ciliary body. 
20. Remove the CyPass applier from the eye.
21. If resistance is encountered or adequate implantation is not achieved at the initial implant 
site, implantation at a location at least 2 clock hours away from any area of ciliary body 
disinsertion can be considered if there is no significant iris trauma, the CyPass Micro-
Stent remains properly positioned on the guidewire, and adequate hemostasis and 
visualization can be maintained. Make sure that the position of the patient’s head and the 
tilt of the microscope allow adequate gonioscopic visualization of the angle structures. 
Increase magnification and fine focus the microscope as needed. Additional viscoelastic 
tamponade may be needed to assure hemostasis and maintain visibility during CyPass 
Micro-Stent implantation. Align the curvature of the CyPass on the guidewire with the 
curvature of the sclera bordering the supraciliary space to reduce the possibility of 
encountering resistance during insertion.  
22. Termination of the procedure should be considered after 2 failed attempts at device 
placement or if adequate visibility cannot be maintained during implantation.
23. Use gonioscopy to confirm CyPass Micro-Stent position. Optimal position of the CyPass 
Micro-Stent is when only the collar and the first retention ring are visible in the AC. 
Anterior positioning with more than 2 retention rings visible in the AC can be associated 
with corneal endothelial cell loss. Posterior positioning such that the collar is not visible 
can be associated with reduced device effectiveness. 
a.
If the CyPass Micro-Stent appears to be too anterior, use the guidewire tube of 
the CyPass applier to gently push the device deeper into the supraciliary space 
until it is optimally positioned. If the proximal end of the CyPass Micro-Stent 
appears to be too posterior, use a micro-forceps to grasp the CyPass Micro-
Stent collar and gently pull it into the AC until the implant is optimally 
positioned. Do not use the irrigation/aspiration (I/A) tip for CyPass Micro-
Stent positioning. 
b. If proper placement cannot be achieved, implant removal should be 
considered. Use direct gonioscopy visualization and supplementary 
viscoelastic for safe removal. 
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1 Day Follow-up (Visit 1)
12.2.3
Visit 1 must occur on the first day postoperatively. The following information will be 
captured at this visit. Ocular assessments will be conducted for the study eye only.
1. Document changes in concomitant medications.
2. Perform pinhole visual acuity measurement using an ETDRS chart at 4 meters.
3. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
4. Conduct slit lamp examination. 
5. Perform Gonioscopy to determine CyPass positioning (goniophotography optional at 
Visit 1)
6. Record any adverse events and/or device deficiencies.
NOTE: Serious adverse events (SAEs) must be entered into EDC within 24 hours of the 
Investigator’s knowledge. Refer to Section 13 for further detail.
1 Week Follow-up (Visit 2)
12.2.4
Visit 2 must occur 5-9 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye only.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
4. Conduct slit lamp examination. 
5. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
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6. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
Refer to Section 13 for further detail.
1 Month Follow-up (Visit 3)
12.2.5
Visit 3 must occur 21-35 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye only.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
4. Conduct slit lamp examination. 
5. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
6. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
Refer to Section 13 for further detail.
3 Month Follow-up (Visit 4)
12.2.6
Visit 4 must occur 70-98 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye only.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Perform specular microscopy.
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4. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
5. Conduct slit lamp examination. 
6. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
7. Conduct dilated fundus examination (including C:D assessment).
8. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
Refer to Section 13 for further detail.
6 Month Follow-up (Visit 5)
12.2.7
Visit 5 must occur 150-210 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye, unless 
otherwise noted.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Perform specular microscopy. If requested by the sponsor, may also be performed in the 
fellow eye.
4. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
5. Conduct slit lamp examination. 
6. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
7. Conduct dilated fundus examination (including C:D assessment).
8. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
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Refer to Section 13 for further detail.
12 Month Follow-up (Visit 6)
12.2.8
Visit 6 must occur 330 - 420 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye, unless 
otherwise noted.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Perform a Humphrey 24-2 SITA standard visual field.
4. Perform specular microscopy. If requested by the sponsor, may also be performed in the 
fellow eye.
5. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
6. Conduct slit lamp examination. 
7. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
8. Conduct dilated fundus examination (including C:D assessment).
9. Conduct central corneal pachymetry.
10. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
Refer to Section 13 for further detail.
