A Prospective, Multicenter Clinical Trial of the VisAbility Micro Insert System for Improvement of Near Visual Acuity In Presbyopic Patients
Phase: NA
Conditions: Presbyopia
Sponsor: Refocus Group, Inc.

 
 
 
 
PROTOCOL VIS-2014 
 
 
A PROSPECTIVE, MULTICENTER CLINICAL TRIAL OF  
THE VISABILITY IMPLANT SYSTEM  
FOR IMPROVEMENT OF NEAR VISUAL ACUITY IN PRESBYOPIC PATIENTS 
 
 
Refocus Group, Inc. 
10300 North Central Expressway 
Suite 104 
Dallas, TX 75231 
 
Date of Protocol: October 13, 2014 
Date of Protocol Amendment 2: March 3, 2015 
 
 
 
I have read and agree to follow the study procedures as outlined in this protocol. 
 
 
 
 
Print Name of Investigator 
 
 
 
 
Investigators’ Signature 
 
 
 
 
 
 Date 
 
 
 
 
CONFIDENTIAL – DO NOT COPY OR DISTRIBUTE 
 
This protocol contains confidential proprietary information with respect to Refocus products and 
clinical trials.  I agree to hold this information in confidence and not to disclose it to any third 
parties for a period of three years from the date of this agreement, or until this information 
becomes a matter of public knowledge or until a formal agreement for that purpose has been 
entered into by the parties. 
 
 

 
 
 
 
PROTOCOL VIS-2014 
TABLE OF CONTENTS 
1.0 
PERSONNEL AND FACILITIES .......................................................... 1 
2.0 
ABBREVIATIONS  .............................................................................. 2 
3.0 
STUDY SYNOPSIS .............................................................................. 4 
4.0 
BACKGROUND AND REGULATORY CHRONOLOGY ..................... 5 
5.0 
SCIENTIFIC BACKGROUND ON PRESBYOPIA ............................... 7 
6.0 
PRIOR SCLERAL IMPLANT CLINICAL STUDIES ........................... 10 
7.0 
STUDY OUTLINE .............................................................................. 13 
8.0 
STUDY METHODS ............................................................................ 16 
9.0 
INVESTIGATIONAL MATERIALS ..................................................... 24 
10.0 
ADVERSE EVENT REPORTING ....................................................... 30 
11.0 
STATISTICAL METHODS ................................................................. 35 
12.0 
MONITORING .................................................................................... 44 
13.0 
REFERENCES ................................................................................... 45 
LIST OF APPENDICES 
Appendix 1  Examination Methods .................................................................. 46 
Appendix 2  VisAbility Implant System Surgical Procedure ......................... 54 
Appendix 3  Patient Reported Outcomes Questionnaire  
(Navq) ............................................................................................ 61 
Appendix 4  Patient Questionnaire .................................................................. 74 
Appendix 5  Data Safety Monitoring Board Charter ....................................... 75 
Appendix 6  Anterior Segment Ischemia; Detection,  
Mitigation and Reporting ............................................................. 81 
Appendix 7  Sponsor Commitments  .............................................................. 88 
Appendix 8  Investigator Commitments and Responsibilities ...................... 89 
Appendix 9  Declaration of Helsinki  ............................................................... 91 
PROTOCOL VIS-2014    
 
 
 
 
       
 
 
 TABLE OF CONTENTS 
Compilation Protocol Amendment 2 - March 3, 2015 

PROTOCOL VIS-2014 
 
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Compilation Protocol Amendment 2 - March 3, 2015 
 
 
 
 
 
1.0 
PERSONNEL AND FACILITIES 
 
STUDY SPONSOR 
 
Refocus Group, Inc. 
 
 
 
 
10300 North Central Expressway 
Suite 104 
 
 
 
 
Dallas, TX 75231 
 
 
 
 
(214) 368-0200 
 
MEDICAL MONITOR  
Mark Packer, M.D. 
 
 
 
 
4075 Southpointe Drive 
 
 
 
 
Eugene, Oregon 97405 
 
 
 
 
(541) 915-0291 
 
CLINICAL MONITOR  
Quality Data Services, Inc. 
 
 
 
 
1000 Continental Drive 
 
 
 
 
Suite 200 
 
 
 
 
King of Prussia, Pennsylvania 19406 
 
 
 
 
(610) 354-0404 
 
 
 
 
 

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2.0 
ABBREVIATIONS  
AE 
 
Adverse Event 
AIDS  
Acquired Immune Deficiency Syndrome 
ASI 
 
Anterior Segment Ischemia 
BCDVA 
Best Corrected Distance Visual Acuity 
BCNVA 
Best Corrected Near Visual Acuity 
BSS 
 
Balanced Salt Solution 
CPS 
 
Critical Print Size 
CRF 
 
Case Report Form 
CRO  
Clinical Research Organization 
CRSE  
Cycloplegic Refraction Spherical Equivalent 
CSLO  
Confocal Scanning Laser Ophthalmology 
dB 
 
Decibel 
DCNVA 
Distance Corrected Near Visual Acuity 
eCRF  
electronic Case Report Form 
EDC 
 
Electronic Data Capture 
GCP 
 
Good Clinical Practice 
HIV 
 
Human Immunodeficiency Virus 
ICC 
 
Intraclass Correlation Coefficient 
ICD 
 
International Classification of Diseases 
ICF 
 
Informed Consent Form 
IDE 
 
Investigational Device Exemption 
IOL 
 
Intraocular Lens 
IOP 
 
Intraocular Pressure 
IRB 
 
Institutional Review Board 
LASIK  
Laser Assisted In-Situ Keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution  
LST 
 
Lamellar Scleral Tunnel 
MD 
 
Mean Deviation 
mm 
 
millimeters 
mm Hg 
Millimeters of Mercury 
MRSE  
Manifest Refraction Spherical Equivalent 
NAVQ  
Near Acuity Visual Questionnaire 
NSAID  
Non-Steroidal Anti-Inflammatory Drug 
OCT 
 
Optical Coherence Tomography 
OD 
 
Right Eye 
OS 
 
Left Eye 
PG 
 
Prostaglandin 
PI 
 
Principal Investigator 
PMA 
 
Premarket Approval 
PMMA  
Polymethylmethacrylate 
PRO 
 
Patient Reported Outcomes 
PSD 
 
Pattern Standard Deviation 
PSI 
 
PresVIEW Scleral Implants 
PTFE  
Polytetrafluoroethylene 
SAE 
 
Serious Adverse Event 
SITA  
Swedish Interactive Threshold Algorithm 
SOP 
 
Standard Operating Procedure 
SPK 
 
Superficial Punctuate Keratitis 

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UADE  
Unanticipated Adverse Device Effect 
UBM  
Ultrasound Biomicroscopy 
UCDVA 
Uncorrected Distance Visual Acuity 
UCIVA  
Uncorrected Intermediate Visual Acuity 
UCNVA 
Uncorrected Near Visual Acuity 
UK 
 
United Kingdom 
US 
 
United States 
VIS 
 
VisAbility Implant 
VIS 
 
VisAbility Implant System 
VR-QOL 
Vision Related Quality of Life 
 
 

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3.0 
STUDY SYNOPSIS   
The objective of this study is to evaluate the safety and effectiveness of the VisAbility Implant 
System (VIS) for the improvement of near visual acuity in presbyopic patients.  This is a 
prospective clinical study that will enroll and determine eligible a total of 360 subjects ranging in 
age between 45 and 60 years of age at up to 14 clinical sites.  Subjects will be implanted with the 
VisAbility Implant model SGP-046 in the primary eye and then in the fellow eye no sooner than 
14 days later.  Subjects will be examined at one day, one week and at 1, 2, 3, 6, 12, 18 and  
24 months post-operatively.   
The study will also include a 60 subject randomized controlled sub-study at 3 investigational sites. 
Subjects enrolled and eligible at these sites will be randomized (1:1 ratio) to a surgery group or a 
control group. Subjects randomized to the surgery group will undergo surgery and will be followed 
for 24 months in the same manner as the larger non-randomized surgical group. Subjects 
randomized to the control group will be followed for 6 months, and will be eligible to undergo 
surgery after completion of this 6-month follow-up period.   
The primary endpoint is achievement of distance corrected near visual acuity (DCNVA) of Snellen 
equivalent 20/40 or better (at 40 cm) and at least 10 letters (ETDRS) improvement in DCNVA in 
the primary eye.  
This endpoint will be evaluated against two objectives, a) 75% or more of primary eyes achieve 
the effectiveness endpoint at 12 months postoperative and b) the percentage of primary eyes 
achieving the effectiveness endpoint at 6 months postoperative (6-month responder rate) is higher 
than the percentage in the randomized control group.   
A PMA application will be submitted when the full study cohort has completed the 12 month follow-
up visit. 
 

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4.0 
BACKGROUND AND REGUALORY CHRONOLOGY 
4.1 
Background 
Clinical evaluation of PresVIEW Scleral Implants (PSI) was initiated in 1997 following FDA 
approval of G970152.  The initial clinical trial was a feasibility study in presbyopic subjects desiring 
improvement in near visual acuity. Based on the encouraging outcomes of the feasibility study a 
large clinical trial of the PSI was initiated in 2003 under Protocol P-277-5, and two models of the 
PSI have been evaluated. 
 