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24 Month Follow-up (Visit 7)
12.2.9
Visit 7 must occur 690-780 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye, unless 
otherwise noted.
1. Document changes in concomitant medications.
2. Perform manifest refraction and record monocular BCDVA using an ETDRS chart at 4 
meters.
3. Perform a Humphrey 24-2 SITA standard visual field.
4. Perform specular microscopy. If requested by the sponsor, may also be performed in the 
fellow eye.
5. Measure IOP with Goldmann tonometer between 8:00 and 10:00 am. 
6. Conduct slit lamp examination. 
7. Perform Gonioscopy (including Shaffer grading for all 4 quadrants) with 
goniophotography of CyPass location.
8. Conduct dilated fundus examination (including C:D assessment).
9. Conduct central corneal pachymetry.
10. Record any adverse events and/or device deficiencies.
NOTE: SAEs must be entered into EDC within 24 hours of the Investigator’s knowledge. 
Refer to Section 13 for further detail.
36 Month Follow-up / Exit / Early Exit (Visit 8)
12.2.10
Visit 8 must occur 1050-1140 days postoperatively. Below is a list of study procedures to be 
undertaken at this visit. Ocular assessments will be conducted for the study eye, unless 
otherwise noted.
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Page 58 of 83
13
DEVICE DEFICIENCIES AND ADVERSE EVENTS
General Information
13.1
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users, or other persons, 
whether or not related to the investigational medical device (test article). Refer to the 
Glossary of Terms for categories of AEs, ADEs, and SAEs.
Figure 13–1
Categorization of All Adverse Events
ADE
Device /
procedure-
related?
Meets 
seriousness 
criteria?
SAE
All AEs
AE
No
No
Yes
Yes
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Figure 13–2
Categorization of All Serious Adverse Events
All SAEs
Device /
procedure 
related?
SAE
SADE
No
Yes
Intraoperative Adverse Events
13.1.1
Anticipated intraoperative adverse events include, but are not limited to, the following 
cataract surgery and other intraoperative complications.
a) Anterior capsule tear
b) Choroidal detachment
c) Posterior capsular rupture
d) Vitreous in the anterior chamber
e) Choroidal hemorrhage or effusion
f)
Cyclodialysis cleft – oversized
g) CyPass non-implantation after penetration of the tissue plane between the ciliary body 
and the scleral spur
h) Descemet’s membrane break
i)
Hyphema obscuring the surgeon’s view 
j)
Inadvertent loss of vitreous not associated with the cataract procedure
k) Inadvertent perforation of sclera
l)
Secondary ocular surgical intervention – AC lavage
m) Significant corneal damage
n) Significant iris injury or trauma
o) Subconjunctival hemorrhage
p) Zonular dialysis
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Postoperative Adverse Events
13.1.2
Anticipated postoperative adverse events include, but are not limited to, the following 
complications.
a) BCDVA loss of 2 lines (10 letters) or more on the ETDRS chart measured at or after 3 
months postoperative compared to BCDVA at Visit 3 (1 Month Follow-up)
b) Persistent (at time of study exit) BCDVA loss of 3 or more lines compared to best 
BCDVA achieved during the course of study
c) 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 compared to Visit 0 (Screening)
d) Endophthalmitis
e) Flat AC with lens cornea touch
f)
Shallow AC with iridocorneal apposition
g) Shallow AC with peripheral iridocorneal apposition
h) Aqueous misdirection
i)
Anterior chamber cell and flare requiring either an increase in the standard protocol 
postoperative steroid regimen or initiation of steroid treatment following completion 
of the protocol postoperative steroid regimen
j)
Conjunctivitis
k) Keratitis
l)
Corneal edema (mild to moderate corneal edema prior to 1 month postoperative is not 
considered an adverse event)
m) Corneal opacification 
n) Corneal decompensation
o) Persistent hyphema of >2 mm present greater than 1 day postoperative
p) Retinal detachment
q) Other retinal complications (eg, dialysis, flap tears, or proliferative vitreoretinopathy)
r)
Increase in C/D ratio of ≥0.3 units on slit lamp biomicroscopic examination
s) Confirmed worsening in the visual field mean deviation (MD) of ≥2.5 dB compared 
to the MD used to determine subject eligibility 
t)
Choroidal hemorrhage or choroidal effusion, defined as a choroidal effusion or 
detachment with at least a partially hemorrhagic component that obstructs vision or 
causes pain (including both peripheral and “kissing” choroidal detachments) lasting 
longer than 1 month 
u) Peripheral anterior choroidal effusion
v) Maculopathy associated with hypotony
w) Maculopathy associated with cystoid edema
x) Hypotony (defined as IOP <6 mmHg) at or after 1 month postoperative
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Page 61 of 83
y) Clinically significant hypotony, defined as IOP <6 mmHg with any of the following 
findings:
i.
Maculopathy
ii.
Flat AC chamber requiring reformation
iii.
Corneal folds
iv.
Worsening of with-the-rule astigmatism by ≥1 diopter, or rotation of against-
the-rule astigmatism to ≥1 diopter of with-the-rule astigmatism
v.
Choroidal effusion requiring surgical drainage
vi.
Suprachoroidal hemorrhage
vii.
BCDVA loss of ≥2 lines from the best postoperative BCDVA 
z) Elevated mean IOP ≥10 mmHg than the qualifying baseline mean IOP at or after 1 
month postoperative
aa) CyPass device obstructed by iris, vitreous, lens, fibrous overgrowth, fibrin, or blood
bb) CyPass device malposition – positioning after deployment such that the device is not 
in the supraciliary space
cc) CyPass device malposition – positioning after deployment such that there is a clinical 
sequela resulting from device position including, but not limited to:
i.
Secondary surgical intervention to modify device position (eg, repositioning, 
proximal end trimming or explantation) 
ii.
Corneal endothelial touch by device 
iii.
Corneal edema leading to loss of BCDVA > 2 lines at the last postoperative
visit, in comparison with preoperative BCDVA
iv.
Progressive ECL, defined as ongoing reduction in endothelial cell count of 
30% or more relative to the screening ECD value, where ‘ongoing reduction in 
endothelial cell count’ is defined as losses continuing after Visit 5 (6 Month 
Follow-up)
v.
Erosion of device through sclera 
vi.
Device obstruction requiring secondary surgical intervention
dd) CyPass device dislodgement or movement, without sequelae, where device movement 
is defined as a change by at least 1 in the number of CyPass rings visible that is not 
attributable to variations in gonioscopic viewing angle or illumination, changes in 
angle anatomy due to concomitant findings such as resolution of hyphema, change in 
anterior chamber depth, or development of focal peripheral anterior synechiae
ee) CyPass device explantation associated with CyPass placement and stability
ff) CyPass device explantation NOT associated with CyPass placement and stability
gg) Unplanned ocular surgical reintervention associated with CyPass placement and 
stability
hh) Unplanned ocular surgical reintervention NOT associated with CyPass placement and 
stability (other than paracentesis to relieve pressure prior to 1 week postoperative or 
Nd:YAG capsulotomy) 
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Printed By: 
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TDOC-0052735
Protocol - Clinical
22-Aug-2017

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Page 65 of 83
Study Sponsor representatives may be contacted for any protocol related question and their 
contact information is provided in the Manual of Procedures that accompanies this protocol.
Further, depending upon the nature of the AE or device deficiency being reported, the Study 
Sponsor may request copies of applicable portions of the subject’s medical records. The 
Investigator must also report all AEs and device deficiencies that could have led to a SADE 
according to the requirements of regulatory authorities or IRB/IEC.
Intensity and Causality Assessments
13.3.1
Where appropriate, the Investigator must assess the intensity (severity) of the AE based on 
medical judgment with consideration of any subjective symptom(s), as defined below:
Intensity (Severity)
Mild 
An AE is mild if the subject is aware of but can easily tolerate the sign or 
symptom.
Moderate 
An AE is moderate if the sign or symptom results in discomfort significant 
enough to cause interference with the subject’s usual activities.
Severe 
An AE is severe if the sign or symptom is incapacitating and results in the 
subject’s inability to work or engage in their usual activities.