The PSI model PSI-001 was implanted in 164 subjects (213 eyes) from 1999 through 2007.  The 
PSI model SGP-046 was introduced in 2009 to provide better fixation of the PSI in the scleral 
tunnel.  Since there were significant differences in the design of the PSI models PSI-001 and 
SGP-046, a full cohort of 330 subjects (645 eyes) was implanted with the SGP-046 model. 
 
Both scleral implant models PSI-001 and SGP-046 consist of four segments which are implanted 
in scleral tunnels in the four oblique quadrants of the eye. From 1999 through 2000, scleral tunnels 
were created using a diamond blade.  An automated, electrically powered, re-usable device 
designed specifically for scleral tunnel creation, called the Scleratome, was introduced in 2003 
and this incision system was used through mid-2012.  In April 2012, FDA approved introduction 
of a smaller, lighter, disposable Scleratome into the ongoing IDE clinical trial.  Since the tunnel 
configuration was the same for both Scleratomes, as demonstrated in performance testing 
submitted in the IDE supplement supporting introduction of the disposable Scleratome, Refocus 
assumed that clinical data from both the re-usable and the disposable Scleratome were expected 
to be comparable. 
 
After introduction of the disposable Scleratome in May 2012, 56 subjects (119 eyes) were 
implanted in incisions made with this improved Scleratome.  An exploratory analysis of 12 month 
clinical outcomes of these eyes as compared to eyes implanted with the earlier reusable 
Scleratome provided evidence of greater improvements in near vision with the disposable 
Scleratome.  While this finding was unanticipated, it was also very encouraging since these 
improvements in near vision were achieved considerably earlier in the postoperative period. 
This finding was also important since it confirmed Refocus’ expectation that improved surgical 
instrumentation would have a favorable effect on postoperative clinical outcomes, as evidenced 
in the transition from the original IDE pilot study in which scleral tunnels were created using a 
diamond blade to use of the automated, re-usable Scleratome introduced in 2003 and to the more 
recent introduction of the disposable Scleratome. 
 
In Protocol P-277-5, conducted under G970152, the location of the scleral incisions for placement 
of the PSI was identified by marking the targeted position of the incisions. This method was not 
completely reliable since the marking can be difficult for the surgeon to see during the procedure. 
As a result, some surgeons had experienced difficulty placing the Scleratome in the proper 
position relative to the marks created.   
 
 
 

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4.2  
Rationale for Protocol VIS-2014 
In a further effort to develop improved surgical instrumentation that would provide more reliable 
placement of the scleral tunnels created by the Scleratome, the company has developed an 
integrated surgical instrumentation system, called the VisAbility Implant System. 
The VisAbility Implant System consists of the: 
 
• 
VisAbility Implant (previously referred to as the PSI model SGP-046), 
• 
VIS Docking Station (previously referred to as the Oculock) 
• 
VIS Scleratome (the Docking and Scleratome together, previously called the  
“Oculock Incision System”) 
• 
Other custom surgical instruments for use during the procedure.  
The Docking Station is a fixation device that addresses sources of variability in the creation of 
scleral tunnels and provides a simple method for placing the Scleratome in the correct location 
on the eye. The Docking Station provides stabilization of the eye and serves to “dock” the 
Scleratome during creation of the scleral tunnels, ensuring consistent placement of the 4 scleral 
tunnels to be created.  Use of the Docking Station with the Scleratome is expected to result in a 
shorter duration procedure as well as in improved reproducibility of the implantation procedure.   
The VisAbility Implant System, and specifically the Docking Station, prevents creation of scleral 
tunnels too close to the limbus by establishing a guide for the positioning of the Scleratome blade 
at a distance of approximately 4.0 millimeters from the corneal limbus. When the Docking Station 
is properly aligned, the 4 PSI segments will be equally spaced between the rectus muscles, 
minimizing the likelihood of pressure on the anterior ciliary muscles, which could result in reduced 
iris perfusion.  It should be noted that the PSI model SGP-046, renamed the VisAbility Implant, 
has not been modified since its introduction into the clinical trial conducted under G970152, 
and there are no plans to modify this implant. 
Given the potential for the VisAbility Implant System to improve results of the implantation 
procedure, Protocol VIS-2014, a new pivotal trial, is being conducted to definitively evaluate the 
safety and effectiveness of the VisAbility Implant System. 
 
 
 

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5.0 
SCIENTIFIC BACKGROUND ON PRESBYOPIA  
Presbyopia is the most prevalent of all visual deficiencies, affecting virtually 100% of the 
population over the course of a normal life span. It is characterized by a progressive, age-related 
loss of accommodation, or the ability of the human eye to focus clearly on objects over a range 
of near to intermediate distances from the eye.  By the fifth decade of life, the amplitude of 
accommodation has declined so that the near point of the eye is more remote than typical reading 
distance.  Once presbyopia occurs, emmetropes will need an optical aid for near vision.  Myopes 
will find they see better at near without their distance correction and hyperopes will require a 
correction for both distance and near vision.  
When the eye accommodates to focus on a near object, convergence and pupil constriction also 
occur.  The combination of these three movements (accommodation, convergence and miosis) is 
under the control of the Edinger-Westphal nucleus and is referred to as the near triad, or 
accommodation reflex.  Accommodation is accomplished by the ability of the human eye to alter 
the refraction of the crystalline lens, depending on the distance of the object from the eye.   In the 
eye of a presbyopic emmetrope, the lens cannot accommodate sufficiently to focus the light rays 
from a near object onto a single point on the retina. Thus, a point object is imaged as a blur circle 
on the retina. Loss of accommodation typically begins in mid-life, eventually culminating in a 
nearly complete loss of the ability of the eye to clearly visualize near objects.     
Currently, no universally accepted surgical treatments are available for presbyopia.  Vision 
correction options include near vision reading glasses and/or contact lenses. As the physiological 
mechanisms of accommodation are investigated, more therapeutic and corrective options are 
being explored.  These include the use of multifocal intraocular lenses (IOLs), monovision and 
anisometropic corneal refractive surgical procedures using laser-assisted in situ keratomileusis 
(LASIK), corneal implant devices, and the VisAbility Implant. 
5.1 
Lenticular and Extralenticular Theories 
The underlying cause(s) of presbyopia, loss of accommodation of the eye over time, is not 
completely understood or agreed upon by the medical community.  Scientific theories for 
accommodative loss may be generally ascribed to two schools of thought: 
• 
Lenticular Theories are broadly based on age-related changes in properties of the lens of 
the eye, including the lens substance, the lens capsule, and the zonular fibers. These 
theories stem not only from purported changes in the elasticity of the tissues, but also from 
continued growth and changes in the thickness and the curvature of the lens with age.  
Helmholtz’s lenticular theory of the loss of accommodation is the most widely accepted of 
these types of theories.1 The majority of current approaches for the treatment of 
presbyopia are based upon lenticular theories of accommodation. 
 
• 
Extralenticular Theories consider age-related changes in the accommodative structures 
outside of the lens, capsule, and zonules. These factors include anatomical, 
morphological, and physiological changes in the ciliary muscle, connective tissue, and 
choroid.  The Scleral Implant approach to the treatment of presbyopia is based on 
extralenticular theories. 
 
 

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5.2 
Theories of Accommodation 
For the past 150 years, Helmholtz's lenticular theory of the loss of accommodation has been the 
accepted basis for the underlying physiological mechanisms that lead to presbyopia1  Helmholtz 
hypothesized that presbyopia is caused by the hardening of the lens with age.  According to 
Helmholtz, as the ciliary body contracts for accommodation, it constricts inwardly and relaxes the 
zonules.  The relaxation of the zonules causes the lens to "round up", and as the lens becomes 
more convex, it adds dioptric power thus bringing near objects into focus.  According to 
Helmholtz’s theory, the decrease in flexibility of the lens and the loss in elasticity of the lens 
capsule that occur with aging progressively hinder the focusing mechanism.   
Although generally accepted, Helmholtz’s theory cannot fully explain the mechanism by which the 
lens alters its shape, nor can it satisfactorily explain the reason or means by which aging uniformly 
affects accommodation across the population.   
An extralenticular theory that may explain age-related changes in accommodation is Dr. Jackson 
Coleman’s catenary theory of accommodation.2,3,4  Coleman’s theory proposes that the lens, 
zonules, and anterior vitreous comprise a diaphragm between the anterior and vitreous chambers 
of the eye.  According to Coleman, this construct behaves in a manner analogous to a hydraulic 
suspension bridge, or catenary.  When the ciliary muscles contract to accommodate the lens, 
pressure is increased in the vitreous compartment. 
Simultaneously, pressure in the anterior chamber is decreased due to the expansion of the 
trabecular meshwork, which occurs with ciliary body contraction.  A pressure gradient is thus 
established between the 2 chambers, resulting in a posterior flattening of the lens and, anteriorly, 
in a steeper radius of curvature in the center of the lens with a slight flattening at the periphery.6 
The anterior capsule and the zonules form a hammock-shaped surface (a modified catenary) that 
can be predicted mathematically based on the circumference of the ciliary body (Müeller’s 
muscle).7  Much like the pylons of a suspension bridge, the ciliary body dictates the shape of the 
catenary.  Thus, the accommodated state appears to be supported by the fluid volume differential 
with very little energy expenditure, much like a viscose-damped hydraulic door closer. 
Coleman’s hypothesis has been tested by comparing a mechanical model of accommodation with 
in vivo measurements of lens geometry changes during accommodation (measurements included 
ultrasound, MRI, and optical techniques).,6,7,8  The mechanical model consisted of fluid-filled latex 
balloons which were supported by a plastic wrap hammock to form a curve that potentially models 
the human lens.  Increasing balloon volumes were used to simulate growth of the aging lens, and 
variations in curvature were measured.   
 