For every AE in the study, the Investigator must assess the causality (Related or Not Related 
to the medical device or study procedure). An assessment of causality will also be performed 
by Study Sponsor utilizing the same definitions, as shown below:
Causality
Related
An AE classified as related may be either definitely related or possibly related 
where a direct cause and effect relationship with the medical device or study 
procedure has not been demonstrated, but there is a reasonable possibility that 
the AE was caused by the medical device or study procedure.
Not Related 
An AE classified as not related may either be definitely unrelated or simply 
unlikely to be related (ie, there are other more likely causes for the AE).
The Study Sponsor will assess the AEs and may upgrade the Investigator’s assessment of 
seriousness and/or causality. The Study Sponsor will notify the Investigator of any AEs that is 
upgraded from non-serious to serious or from unrelated to related.
Return Product Analysis
13.4
Study Sponsor representatives and their contact information are provided in the MOP that 
accompanies this protocol. 
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Page 66 of 83
Alcon products associated with device deficiencies and/or product related AEs should be 
returned and must include the Complaint # which will be provided by Study Sponsor after the
case is entered in the Study Sponsor’s Global Product Complaint Management System
(GPCMS). 
Unmasking of the Study Information
13.5
Not applicable; this study is open-label.
Follow-Up of Subjects with Adverse Events
13.6
The Investigator is responsible for adequate and safe medical care of subjects during the 
study and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the study. 
The Investigator should provide the Study Sponsor with any new safety information (which 
includes new AEs and changes to previously reported AEs) that may affect the safety 
evaluation of the device. For AEs that are unresolved/ ongoing at time of subject exit from 
study, any additional information received at follow-up should be documented in the eCRFs 
up to study completion (ie, database lock). 
All complaints received after this time period will be considered and processed as 
spontaneous (following the post-market vigilance procedures) and should be communicated 
to the medical device’s manufacturer as per local requirements.
The Investigator should also report complaints on non-Alcon products directly to the 
manufacturer as per the manufacturer’s instructions or local regulatory requirements.
Pregnancy in the Clinical Study
13.7
Pregnancy is not reportable as an AE; however, complications may be reportable and will be 
decided on a case–by-case basis. An Alcon form will be utilized to capture all pregnancy-
related information until birth of the child. 
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Effective Date:  
Document:  
Version:  
Status:  
Printed By: 
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Effective
4.0; Most-Recent; Effective; CURRENT
TDOC-0052735
Protocol - Clinical
22-Aug-2017

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Data Review and Clarifications
14.2
Upon completion of the eCRFs, the data will be reviewed by Alcon study personnel for 
accuracy and completeness. If corrections and/or any additions to the data are deemed 
necessary, queries will be generated by Alcon data management or the site management 
(study monitor) team and forwarded to the investigative site. Staff at each site are expected to 
respond to data queries in a timely manner and ensure that the corrections and changes made 
to the data in the EDC system are reflected in the subjects’ source documentation. In addition, 
prior to study start (first subject first visit) a plan for data validation will be completed by 
Alcon Clinical Data Management and agreed upon by members of the Clinical Trial 
Management (CTM) team.
Concomitant medications entered into the database will be coded using the current version of 
the WHO (World Health Organization) Drug Reference List. Medical history and adverse 
events will be coded using the medical dictionary for regulatory activities (MedDRA) 
terminology.
Upon completion of the study and once the database is declared complete and accurate, the 
database will be locked and data will be available for the final data analysis. Any changes to 
the database after lock will be implemented upon agreement between Alcon’s clinical trial 
management and biostatistics department, and will be completed following Alcon’s 
procedures for changes to a database after database lock.
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15
ANALYSIS PLAN
This information may also be contained within a separate biostatistical analysis plan which 
will be prepared and finalized prior to database lock.
Subject Evaluability
15.1
All patients will be considered enrolled once they have signed the informed consent form. 
The assignment of each study eye to the study analysis sets will be made prior to database 
lock.
Analysis Data Sets
15.2
All eligible subjects will be screened to determine if they meet all inclusion and no exclusion 
criteria. Subjects who do so and provide informed consent will be considered enrolled in the 
study.
Intention to Treat
15.2.1
The intention to treat (ITT) analysis set will be defined as the set of study eyes for which a 
CyPass Micro-Stent implant is attempted; the ITT analysis set will be the primary analysis set 
for all study analyses.