 

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Schachar proposed an alternative extralenticular theory.  He hypothesized that presbyopia is a 
result of a decrease in distance between the ciliary muscles and lens equator.  It is known that 
lens tissue continues to grow over the lifetime of an individual,8 while sclera stops growing at 
approximately age 13.10 Therefore, there is a linear decrease in the distance between the ciliary 
muscles and the lens over time.  Ciliary muscles are smooth with striations, and thus, the amount 
of tension they can develop is directly related to the degree to which they are stretched.  Over 
time, the amplitude of accommodation is reduced because the distance between the lens and the 
muscles is decreased, resulting in presbyopia.  Stretching the ciliary muscles by surgical 
intervention would increase their ability to exert force on the lens and improve near vision. 
More recently, Goldberg and colleagues have made efforts to incorporate the research findings 
of others in a computer-animated model of accommodation11.  Dr. Goldberg notes that, “A team 
of European investigators (Elke Lutjen-Drecoll, MD, and colleagues at the Institute of Anatomy in 
Erlangen, Germany) and American investigators (Mary Ann Croft, MS; Paul Kaufman, MD; and 
colleagues at the National Primate Lab and University of Wisconsin in Madison) have used 
electron microscopy and video ultrasound biomicroscopy (UBM) and endoscopy to define the 
complex, separate elements of the zonules and document the interconnected movements of the 
extralenticular tissues.”  Dr. Goldberg suggests that the mechanism of accommodation should 
include a new theory of reciprocal zonular action, which he describes as follows: “During ciliary 
body contraction, the anterior zonules lose tension while the posterior zonules stretch.  During 
ciliary body relaxation, the posterior zonules lose tension as the lens flattens and is pulled back 
by the increasing tension of the anterior zonules.”     
The exact cause of the loss of accommodation over time is not known and may be associated 
with the above theories, a combination of these theories, or theories not yet introduced.  
 
 
 

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6.0 
PRIOR SCLERAL IMPLANT CLINICAL STUDIES 
As briefly described in the introduction to this protocol, Refocus has conducted a feasibility study 
of the scleral implants in 29 presbyopic subjects, followed by a pivotal trial that enrolled 135 
subjects with the PSI-001 design of the PresVIEW Scleral Implant and 330 subjects with the SGP-
046 design. The results of these studies are described briefly below. 
6.1 
Feasibility Clinical Study 
Clinical evaluation of the scleral implants was initiated in March 1999 following FDA approval of 
G970152.  The feasibility clinical trial enrolled 29 presbyopic subjects desiring improvement in 
near visual acuity at 6 clinical sites. Subjects were implanted in the primary eye only and followed 
for 24 months. Four PMMA segments were implanted in partial thickness scleral tunnels in the 
four oblique quadrants of the eye. The scleral tunnels were made using a diamond blade.   
While some study subjects experienced a clinically significant improvement in near visual acuity 
in this study, the effectiveness results were mixed as a result of difficulty in accurately and 
consistently creating the scleral tunnels. Notwithstanding these challenges, the initial results 
provided evidence of safety and effectiveness and supported initiation of a larger clinical trial.  
Importantly, the findings regarding difficulty in scleral tunnel creation led to development of an 
automated, electrically powered, re-usable incision device, the Scleratome, which was used in 
subsequent clinical studies.   
6.2 
Pivotal Trial of the PSI-001 Scleral Implant (Protocol P-277-5) 
A prospective, randomized controlled multicenter clinical trial of the PSI-001 scleral implant was 
approved by FDA in December 2003.  Subjects were implanted with the PSI-001 and followed for 
24 months.  In the initial randomized controlled stage of this study, 150 subjects were to be 
randomized in a 2:1 ratio either to a surgical cohort (N=100) or to a Deferred Treatment / Control 
cohort (N=50) with an interim report to be provided to FDA upon obtained preliminary data on 75 
randomized subjects.  Subjects randomized to the deferred surgery/control cohort were eligible 
to receive the implant after completion of 6 months of follow-up in the study.  
In the initial stage of this study, a total of 81 subjects were enrolled and randomized to either the 
PSI Treatment Group (53) or the Deferred Treatment Control Group (28) at a ratio of 2:1 per the 
study protocol. At the 3-month visit, 64% (23/36) of the eyes assigned to the PSI Treatment Group 
had distance corrected near visual acuity 20/40 or better, as compared with 6% (1/18) of Deferred 
Treatment Control Group.  At the 6-month postoperative exam 70% (30/43) of the eyes in the PSI 
Treatment Group eyes had distance corrected near visual acuity 20/40 or better, as compared 
with 4% (1/23) of the Deferred Treatment Control eyes.   
While these data supported expansion to the full study cohort of 330 subjects and up to 660 eyes, 
with bilateral implantation, only a total of 184 eyes of 135 subjects were implanted with the PSI-
001 under this protocol.   
 
 

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Initial effectiveness outcomes were consistent with the results of the initial subjects in the 
randomized substudy, however the improvement in near visual acuity was not sustained over time 
in some subjects. During investigation of this unexpected finding, imaging of the PSI-001 
segments using the Visante OCT (Carl Zeiss Meditec, Jena, Germany) revealed displacement of 
at least one of the implant segments in subjects who experienced an initial improvement in near 
vision followed by loss of this improvement.  
Subsequently, in a group of patients with displaced segments, repositioning and suturing of the 
segments was associated with clear improvements in near acuity, and confirmed that the stability 
of the PSI-001 segments in the scleral tunnel was directly related to clinical efficacy. 
Since suturing of the PSI-001 significantly increased procedure time and complexity, Refocus 
deferred further enrollment in the study pending design changes to the scleral implant segment 
to resolve the displacement issue.  A new design was developed, which incorporated a two part 
implant segment; a main body with “feet” at both ends that protruded beyond the edges of the 
tunnel and a secondary locking insert. This design, known as the PSI model SGP-046, was 
introduced into Protocol P-277-5, and has been shown to reliably maintain the implant segment 
firmly in place, as described further below. 
6.3 
Pivotal Trial of the SGP-046 Scleral Implant (continuation of Protocol P-277-5) 
The PSI model SGP-046, designed to provide better fixation of the PSI in the scleral tunnel, was 
introduced into Protocol P-277-5 in June 2009. Since 135 subjects had already been enrolled and 
implanted with the PSI-001 design, enrollment was increased to 465 subjects to ensure that 330 
subjects could be enrolled and implanted with the PSI SGP-046 in support of a Premarket 
Approval Application (PMA).  
With the modified design of the PSI segment, another 48 patients were to be enrolled in a sub-
study and randomized (2:1 ratio) with 32 patients receiving the PSI SGP-046 and 16 deferred 
surgery/control patients. As before, subjects randomized to the deferred surgery/control cohort 
were eligible to receive the PSI after completion of 6 months of follow-up in the study. The results 
of patients who elected to have PSI surgery after completion of 6 months of follow-up in the 
deferred/control surgery group were included in the total patient cohort. 
A smaller, lighter, disposable Scleratome was also introduced into the ongoing IDE clinical trial in 
April 2012.  Since the tunnel configuration was the same for both Scleratomes, as demonstrated 
in performance testing, Refocus assumed that clinical data from both the re-usable and the 
disposable Scleratome would be comparable. However, an exploratory analysis of 12 month 
clinical outcomes for 56 primary eyes (119 total eyes) implanted with PSI using the disposable 
Scleratome showed greater improvements in near vision following surgery with this improved 
surgical tool as compared to earlier subjects in the cohort.  While this finding was unanticipated, 
it was also very encouraging since the improvements in near vision were also achieved 
considerably earlier in the postoperative follow-up period. These findings were important since 
they confirmed Refocus’ expectation that improved surgical instrumentation would have a 
favorable impact on the post-operative clinical outcomes, as evidenced in the transition from the 
original IDE pilot study in which scleral tunnels were created using a diamond blade to use of the 
automated, re-usable Scleratome introduced in 2003 and to this more recent introduction of the 
disposable Scleratome.  
 
 

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A total of 645 eyes of 330 subjects were enrolled and implanted with the PSI SGP-046 in this 
clinical study. Subjects implanted with the PSI SGP-046 experienced clinically meaningful 
improvement with DCNVA (Sloan) at 40cm.  DCNVA (Sloan) of 20/40 or better was achieved by 
80% (237/298) of subjects at 12 months, by 84% (210/249) of subjects at 18 months and by 91% 
(120/132) of subjects at 24 months. 
Further, during the course of this clinical trial no persistent loss in BCDVA or BCNVA was 
observed in any eye.  BCDVA remained generally unchanged from baseline through the 24 month 
visit and all (100%) of the PSI treated eyes achieved BCNVA of 20/32 or better at all postoperative 
examinations.  
The PSI model SGP-046 has not been modified since its introduction into the clinical trial 
conducted under G970152, and there are no plans to modify this model of the PSI.  
Frequently reported ocular adverse events in this clinical trial were dry eye and improper 
conjunctival closure after the surgical procedure, the latter resulting in exposed implant segments.  
Exposed segments were treated with revised conjunctival closures.  Other ocular adverse events 
included conjunctival tags, corneal abrasions, conjunctival injection, superficial punctuate keratitis 
(SPK), conjunctival thinning, and exposed suture.  All of these were transient in nature and 
resolved without sequelae, generally with no or limited medical intervention. IOP increases 
secondary to postoperative administration of topical steroid drops were reported; in all cases, IOP 
returned to the baseline level after discontinuation of the steroid drops and/or short-term use of 
IOP lowering medications in a few cases.  
Three (3) cases of decreased iris vascular perfusion resulting in decreased pupil reactivity to light, 
and iris atrophy were reported in the complete cohort of 858 eyes of this IDE study for an incidence 
of 0.35%.  This adverse event has been mitigated with a high level of standardization of the 
immediate post-operative surgical protocol to ensure detection of any adverse change in pupil 
function where recovery falls below minimum standards.  In those rare cases, the implant 
segments will be removed on the day of surgery prior to discharge, thereby reversing any 
decrease in iris vascular perfusion. All prior cases achieving a measured pupillary response of ≥ 
25% constriction by digital infrared pupillometry within 6 hours post-operatively have 
demonstrated no long-term compromise in pupillary function, nor have they developed any further 
signs or symptoms of decreased perfusion.  Therefore, this protocol will require removal of implant 
segments on the day of surgery in the rare circumstance that the pupillary constriction does not 
return to an acceptable level in the immediate postoperative period.   
In summary, adverse events were observed in the original IDE study but these were generally 
mild in nature, self-limiting and largely resolved by 6 months postoperatively. The majority of the 
adverse events occurred during the early postoperative period, with no serious or significant 
adverse events observed in the late postoperative period, i.e., at 6 months or later. 
 
 
 

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7.0 
STUDY OUTLINE  
7.1 
Study Objective  
The primary objective of this study is to evaluate the safety and effectiveness of the VisAbility 
Implant System with the VisAbility Implant, model SGP-046, for improvement in distance 
corrected near visual acuity (DCNVA) in presbyopic subjects.   
7.2 
Study Design 
This is a prospective multicenter clinical study that will enroll and determine eligible 360 subjects 
ranging in age between 45 and 60 years of age with distance corrected near visual acuity 
(DCNVA) and uncorrected near visual acuity (UCNVA) of 20/50 to 20/80 (inclusive).  Subjects will 
be enrolled at up to 14 clinical sites with no site enrolling and determining eligible more than 20% 
of the 360 eligible subject cohort. A PMA application will be submitted when all study subjects 
have completed 12 months of follow-up.     
Subjects will be consented and screened based on medical history, ocular history and visual 
acuity criteria.  Subjects will be required to satisfy specific inclusion and exclusion criteria during 
a baseline examination to be eligible for surgery.  Subjects will be implanted with the VisAbility 
Implant model SGP-046 in the dominant eye, which will be designated as the primary eye.  The 
fellow eye will be implanted no sooner than 14 days after the primary eye and only in the absence 
of unresolved adverse events in the primary eye. Subjects primary eye will be examined at one 
day, one week and at 1, 2, 3, 6, 12, 18 and 24 months post-operatively. The fellow eye will be 
examined at one day, one week and one month postoperatively. The one week and one month 
examinations of the fellow eye may be combined with visits for the primary eye if the visit windows 
permit. After the fellow eye one month visit, the fellow eye will be examined in accordance with 
the subsequent primary eye examination visits. A validated Patient Reported Outcome 
Measurement instrument (the NAVQ) will be given to all enrolled and eligible subjects pre-
operatively and at 6, 12, 18 and 24 months.  
The study also includes a 60 subject randomized controlled sub-study at 3 investigational sites. 
Eligible subjects enrolled at these sites will be randomized (1:1 ratio) to a surgery group or a 
control group. Subjects assigned to the randomized surgery group will be implanted and followed 
for 24 months in the same manner as the larger non-randomized surgery group. Subjects 
randomized to the control group will be followed for 6 months, and will be eligible to undergo 
VisAbility Implant surgery after completion of the six month observation period.  These subjects 
that elect surgery will be followed for 24 months in accordance with the same schedule as the 
non-randomized surgery group.  Randomized control group subjects who do not chose to undergo 
VisAbility Implant surgery at the end of the 6 month observation period will be exited from the 
study at that time.  
7.3 
Effectiveness Endpoint 
The primary endpoint is achievement of distance corrected near visual acuity (DCNVA) of Snellen 
equivalent 20/40 or better (at 40 cm) and at least 10 letters (ETDRS) improvement in DCNVA in 
the primary eye.  
 
This endpoint will be evaluated against two objectives, a) 75% or more of primary eyes achieve 
the effectiveness endpoint at 12 months postoperative and, b) the percentage of primary eyes 
achieving the effectiveness endpoint at 6 months postoperative (6-month responder rate) is higher 
than the percentage in the randomized control group.   

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7.4 
Analysis of Safety Data 
Safety data analyses will be performed and separate summaries will be provided for 
primary and all eyes.  Descriptive statistics on the following attributes will be provided: 
• 
BCDVA  
• 
IOP 
• 
Slit Lamp findings  
• 
Fundus exam findings 
• 
Rate of adverse events 
7.5 
Study Population 
A total of 360 subjects who meet the following criteria will be enrolled and determined eligible in 
this study:  
7.5.1 
Inclusion Criteria 
1. Subjects must be between ages of 45 to 60 at the time of enrollment. 
 
2. Subjects must have best corrected distance visual acuity (BCDVA) of 20/20 in each eye. 
 
3. Subjects must have distance corrected near visual acuity (DCNVA) @ 40 cm of 20/50, 
20/63 or 20/80 in each eye.   
 
4. Subjects must have uncorrected near visual acuity (UCNVA) @ 40 cm of 20/50, 20/63 
or 20/80 in each eye.  
 
5. Subjects must have preoperative manifest refraction spherical equivalent (MRSE) in 
each eye of -0.75 to +0.50 diopters with no more than 1.00 diopter of astigmatism. The 
difference between the MRSE and cycloplegic refraction spherical equivalent (CRSE) 
should be ≤0.50 diopter. 
 
6. Subjects must require a minimum add of +1.25 or greater to read 20/20 at near (40 cm). 
 
7. Subjects must be phakic in each eye. 
 
8. Subjects must be alert, mentally competent, and able to understand and comply with the 
requirements of the clinical study, and be personally motivated to abide by the 
requirements and restrictions of the clinical study.  Patients must be available for the 
follow-up period.  
 
9. Subjects must be able to provide written informed consent. 
7.5.2 
Exclusion Criteria  
1. Subjects where either pupil has a baseline percent change from scotopic to photopic of 
less than 30% or an absolute difference of less than 1.00 mm between scotopic and 
photopic pupil size as measured by the NeurOptics Pupillometer. 

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2. Subjects with ocular inflammation, chronic uveitis, or other recurrent anterior or posterior 
segment inflammatory conditions in either eye; subjects with any ocular or systemic 
disease(s) posting a significant risk for ocular inflammation, including but not limited to 
autoimmune disorders (e.g., rheumatoid arthritis, ankylosing spondylitis, Reiter's 
syndrome, ulcerative colitis, Crohn’s disease, psoriasis, sarcoidosis, Behcet’s 
disease), infections (toxoplasmosis, cat-scratch fever, West Nile virus, syphilis, 
tuberculosis, herpes zoster, herpes simplex, adenovirus), ocular trauma, or gout. 
3. Subjects with scleral thickness of less than 530 microns as measured 3.5 to 4.0 mm 
posterior to the superior temporal quadrant limbus in either eye.  
4. Subjects with a history of any prior intraocular procedure (e.g., corneal transplant, 
filtering procedures for glaucoma, vitrectomy, retinal detachment repair, cataract 
surgery) or any prior refractive procedure (e.g. LASIK, surface excimer, or incisional 
surgery) in either eye. 
5. Subjects with any history of prior extraocular muscle surgery or orbital surgery. 
6. Subjects with chronic ocular disease, including but not limited to corneal pathology, 
primary or secondary glaucoma, iritis, herpes simplex, uveitis, trachoma, ocular 
pemphigoid, Sjogren’s disease, uveal melanoma, Thyroid Related Immune Orbitopathy 
or clinically significant retinal pathology in either eye. 
7. Subjects with any acute ocular disease that has not been completely treated and 
resolved for at least three months such as conjunctivitis, blepharitis, chalazion, corneal 
abrasion or keratitis in either eye. 
8. Subjects with chronic systemic diseases which may affect the eye, including but not 
limited to diabetes, ulcerative colitis, systemic lupus erythematosus, Crohn’s disease, 
collagen vascular disease, rheumatoid arthritis, any bleeding diathesis, or systemic 
manifestations of HIV/AIDS.  Any other uncontrolled systemic disease (e.g., 
hypertension, cancer, etc.) that could compromise the patient’s participation. 
9. Use of any medication, such as coumadin, that could make the surgical procedure more 
difficult.  Subjects using Coumadin, aspirin or NSAID medication under orders from a 
doctor must be able to provide written approval from the treating doctor for discontinuing 
this medication at least ten (10) days prior to surgery. 
10. Subjects with chronic ocular surface disease, including but not limited to subjects with a 
prior diagnosis of chronic dry eye syndrome based on tests such as but not limited to, 
corneal or conjunctival staining, Ocular Surface Disease Index symptom score or 
Schirmer tear testing.   
11. Subjects who are allergic to any medications used in the protocol. 
12. Subjects who are pregnant, lactating, or of child-bearing age and not practicing a 
medically approved method of birth control 
 
 

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8.0 
STUDY METHODS 
8.1 
Patient Screening and Enrollment  
Prior to enrollment in the study, interested subjects will be screened to determine initial eligibility. 
The investigator or a designee will explain the study purpose and summary procedures and 
subject responsibilities to the potential subject.  If it appears that the subject is interested and may 
be a candidate for the study, the subject will be asked to review and sign a Screening Informed 
Consent.  The Screening Informed Consent provides a summary of the preliminary screening 
testing which will include standard of care testing including a medical history, vision testing and 
an examination of ocular health.  
 