 
 
Demographics and Baseline Characteristics
15.3
Demographics and baseline characteristics will be summarized with appropriate summary 
statistics. Eye level summaries will be based on all study eyes in the ITT analysis set; subject 
level summaries (eg, age) will be based on all subjects with an eye in the ITT analysis set.
Effectiveness Analyses
15.4
Primary Effectiveness
15.4.1
There is no primary effectiveness endpoint for this study.
Secondary Effectiveness
15.4.2
The secondary effectiveness endpoints are listed in Section 8.2.1.2.
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Statistical Hypotheses
15.4.2.1
There are no statistical hypotheses for the secondary effectiveness endpoints which will be 
summarized descriptively.
Analysis Methods
15.4.2.2
Continuous endpoints will be summarized by number of observations (n), mean, median, 
standard deviation, minimum and maximum; binary endpoints will be summarized by 
numerator (number of eyes meeting the endpoint), denominator , and the proportion of ITT 
eyes meeting the endpoint. Denominators for adverse events, slit lamp findings, and other 
events will be the number of eyes in the ITT set. Denominators for data such as visual acuity 
and other subject data that is collected at protocol-required visits will reflect the number of 
eyes with non-missing data in the ITT set. Summary statistics will be presented at all 
postoperative visits for which the endpoint data are collected. Supportive analysis will be 
conducted using the DI analysis set for all secondary effectiveness outcomes.
Safety Analyses
15.5
Primary Safety
15.5.1
The primary safety endpoint is detailed in Section 8.2.2.1.
Statistical Hypothesis
15.5.1.1
The primary null hypothesis to be tested is that the observed rate of clinically relevant 
complications associated with CyPass Micro-Stent placement and stability is greater than or 
equal to the performance target rate of 7%. The corresponding alternative hypothesis to be 
tested is that the observed rate of complications is less than the performance target rate. These 
hypotheses are expressed formulaically as:
H0: pC ≥ 7%
H1: pC < 7%
where pC is the population proportion of eyes experiencing a complication event at 36 
months.
Analysis Methods
15.5.1.2
The primary safety hypothesis will be tested with an exact one-sided binomial test with type I 
error 0.05. The ITT analysis set will be used for the primary safety analysis.
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Secondary Safety
15.5.2
The secondary safety endpoints are listed in Section 8.2.2.2.
Statistical Hypotheses
15.5.2.1
There are no statistical hypotheses for the secondary safety endpoints.
Analysis Methods
15.5.2.2
Continuous endpoints will be summarized by number of observations (n), mean, median, 
standard deviation, minimum and maximum; binary endpoints will be summarized by 
numerator (number of eyes meeting the endpoint), denominator (number of eyes in the ITT 
set), and the proportion of eyes meeting the endpoint. Summary statistics will be presented at 
all follow-up visits for which the endpoint data are collected. Supportive analysis will be 
conducted using the DI analysis set for all secondary safety outcomes.
Other Safety
15.5.3
The other safety endpoints are listed in Section 8.2.2.3.
Statistical Hypotheses
15.5.3.1
There are no statistical hypotheses for the other safety endpoints.
Analysis Methods
15.5.3.2
Continuous endpoints will be summarized by number of observations (n), mean, median, 
standard deviation, minimum and maximum; binary endpoints will be summarized by 
numerator (number of eyes meeting the endpoint), denominator (number of eyes in the ITT 
set), and the proportion of eyes meeting the endpoint. Summary statistics will be presented at 
all follow-up visits for which the endpoint data are collected. Supportive analysis will be 
conducted using the DI analysis set for all other safety outcomes.
Ocular Adverse Events
15.5.4
The number of events, number of eyes experiencing the event, and the rate of the event will 
be reported for all postoperative ocular adverse events occurring in study eyes. Any ocular 
events occurring pre-operatively in study eyes will be listed separately. Any ocular events 
occurring in non-study eyes will also be listed separately.
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Non-Ocular Adverse Events
15.5.5
The number of events, number of subjects experiencing the event, and the rate of the event 
will be reported for all non-ocular adverse events.
Device Deficiencies
15.5.6
The number of device deficiencies by type will be calculated, and a listing of all device 
deficiencies will be provided.