If preliminary eligibility is met, the subject will be asked to sign a Study Informed Consent Form 
which describes the surgical procedure; the potential benefits and risks, study examinations to be 
conducted, the frequency of follow-up visits, the expense reimbursement to be provided to the 
subject as well as other topics.  When the Study Informed Consent is signed by the subject and 
by the Investigator or designee, the Subject is considered to be enrolled. Additional study specific 
testing of the subject’s ocular and medical condition as specified in the baseline examination will 
be performed to determine eligibility. If during this testing, the Investigator or Sub-Investigator 
determines that the subject will not meet the protocol inclusion or exclusion criteria the 
examination may be terminated. 
 
If the subject satisfies all inclusion and exclusion criteria, the full baseline examination data will 
be provided to the Sponsor for verification that all data have been obtained and meets eligibility 
criteria.  Upon approval by the Sponsor, the subject will be scheduled for surgery if the subject 
has been enrolled and determined to be eligible at an Investigational site that is participating in 
the non-randomized cohort.   
 
If the subject has been enrolled and determined to be eligible at an Investigational site that is 
participating in the randomized controlled sub-study, the subject will be randomized (1:1 ratio) to 
either the surgery group or the control group. Subjects randomized to the control group will be 
followed for 6 months, and will be eligible to undergo VisAbility Implant surgery after completion 
of the six month observation period.   
     
8.2 
Clinical Parameters and Examination Schedule 
The clinical parameters to be recorded at baseline and post-operative examinations are shown in 
Table 1: Schedule of Visits and Measurements on the following page.  
  
 
 

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TABLE 1:  SCHEDULE OF VISITS AND MEASUREMENTS 
 
 
Initial 
Follow-up 
Pre-Op 
0    Day 
1    Day 
1     
Week 
1    
Month 
2   
Months 
3   
Months 
6   
Months 
12  
Months 
18 
Months 
24 
Months 
Slit Lamp Biomicroscopy  
OD, OS 
✓2 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Applanation Tonometry  
OD, OS 
✓2 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Gonioscopy  
OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
 
Scleral Thickness 
Measurement  
OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
Implant Assessment 
OD, OS 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Axial Length  / ACD 
OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
Corneal Topography / 
Keratometry  OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
Pupillometry  
OD, OS 
✓2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Posterior Pole  exam with 78  
/90D lens      
OD, OS 
✓2 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
 
Dilated Indirect 
Ophthalmoscopy 20/30D lens  
OD, OS 
✓ 
 
 
✓ 
 
 
 
 
✓ 
 
✓ 
Visual Fields  
OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
Cup/Disk Ratio OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
Cycloplegic Refraction w/ VA 
OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
Manifest Refraction  
OD, OS 
✓ 
 
 
✓4 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
BCDVA  
OD, OS 
✓2 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
UCDVA 
OD, OS 
✓ 
 
✓1 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
UCNVA @ 40 cm  
OD, OS, OU 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
UCIVA @ 66 cm  
 OU 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
DCNVA @ 40 cm  
OD, OS, OU 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Patient Preferred Distance  
DCN - OD, OS, OU 
UCN - OU 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Minimum add to achieve 
20/20 
✓ 
 
 
 
 
 
✓3 
✓3 
✓3 
✓3 
✓3 
NAVQ (Validated PRO) & 
Patient Questionnaire 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
Sub-Study Only 
Wavefront measurements³ 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Sub-Study Only 
Defocus Curve³ 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
1Visual acuity will be measured using pinhole on day 1 
2Fellow Eye Safety Exam (when fellow eye surgery is 61-180 days after primary eye surgery) 
3Randomized Sub-study subjects only – control group subjects are examined through 6 months and the surgery group through 24 months.  
4Measure BCDVA using baseline refraction 

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Examination methods are provided in Appendix 1: Examination Methods. 
 
8.3 
Surgical Procedure 
The VisAbility Implant System surgical procedure will be performed by the Investigator 
according to the detailed steps described in Appendix2: VisAbility Implant System Surgical 
Procedure. The surgical procedure involves the following basic steps: 
 
• 
Marking – To indicate the correct rotational position of the VIS Docking Station, 
two or more drops of xylocaine 2% sterile solution without epinephrine or the 
equivalent are used topically for anesthesia and marks are made at the 12:00 and 
6:00 limbus along the axis of the center of the superior and inferior recti muscle 
insertions.  Additional marking from these two points with the VIS Barrel Marker 
further aids in VIS Docking Station positioning by providing Vernier visual 
feedback of proper x/y centering and rotational placement of the VIS Docking 
Station. 
 
• 
Peritomy – Additional xylocaine 2% sterile solution without epinephrine or the 
equivalent is suffused in the anterior subtenon’s space for anesthesia. Opening of 
the conjunctiva and Tenon’s capsule at the limbus by standard techniques such 
as might be used in certain strabismus, glaucoma, or retina surgery is done to 
provide exposure of the sclera in the area of VIS Docking station fixation points 
and scleral tunnels.  Due to the potential detrimental effect on perfusion and 
scleral thickness, bipolar and or thermal cautery should not be used during this 
procedure.   
 
• 
Placement of the VIS Docking Station – The VIS Docking Station uses a four point 
fixation system to provide ocular fixation and a fixed docking location for the VIS 
Scleratome.  The VIS Docking Station is centered around the limbus with its 
internal arrow points on the 6:00 and 12:00 marks and the channels lined up with 
the four radial lines from the VIS Barrel Marker.  Each of the four VIS Docking 
Station’s fixation points are then actuated 180 degrees clockwise to its stop.  The 
surgeon should assess fixation and position and correct any deficiency prior to 
proceeding.   
 
• 
Scleral Tunnel Creation – The VIS Scleratome locating ridge is docked to the VIS 
Docking Station channel with the blade guard flush with its corresponding edge.  After 
the footplate is squarely on the sclera, the VIS Scleratome is activated to form each of 
four scleral tunnels at a fixed position approximately 4mm from the limbus and 
centered between adjacent recti muscles. USE OF A MANUAL LAMELLAR BLADE 
IS NOT ALLOWED FOR USE IN CREATING OR AUGMENTING ANY SCLERAL 
TUNNEL. To minimize manipulation of the eye, a VisAbility Implant Segment should 
be placed in each Lamellar Scleral Tunnel made prior to proceeding to the creation of 
the next Lamellar Scleral tunnel. 
 
 
 

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• 
Implantation of the VisAbility Implant – Pre-operatively, The VisAbility Implant Main 
Body is loaded into the VIS Feeder Tube to close the leading stabilization feet and 
facilitate their placement thru the scleral tunnel.  The VIS Feeder Tube is guided by 
the blunt titanium VIS shuttle to transit the tunnel.  After the leading stabilization feet 
fully traverse and exit the scleral tunnel it is disinserted from the VisAbility Implant Main 
Body.  With the VisAbility Implant Main Body in this position, the VIS Center Insert is 
clasped to lock into place, creating a uniform, smooth and stable VisAbility Implant 
Segment in each of the four oblique quadrants. If for any reason, only one or two 
Scleral Tunnels can be implanted with VisAbility Implant Segments, these segments 
will be removed from the eye.  
 
• 
VIS Docking Station Removal – The VIS Docking Station fixation is detached at 
each of its four points of fixation with 180 degree counterclockwise reverse 
actuation to the stop and it is removed in a careful manner to avoid corneal 
abrasion. 
 
• 
Conjunctival Closure – Assess all VisAbility Implants for position.  Should 
hemostasis be required, Evicel fibrin sealant (Omrix Biopharmaceuticals, Ltd., Kiryat 
Ono, Israel) or TISSEEL fibrin sealant (Baxter International, Inc., Deerfield, IL) may be 
used.  The conjunctiva is brought up to cover the VisAbility Implants and re-
approximated to the perilimbal area with 9-0 braided vicryl suture or equivalent as 
needed.  Special care should be taken to have a smooth, minimally wrinkled or 
bunched closure to the limbus that fully covers the VisAbility Implants. 
 
• 
After Conjunctival Closure – At the completion of the surgery, a removable 
punctual plug should be placed in the inferior punctum and an initial dose of 
antibiotic drops such as moxifloxacin ophthalmic solution or equivalent and steroid 
drops such as prednisolone acetate 1% ophthalmic suspension or equivalent 
should be instilled in the eye.  
 
8.4 
Post-Operative Care  
Following surgery, physicians should adhere to the following guidelines of topical ophthalmic 
medications and care: 
 
• 
To help control pain postoperatively, an icepack should be applied to the eye at 
intervals for approximately 30 minutes or longer as needed.  A topical non-steroidal 
anti-inflammatory drug (NSAID) such as nepafenac ophthalmic suspension or 
equivalent may also be instilled immediately postoperatively.  Chilled BSS may be 
instilled every 15 minutes and topical steroid drops such as prednisolone acetate 
1% ophthalmic suspension or equivalent may be used every 15 to 30 minutes until 
the pupil reaction is greater than 25% as described in the next step. Prior to discharge 
the patient should be given Diamox 500mg Sequel PO or equivalent. 
 
 
 

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• 
Pupil functionality will be evaluated postoperatively using a NeurOptics Pupillometer 
every 15 to 30 minutes until the percent pupil constriction reading is at least 25%.  A 
second, confirmatory reading may be taken as soon as 5 minutes after the first.  If two 
pupil constriction readings of at 25% or greater are not achieved within the first 4 hours 
after surgery, preparation for removal of the implant segments will commence.  The 
Investigator must remove all four implant segments no later than 6 hours after the 
surgery if two pupil constriction readings of 25% or greater are not achieved within 6 
hours postoperatively.  
 
• 
During the first week after the surgery, antibiotic drops such as moxifloxacin 
ophthalmic solution or equivalent and a topical steroid such as Lotemax gel or 
equivalent should be instilled in the eye. Additionally, NSAIDs such as topical 
nepafenac ophthalmic suspension or equivalent and / or oral medications such as 
naproxen or equivalent or acetaminophen with codeine or equivalent may be given as 
needed for pain during this time. 
 
• 
Absorbable and / or non-absorbable conjunctival sutures may be removed at one week 
post-operatively or later as needed. 
 
8.5 
Scheduled Post-Operative Visit Schedule 
 
8.5.1  Primary Eye Visit Schedule 
Subjects enrolled and eligible in the non-randomized cohort of the study and subjects 
enrolled, eligible and assigned to the randomized surgery group will be examined 
according to the following schedule based on the date of primary eye surgery.  Surgery 
on the primary eye may not occur more than 60 days after a baseline examination 
establishing eligibility.  Visit windows are calculated on a 30 day month. 
 
 
Pre-operative Baseline Evaluation 
 
 
(Day -60 to Day -1) 
 
 
 
Surgery 
 
 
 
 
 
(Day 0) 
 
 
One Day Exam 
 
 
 
 
(18 to 36 hours) 
 
 
One Week Exam 
 
 
 
 
(7 days +/- 2 days) 
 
 
One Month Exam 
 
 
 
 
(1 month +/- 7 days) 
 
 
Two Month Exam 
 
 
 
 
(2 months +/- 14 days) 
 
 
Three Month Exam 
 
 
 
 
(3 months +/- 14 days) 
 
 
Six Month Exam 
 
 
 
 
(6 months +/- 21 days) 
 
 
Twelve Month Exam  
 
 
 
(12 months +/- 45 days) 
 
 
Eighteen Month Exam 
 
 
 
(18 months +/- 45 days) 
 
 
Twenty-four Month Exam 
 
 
 
(24 months +/- 60 days) 
 
 

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8.5.2 Subjects Randomized to the Control Group – Visit Schedule 
Subjects enrolled, eligible and assigned to the randomized control group will be examined 
within the visit windows according to the following schedule. 
 
 
Enrollment Randomization 
 
 
 
(Day 0) 
 
 
Three Month Exam 
 
 
 
 
(3 months +/- 14 days) 
 
 
Six Month Exam 
 
 
 
 
(6 months +/- 21 days) 
 
 
 
Subjects in the randomized control group that have completed the 6 month follow-up exam 
may elect to undergo placement of the VisAbility Implant.  For these subjects, the 6 month 
visit will serve as the baseline eligibility examination. Subjects that undergo surgery will 
be examined in accordance with the primary eye visit schedule shown above.   
 
8.5.3 Fellow Eye Visit Schedule 
Subjects undergoing surgery in the fellow eye will be examined according to the following 
visit schedule.  The one week and one month examinations may be combined with visits 
for the primary eye if the visit windows permit.  After the one month visit, the fellow eye 
will be examined at the same time as scheduled follow-up visits for the primary eye.  
 
Surgery 
 
 
 
 
 
(Day 0) 
 
 
One Day Exam 
 
 
 
 
(18 to 36 hours) 
 
 
One Week Exam 
 
 
 
 
(7 days +/- 2 days) 
 
One Month Exam 
 
 
 
 
(1 month +/- 14 days) 
 
If the fellow eye surgery is 61 to 180 days after the primary eye surgery, the fellow eye will 
be examined postoperatively after the one month visit, on a separate visit schedule for the  
3 and 6 month visits only, established based on the same intervals and visit windows as 
shown above for the primary eye. Subsequent to the 6 month visit, the fellow eye will be 
examined at the same visit as the primary eye. Fellow eye and OU data will be recorded as 
attributable to the fellow eye visit timing through the fellow eye 6 month postoperative visit. 
 
8.5.4 Fellow Eye Supplemental Baseline Examination  
Fellow eye surgery may be performed 61 to 180 days after the baseline examination that 
has determined eligibility if a safety exam is performed and the findings do not alter the 
subject’s continued eligibility.  The following clinical parameters will be evaluated in the 
safety exam: 
 
1. 
Medical history 
2. 
BCDVA 
2. 
Slit lamp biomicroscopy 
3. 
Goldmann tonometry 
4. 
Pupillometry 
5. 
Posterior pole examination. 
 

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If fellow eye surgery is to be performed 181 days or more after a baseline exam 
determining eligibility, a complete baseline examination must be repeated.  Baseline 
efficacy data for the fellow eye and for OU will always be from the baseline examination 
established prior to the primary eye surgical intervention.  
 
8.5.5 Long-Term Follow-Up 
 
Long-term follow-up (up to an additional 3 years beyond the end of this study) may be 
required by the FDA for this study. If required study participants will be examined 
according to the following schedule based on the primary eye surgery if they choose to 
participate,  
 
Thirty-six Month Exam 
 
 
 
(36 months +/- 60 days) 
Forty-eight Month Exam 
 
 
 
(48 months +/- 60 days) 
Sixty Month Exam 
 
 
 
 
(60 months +/- 60 days) 
 
The clinical parameters to be recorded for these long-term follow-up examinations will be  
established in accordance with the FDA’s requirements. 
 
8.6 
Data Collection 
Sample paper source documents will be provided by the Sponsor for each subject enrolled and 
determined eligible in the study and will be completed by the Investigator or Sub-Investigator at 
the time of the subject examination.  The source documents will be completed in a clear and 
legible manner in black or blue ink and then signed and dated by the Investigator as indicated on 
the form.  Any correction will be made by drawing a single line through the incorrect entry, adding 
the correct entry, and then initialing and dating the corrected entry.  
The information recorded on the source documents will then be entered into the electronic case 
report form (eCRF) in the Electronic Data Capture (EDC) System by the Investigator, Sub-
Investigator or designee.  The original dated and signed source document will be kept in the 
subject’s study file at the Investigator’s site.  Instructions for the entry of data into the EDC will be 
provided to the clinical sites.   
8.7 
Study Completion 
Subjects are considered to have completed the study when they complete the 24 month exam 
regardless of earlier missed visits. The length of participation of subjects in the study is as follows.  
 
• 
Subjects enrolled and eligible in the non-randomized surgery cohort and subjects that are 
enrolled and eligible in the randomized surgery group as part of the randomized sub-study 
will participate in the study for 24 months. 
 
• 
Subjects enrolled and eligible in the control group of the randomized sub-study who elect 
not to under surgery will participate in the study for 6 months. 
 
• 
Subjects enrolled and eligible in the control group of the randomized sub-study who elect 
to undergo surgery after 6 months in the observation period will participate in the study for 
30 months. 
 
 
 

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8.8 
Subject Termination or Withdrawal 
Subjects may be terminated from the study if the Investigator believes that continued participation 
in the study may jeopardize the subject’s health or welfare.  Subjects may also elect to withdraw 
from the study at their discretion.  Every effort will be made to encourage the subject to maintain 
compliance with the protocol and to continue in the study.  Further, every effort will be made in 
both instances to conduct examinations as determined by the Investigator to ensure the safety of 
the subject.  The Sponsor should be notified promptly by the Investigator upon the termination or 
withdrawal of a subject by completion of the Study Exit form.  Terminated or withdrawn subjects 
may not be replaced with additional enrolled and eligible subjects. Subjects who have all implant 
segments removed (explanted) from both eyes will be exited from the study after at least 3 months 
post-explant follow-up. 
 