Endothelial Cell Count
15.5.7
Specular microscopy data at baseline and at each follow-up visit at which the exam is 
conducted will be summarized with number of observation (n), mean, median, standard 
deviation, minimum, and maximum. Change and percentage change from baseline as well as 
change between two consecutive visits will also be summarized with number of observations 
(n), mean, median, standard deviation, minimum, and maximum.
Slit Lamp and Fundus Examinations
15.5.8
Slit lamp and fundus examination results at baseline and at each follow-up visit at which the 
exams are conducted will be summarized by the number of subjects in each category 
(numerator), the number of subjects with data (denominator), and the percentage of subjects 
in each category (numerator / denominator).
Corneal Pachymetry
15.5.9
Corneal pachymetry data recorded at screening and at each follow-up visit at which the exam 
is conducted will be summarized descriptively with number of observations (n), mean, 
median, standard deviation, minimum, and maximum.
Visual Field Loss Mean Deviation Testing
15.5.10
The visual field mean deviation testing data collected at baseline and at each follow-up visit 
at which the exam is conducted will be summarized with number of observations (n), mean, 
standard deviation, minimum, and maximum.
Manifest Refraction
15.5.11
The number of observations (n), mean, median, standard deviation, minimum, and maximum 
for sphere, cylinder, and manifest refraction spherical equivalent will be reported at baseline 
and at each follow-up visit for which manifest refraction is scheduled.
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Handling of Missing Data
15.6
A tipping point analysis will be performed for the primary safety endpoint.
In addition, a comparison of baseline characteristics including age, gender, race, site, and 
baseline unmedicated IOP will be performed between those subjects who complete Visit 8 
(36 Month Follow-up) and those who do not.
Interim Analyses
15.7
Interim reports pertaining to the progress of the post approval study will be submitted to the 
FDA for review every 6 months for the first two years, starting from the date of approval, and 
will continue to be submitted annually thereafter, until study completion.
For each interim report, the number of subjects enrolled and implanted with the CyPass 
device will be reported. In addition, the number of clinically relevant complications 
associated with CyPass Micro-Stent placement and stability (events toward the primary 
endpoint) will be reported, and a listing and summary table with the number of events, and 
number and proportion of subjects experiencing all such events will be provided. A listing of 
all ocular SAEs will also be provided. A summary of the secondary effectiveness endpoints 
will be reported once 50% of the subjects in the ITT set have completed Visit 5 (6 Month 
Follow-up Visit).
Sample Size Justification
15.8
The performance target for the primary safety endpoint is 7.0%.  
An evaluation of COMPASS (TMI-09-01) data showed that through 24 months of follow-up, 
there were two eyes with failures to implant and eight eyes with CyPass malposition events, 
respectively, corresponding to the above definitions. In addition, there were four eyes with 
documentation of three rings visible within the first postoperative week that likely would 
have undergone early secondary surgical intervention due to anterior CyPass positioning 
under the approach documented in the Instructions for Use (IFU). Inclusion of these cases 
would increase the number of observed events from 10 to 14 (3.74%, 95% confidence 
interval:  2.1% – 6.2%). Of note, not all investigators documented the number of rings visible 
in the early postoperative period because this was not a study requirement (data regarding the 
number of rings is recorded for only 96 subjects at 1 Day and 139 subjects at 1 Week), so this 
number likely underestimates the number of subjects who would have been candidates for 
early surgical re-intervention under the new criteria described in the IFU.
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Page 75 of 83
16
ADMINISTRATIVE PROCEDURES
Regulatory and Ethical Compliance
16.1
This clinical trial will be conducted in accordance with the principles of the Declaration of 
Helsinki, and in compliance with ISO 14155:2011 Clinical investigation of medical devices 
for human subjects, Good Clinical Practice (GCP), and the Code of Federal Regulations 
(CFR). The study will also be conducted in accordance with the Sponsor’s Standard 
Operating Procedures (SOPs), and the SOPs of Contract Research Organizations participating 
in the conduct of the clinical trial, and all other applicable regulations. The Investigator and 
all clinical trial staff will conduct the clinical trial in compliance with this protocol. The 
Investigator will ensure that all personnel involved in the conduct of the clinical trial are 
qualified to perform their assigned duties through relevant education, training, and 
experience.
Informed Consent Procedures
16.2
Voluntary informed consent will be obtained from every subject  prior to the initiation of any 
screening or other clinical trial-related procedures.  The Investigator must have a defined 
process for obtaining consent. Specifically, the Investigator, or designee, will explain the 
clinical trial to each potential subject and the subject must indicate voluntary consent by 
signing and dating the IRB/IEC approved informed consent form. The subject must be 
provided an opportunity to ask questions of the Investigator, and if required by local 
regulation, other qualified personnel. The Investigator must provide the subject with a copy 
of the consent form written in a language the subject understands. The consent document 
must meet all applicable local laws and will provide subjects with information regarding the 
purpose, procedures, requirements, and restrictions of the clinical trial, along with any known 
risks and potential benefits associated with the investigational product, the available 
compensation, and the established provisions for maintaining confidentiality of personal, 
protected health information. Subjects will be told about the voluntary nature of participation 
in the clinical trial and will be provided with contact information for the appropriate 
individuals should questions or concerns arise during the clinical trial. The subject also will 
be told that their records may be accessed by appropriate authorities and Sponsor-designated 
personnel. The Investigator must keep the original, signed copy of the consent and must 
provide a duplicate copy to each subject.
Responsibilities of the Investigator and IRB/IEC
16.3
Before clinical trial initiation, this protocol, the informed consent form (and assent form, if 
applicable), any other written information provided to subject, and any advertisements 
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planned for subject recruitment must be approved by an Institutional Review Board / 
Independent Ethics Committee (IRB/IEC). Documentation of IRBs/IECs for this clinical trial 
can be found in the Trial Master File. The Investigator must provide documentation of 
IRB/IEC approval to the Sponsor. The approval must be dated and must identify the 
applicable protocol, amendments (if any), informed consent form, assent form (if any), all 
applicable recruiting materials, written information for subjects, and subject compensation 
programs. The IRB/IEC must be provided with a copy of the Investigator’s Brochure, any 
periodic safety updates, and all other information as required by local regulation and/or the 
IRB/IEC. At the end of the clinical trial or in the case of early termination, the Investigator 
will notify the IRB/IEC of the clinical trial’s final status. Finally, the Investigator will report 
to the IRB/IEC on the progress of the clinical trial at intervals stipulated by the IRB/IEC.
Sponsor and Monitoring Responsibilities
16.4
The Sponsor will designate a monitor to conduct the appropriate site visits at the appropriate 
intervals. The clinical investigation will be monitored to ensure that the rights and wellbeing 
of the subjects are protected; the reported data are accurate, complete, and verifiable from the 
source documents; the equipment used to assess variables in the clinical investigation is 
maintained and calibrated per manufacturer instructions and Sponsor requirements; and the 
study is conducted in compliance with the current approved protocol (and amendment[s], if 
applicable), with current GCP, and with applicable regulatory requirements.
All investigative sites will have a site initiation. Monitoring will be conducted periodically 
while the clinical study is ongoing. Monitoring methods may include site visits, telephone, 
written, and fax correspondence. The assigned CSM will contact each site at appropriate 
intervals. The Lead Clinical Site Manager (LCSM) will determine the frequency of site visits. 
Close-out visits will take place after the last visit of the last subject.
Enrollment will be tracked and reported at regular intervals. Details regarding enrollment (eg, 
number of subjects pre-screened, screened, reasons for screen failures, etc.) may be requested 
of the investigative site and must be provided within a reasonable time period.
The Sponsor will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure the study is conducted and data are generated, documented 
and reported in compliance with the protocol, GCP and applicable regulatory requirements. 
The Sponsor will secure agreement from all involved parties to ensure direct access to all 
study related sites, source data and documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by domestic and foreign regulatory authorities.
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Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. Agreements made by the Sponsor with the 
Investigator/Institution and any other parties involved in the clinical study will be provided in 
writing as part of the protocol or as a separate agreement.