 
 

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9.0 
INVESTIGATIONAL MATERIALS 
The investigational materials provided for the clinical study of the VisAbility™ Implant System 
include the following: 
• 
VisAbility Implant 
• 
VisAbility Incision System: 
• VIS Scleratome  
• VIS Docking Station 
• 
VIS Feeder Tube and VIS Shuttle 
• 
VIS Instrument Set 
9.1 
VisAbility Implant Segment 
The VisAbility Implant is a curved scleral implant segment that is injection molded from 
polymethylmethacrylate (PMMA), a material with an extensive history of long-term implantation in 
the human eye, including intraocular lenses (IOLs).  Four (4) VisAbility Implant segments are 
placed in a single presbyopic eye to improve near vision. 
Each VisAbility Implant segment consists of 2 pieces, a main body with 2 legs and a center insert. 
The center insert has trans-longitudinal grooves on both sides that correspond to 2 small “rails” 
on the interior edges of the legs of the main body (Figure 1). These features allow the insert to 
be smoothly snapped into place in the main body. The design of the VisAbility Implant segments 
includes stabilization feet at each end intended to fixate at the entrance and exit sides of the 
scleral tunnel incision, thereby preventing displacement or migration of the implanted 
VisAbility Implant segments. The VisAbility Implant segments are provided sterile in a Tyvek® 
peel pouch. 
 
FIGURE 1:  VISABILITY IMPLANT SEGMENT SHOWING 2 INTERLOCKING PIECES AND  
STABILIZATION FEET 
Each VisAbility Implant segment is implanted in a scleral tunnel approximately 4.0 mm 
posterior to the corneal limbus through scleral belt loop incisions centered at the 10:30, 
1:30, 4:30 and 7:30 oblique quadrants.  Figure 2 shows a human eye implanted with the 4 
VisAbility Implants. 
 
 
 
 
 

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FIGURE 2: PLACEMENT OF VISABILITY IMPLANT SEGMENTS 
9.2 
VisAbility Incision System 
The VisAbility Incision System consists of the specialized surgical instruments provided to create 
precisely positioned scleral tunnels: 
• 
VIS Scleratome 
• 
VIS Docking Station 
9.2.1 
VIS Scleratome 
The VIS Scleratome (Figure 3) is a custom designed disposable Scleratome used to create 
the scleral tunnel incisions into which the VisAbility Implants segments are placed.  The VIS 
Scleratome is designed to create consistent scleral tunnel incisions for implantation of the 
VisAbility Implant segments. Ultrasound imaging is performed as part of the patient screening 
examination to confirm that the thickness of the sclera in the region of placement of the 
VisAbility Implant segments satisfies the requirements for making the scleral incisions. The 
VIS Scleratome is provided sterile in a disposable plastic tray with a Tyvek® cover and is for 
single patient use only. 
 
FIGURE 3: VIS SCLERATOME 
9.2.2 
VIS Docking Station 
The VIS Docking Station (Figures 4A and 4B) is a template made of titanium and medical 
grade stainless steel that is temporarily fixated on the eye centered around the geometric 
corneal limbus to provide a guide for placement of the VIS Scleratome.   The VIS Scleratome 
docks with the VIS Docking Station to provide a consistent location for the scleral tunnel 
incisions (Figures 5A and 5B).   
 
 
 
 
 
 
FIGURES 4A AND 4B: VIS DOCKING STATION 
 
 

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FIGURES 5A AND 5B: VIS SCLERATOME IS USED WITH VIS DOCKING STATION 
 
 

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When the VIS Docking Station is placed on the eye, a point on the VIS Docking Station is 
positioned to align with the 6:00 and 12:00 o’clock hour marks on the patient’s limbus  
(Figure 4) corresponding to the radial center of the inferior and superior recti muscles. The 
surgeon is then able to verify that the VIS Scleratome docking channels in the oblique 
quadrants are properly located between the rectus muscles.  The VIS Docking Station is then 
temporarily fixated to the eye with 4 titanium double helix twist picks. The VIS Scleratome is 
then docked, 1 quadrant at a time, into each of the channels located at the 1:30, 4:30, 7:30, 
and 10:30 clock positions of the VIS Docking Station. The VIS Scleratome is docked using 
the “locating ridge” on the blade guard of the Scleratome (see Figure 5).   
Actuate the Scleratome by turning the integrated winding knob in the clockwise direction. After 
placing the VIS Scleratome in position on the sclera using the VIS Docking Station, the 
actuator button on the Scleratome handle is pressed, releasing and retracting the blade and 
creating the scleral tunnel. The Scleratome is then reloaded for the next actuation by turning 
the integrated winding knob in the clockwise direction. 
The VIS Docking Station is a re-usable instrument that can be sterilized by standard autoclave 
procedures.  It is provided in a plastic case along with the other re-usable surgical instruments.  
Directions for cleaning and autoclave sterilization of the VIS Docking Station and the other re-
usable surgical instruments are provided to the surgeon. 
9.3 
VIS Feeder Tube and VIS Shuttle 
After the scleral tunnels have been formed, the VisAbility Implant segments are inserted using 
the VIS Feeder Tube and VIS Shuttle.  The VIS Feeder Tube is made of PTFE (Teflon), a 
commonly used medical grade polymer.  The soft, lubricious and flexible PTFE tubing provides 
the optimal means of traversing the lamellar scleral tunnel with the least amount of external stress 
on surrounding tissue.  Each VisAbility Implant main body can be loaded into a VIS Feeder Tube 
by the surgical assistant prior to transport from the assistant’s sterile workspace to the surgeon 
for implantation.   

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The VIS Shuttle is a titanium instrument consisting of 2 sections: a trailing section, cylindrical in 
shape, which is inserted into the tubing of the VIS Feeder Tube, and a leading section that 
tapers from the tubing outer diameter down to a dull round tip to facilitate positioning into the 
scleral tunnel.   
The VIS Shuttle is inserted into the larger end of the VIS Feeder Tube.  The main body of the 
VisAbility Implant segment is compressed into the other end.   The VIS Shuttle is then passed 
through the scleral tunnel, pulling with it the VIS Feeder Tube with the compressed main body of 
the VisAbility Implant segment.  As the tube exits the tunnel, the trailing stabilization feet on the 
legs of the implant catch the entrance of the tunnel and hold it in place as the tubing is removed, 
and the forward locking stabilization feet open to engage the exit incision.  Final assembly of the 
implant follows, as the center insert is positioned and snapped into place creating a single 
VisAbility Implant segment.  Figure 6 shows how the VisAbility Implant main body is used with 
the VIS Feeder Tube and VIS Shuttle.   
Figures 7A, 7B and 7C shows how the VIS Feeder Tube and VIS Shuttle are used to place the 
VisAbility Implant segments in the scleral tunnel. 
 
FIGURE 6:  VISABILITY IMPLANT MAIN BODY, VIS FEEDER TUBE AND VIS SHUTTLE (LEFT TO RIGHT) 
 
 
FIGURES 7A, 7B AND 7C:  PLACEMENT OF VISABILITY IMPLANT SEGMENTS WITH  
VIS FEEDER TUBE AND VIS SHUTTLE 
 
 

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The VIS Feeder Tubes are provided sterile in a Tyvek® peel pouch.  The VIS Shuttle is a 
re-usable component that can be sterilized by standard autoclave procedures.  Four (4) VIS 
Shuttles are provided in a plastic case along with the other re-usable surgical instruments.  
Directions for cleaning and autoclave sterilization of the VIS Shuttles and the other re-usable 
surgical instruments are provided to the surgeon. 
9.4 
VIS Instrument Set 
The VIS Instrument Set contains an array of Class 1 re-usable manual surgical instruments, 
including the VIS Docking Station and the VIS Shuttles.  All of these instruments are manufactured 
from 6Al 4V titanium alloy and/or medical grade stainless steel materials that have a lengthy 
history of safe use in ophthalmic surgical procedures.  These instruments are provided non-sterile 
in a plastic case.  They may be sterilized by standard autoclaving procedures and are provided 
with instructions for cleaning and sterilization.   
9.5 
VisAbility Implant Removal 
In the event that VisAbility Implant segments require removal, this can be accomplished easily by 
utilizing the VisAbility Implant Removal Cutter instrument provided in the VIS Instrument Set to 
remove the locking barbs from solid end of the VisAbility Implant segment, then using forceps to 
withdraw the remaining implant segment through the scleral tunnel (Figures 8A, 8B and 8C). 
 
 
FIGURES 8A, 8B AND 8C: VISABILITY IMPLANT REMOVAL PROCEDURE 
 
 
 

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10.0 
ADVERSE EVENT REPORTING 
An Adverse Event (“AE”) is any untoward sign, symptom or disease observed during the course 
of the study regardless of the suspected cause.  Conditions or diseases that are pre-existing or 
chronic but stable are not Adverse Events.  Changes in pre-existing or chronic conditions or 
diseases that are consistent with natural disease progression are not Adverse Events.   
10.1 
Serious Adverse Events (SAE) 
An Adverse Event should be classified as a Serious Adverse Event (“SAE”) and reported as such, 
if it meets one or more of the following criteria: 
• 
It results in death (i.e., the Adverse Event actually causes or leads to death). 
 
• 
It is life threatening (i.e., the Adverse Event places the subject at immediate risk of death). 
 
• 
It is considered sight-threatening (i.e., the Adverse Event involves loss of vision at the time 
of diagnosis and carries a relatively grave prognosis of irrevocable loss of vision without 
timely high risk intervention). 
 
• 
It requires or prolongs inpatient hospitalization (i.e., the Adverse Event requires at least a 
24-hour inpatient hospitalization or prolonged hospitalization beyond the expected length 
of stay) Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions are not SAEs. 
 
• 
It results in persistent or significant disability/incapacity (i.e., the Adverse Event results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the investigational product. 
 