Regulatory Documentation and Records Retention
16.5
The Investigator is accountable for the integrity, retention, and security of all study related 
data. The Investigator must maintain accurate, complete, and current records relating to the 
clinical study. The Investigator must maintain the required records during the investigation 
and for a period of time specified by local law or per the Clinical Study Agreement, 
whichever is longer. If the Investigator retires, relocates, of for any other reason withdraws 
from responsibility of keeping the study records, the Sponsor must be notified and suitable 
arrangements made for retention of study records and source documents needed to comply 
with national and international regulations.
Clinical Trial Results 
16.6
Any information other than that which is disclosed upon registration should not be discussed 
with persons outside the study. The protocol, study data, and information related to the study 
or to Alcon’s products or research programs that is provided by Alcon (Confidential 
Information) is to be kept confidential, and not disclosed directly or indirectly to any third 
party other than those involved in the study who have a need to know.
All data and discoveries arising out of the study, patentable or non-patentable, shall be the 
sole property of Alcon, Inc. Alcon reserves the right of prior review of any publication or 
presentation of information related to the study. Alcon may use these data now and in the 
future for presentation or publication at Alcon’s discretion or for submission to government 
regulatory agencies.
The existence of this clinical study is confidential and should not be discussed with persons 
outside of the study. You shall hold confidential, and not disclose directly or indirectly to any 
third party other than those persons involved in the study who have a need to know, the 
protocol, the data arising out of the study, and any other information related to the study or to 
Alcon’s products or a research program that is provided by Alcon to you (the “Confidential 
Information”). All such persons must be instructed not to further disseminate this information 
to others. You shall not use the Confidential Information for any purpose other than the study.
The foregoing obligations of confidence and non-use assumed by you shall not apply to : (a) 
information which at the time of disclosure is in the public domain; (b) information which 
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thereafter lawfully becomes part of the public domain other than through disclosure by or
through you; (c) information which, as evidenced by your written records, was known by you
prior to Alcon’s disclosure; (d) information which is lawfully disclosed to you by a third party 
not under any obligation of confidence to Alcon; or (e) information which is required to be 
disclosed by law or government regulatory agency, provided reasonable advance notice of
such disclosure is given to Alcon.
In signing this protocol, you agree to the release of the data from this study and acknowledge
the above confidentiality and publication policy. The provisions of this Statement shall
survive the completion of the study.
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17
REFERENCES
The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The 
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Ophthalmol 2000;130:429-40. 
The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 13. 
Comparison of treatment outcomes within race. 10-year results. Ophthalmology 
2004;111:651-64. 
Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous 
progression between untreated patients with normal-tension glaucoma and patients with 
therapeutically reduced intraocular pressures. Am J Ophthalmol 1998;126:487-97. 
Congdon N, for The Eye Diseases Prevalence Research Group. Causes and prevalence of 
visual impairment among adults in the United States. Arch Ophthalmol 2004;122:477-85. 
The European Glaucoma Prevention Study (EGPS) Group. The European Glaucoma 
Prevention Study design and baseline description of the participants. Ophthalmology 
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The European Glaucoma Prevention Study (EGPS) Group. Results of the European 
Glaucoma Prevention Study. Ophthalmology 2005;112:366-75. 
Friedman DS, for The Eye Diseases Prevalence Research Group. Prevalence of open-angle 
glaucoma among adults in the United States. Arch Ophthalmol 2004;122:532-8.
The Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT). 2. Results of 
argon laser trabeculoplasty versus topical medicines. Ophthalmology 1990;97:1403-13. 
The Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma 
Laser Trial Follow-up Study: 7. Results. Am J Ophthalmol 1995;120:718-31. 
Gordon MO, Kass MA, for the Ocular Hypertension Treatment Study Group. The Ocular 
Hypertension Treatment Study. Design and baseline description of the participants. Arch 
Ophthalmol 1999:573-83. 
Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, for the Early Manifest 
Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression. Results 
from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268-79. 
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Javitt JC, Chiang YP. Preparing for managed competition. Utilization of ambulatory eye care 
visits to ophthalmologists. Arch Ophthalmol 1993;111:1034-5. 
Jay JL, Allan D. The benefit of early trabeculectomy versus conventional management in 
primary open-angle glaucoma relative to severity of disease. Eye 1989;3:528-35. 
Jordan JF, Dietlein TS, Dinslage S, Lüke C, Konen W, Krieglstein GK.  Cyclodialysis ab 
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18
APPENDICES
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