• 
It does not meet any of the above serious criteria but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
If a subject is hospitalized to undergo a medical or surgical procedure as a result of an Adverse 
Event, the event responsible for the procedure, not the procedure itself, should be recorded as 
the event. (For example, if a subject is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass). 
Investigators must notify Refocus of any SAE within 24 hours of observing or learning of the 
event.  For initial SAE reports, Investigators should record all case details that can be gathered 
within 48 hours on the SAE Form and fax immediately upon completion to Refocus. 
10.2 
Unanticipated Adverse Device Effects (UADE) 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening or sight-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. UADEs also include any unanticipated sight-threatening events and any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare 
of subjects.  

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Investigators must notify Refocus of any UADE within 24 hours of observing or learning of the 
event.  Refocus will be responsible for informing Regulatory Authorities and all other IRBs and 
Investigators participating in the study of the UADE.    
10.3 
Adverse Event Assessment  
All subjects who have been exposed to the study treatment will be evaluated for Adverse Events 
as defined in this protocol. All adverse events, regardless of severity and whether or not they are 
ascribed to the study treatment, will be recorded in the source documents using standard medical 
terminology. Pre-existing conditions or diseases present at baseline that remain stable or change 
in a manner consistent with natural disease progression are not considered Adverse Events.   
All Adverse Events will be evaluated beginning at the time of onset, and evaluation will continue 
until resolution or until the investigator determines that the subject’s condition is stable. The 
investigator will take appropriate and necessary therapeutic measures required for resolution of 
the Adverse Event. Any medication necessary for the treatment of an Adverse Event must be 
recorded on the concomitant medication source document.  
All AEs will be characterized by the following criteria: 
• 
Event term 
• 
Intensity or severity 
• 
Expectedness 
• 
Relationship to study treatment 
• 
Outcome 
• 
Treatment or action taken. 
Whenever possible, recognized medical terms should be used when recording AEs. Colloquialisms 
and/or abbreviations should not be used. Only one medical concept, preferably a diagnosis instead 
of individual symptoms, should be recorded as the event. 
If known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be recorded on 
the source document rather than individual signs and symptoms (e.g., record congestive heart 
failure rather than dyspnea, rales, and cyanosis). If a constellation of signs and/or symptoms 
cannot be characterized with a single medical diagnosis or syndrome and they are considered 
unrelated to an encountered syndrome or disease at the time of reporting, these individual events 
should be recorded as separate AEs (e.g., if congestive heart failure and severe headache are 
observed at the same time, each event should each be recorded as an individual AE). If a 
diagnosis was not initially reported, and is subsequently established it should be reported as 
follow-up information and the original AE documents updated accordingly. 
Adverse Events occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause; a "primary" event, if clearly identifiable, should represent the most accurate clinical 
term to record as the AE event term.  For example: 
Orthostatic hypotension   fainting and fall to floor  head trauma  neck pain 
The primary event is orthostatic hypotension and the sequelae are head trauma and neck pain. 
 

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10.4 Classification of Adverse Events by Intensity / Severity 
All Adverse Events should be graded on a four-point scale (mild, moderate, marked, severe) for 
intensity/severity. These definitions are as follows: 
Mild: Transient discomfort; no medical intervention/therapy required and does not 
interfere with daily activities. 
Moderate:  
Low level of discomfort or concern with mild to moderate limitation in daily 
activities; some assistance may be needed; minimal or no medical intervention/therapy 
required. 
Marked: Considerable discomfort with limitation in daily activities, some assistance 
usually required; medical intervention/therapy usually required. 
Severe: Extreme discomfort and limitation in daily activities, significant assistance 
required; significant medical intervention/therapy required. 
There is a distinction between the severity and the seriousness of an Adverse Event. Severity is 
a measurement of intensity; thus a severe reaction is not necessarily a Serious Adverse Event. 
For example, a headache may be severe in intensity, but would not be serious unless it met one 
of the criteria for Serious Adverse Events. 
10.5 Classification of Adverse Events by Expectedness / Relatedness 
All AEs will be evaluated as to whether they are expected or unexpected, as defined below:  
Expected (anticipated): An Adverse Event is expected when the nature, severity, or 
degree of incidence was previously described.   
Unexpected (unanticipated): An Adverse Event is unexpected when the nature, severity, 
or degree of incidence was not previously described.  
 
   All AEs will be evaluated as to whether they are related to the device, as defined below: 
Not Related: Strong evidence exists that the Adverse Event definitely has a cause other 
than the investigational device (e.g. pre-existing condition or underlying disease, 
concurrent illness, or concomitant medication), or the investigational device cannot be 
implicated based on the available information  
Possibly Related: 
There is a temporal association with the investigational device and 
it cannot be excluded as a cause but other etiologies are also likely to be the cause based 
upon available information 
 
Probably Related: 
There is a temporal association with the investigational device 
which makes a causal relationship probable where other etiologies are possible but 
unlikely to be the cause, based upon available information. 
Definitely Related: 
Strong evidence exists that the investigational device definitely 
caused the Adverse Event.  There is a temporal relationship between the event onset and 
the investigational device and the subject’s clinical state and concomitant therapies have 

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been ruled out as a cause, based upon available information. 
10.6 
Adverse Event Outcome 
The clinical outcome of an Adverse Event will be recorded and characterized as follows: 
• 
Resolved without sequelae 
• 
Resolved with sequelae (specify) 
• 
Ongoing (i.e. continuing at time of study discontinuation) 
• 
Death. 
10.7 
Treatment or Action Taken 
The clinical treatment of an Adverse Event will be documented and characterized as follows: 
• 
None 
• 
Medical Intervention 
• 
Surgical Intervention 
• 
Other 
10.8 
Anticipated Adverse Events 
Adverse Events that might reasonably be expected to occur in this study are listed below. The 
time periods refer to the exam visit that occurs corresponding to the post-operative follow-up visit 
schedule (i.e., 3 months means the 3 month postoperative visit).  Exams for the primary eye and 
fellow eye may be done at the same visit if windows permit.  For purpose of determining 
whether a fellow eye event is an Adverse Event, the time period used shall be based on the date 
of the fellow eye surgery.  
    
These specific examples of anticipated Adverse Events include, but are not limited to: 
 
 
Intraoperative Events 
• 
Scleral perforation 
• 
Scleral perforation with vitreous prolapse 
Lids and Lashes 
• 
Ptosis 
• 
Onset of or worsening to severe clinically significant lid margin disease 
 
(e.g., blepharoconjunctivitis, blepharitis, meibomitis, meibomian gland 
dysfunction, etc.) after 3 months postoperative  
Cornea 
• 
Corneal dellen after 1 week postoperative  
• 
Corneal abrasion > 2mm after 1 week postoperative 
• 
Dry eye signs (moderate or severe) of corneal and/or conjunctival staining, etc., 
 
requiring prescription medication after 6 months postoperative 
• 
Corneal edema (moderate or severe) after 1 month postoperative  
• 
Corneal infiltrate or ulcer 
 
 

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Conjunctiva/Sclera 
• 
Conjunctival cyst 
• 
Conjunctival thinning or erosion 
• 
Moderate or severe conjunctival injection at 3 months postoperative or later 
• 
Subconjunctival hemorrhage after 3 months postoperative 
  
 
Anterior Segment, Iris, Lens 
• 
Pupil abnormalities persisting after 3 months 
• 
Grade 4 anterior segment ischemia (corneal edema, anterior chamber reaction, 
  
and decreased pupil reactivity)* 
• 
Anterior chamber cells or flare greater than mild at Day 1 through 1 Week 
• 
Anterior chamber cells or flare after 1 week postoperative 
• 
Intraocular Inflammation other than anterior chamber cells and flare (e.g.,vitritis) 
• 
Two grade change in lens opacity compared to baseline on two consecutive 
 
post-operative visits 
• 
Displaced or missing implant segments 
Intraocular Pressure 
• 
Hypotony (IOP < 6mmHg)  
• 
Increase in IOP of > 10mm Hg over baseline or IOP > 30mm Hg at two 
 
consecutive visits at 1 week or later 
 
BCDVA Loss 
• 
Decrease in BCDVA of greater than or equal to 2 lines (≥10 letters ETDRS) 
 
at 3 months or later 
Fundus 
• 
Choroidal effusion 
• 
Retinal detachment 
• 
Retinal or vitreous hemorrhage 
Secondary Surgical Intervention 
• 
Implant segment removal 
• 
Exposed implant segments or conjunctival retraction requiring conjunctival re-
approximation   
Other 
• 
Eye pain requiring oral prescription pain medication after 1 week postoperative 
• 
Allergic reactions to medications, devices, sutures or anesthesia 
• 
Other findings worsening two grades from baseline to a grade of +3 or +4 
 
* Refer to Appendix 6: Anterior Segment Ischemia (ASI): Detection, Mitigation and Reporting  
 
 

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11.0 STATISTICAL METHODS 
This is a prospective, multicenter study with a randomized, controlled sub-study that is designed 
to evaluate the safety and effectiveness of the scleral implant procedure. The percentage of 
primary eyes achieving the effectiveness endpoint will be evaluated at 12 months postoperatively.  
Within the study cohort, a subgroup will be randomized on a 1:1 ratio to a surgery group and a 
control group.  Subjects in the randomized control group will not receive surgery and will be 
examined at 3 months and 6 months.  After completion of the 6 month observation period, subjects 
in the randomized control group will be eligible to receive surgery as part of the 360 subject cohort.  
This randomized controlled sub-study will be used to evaluate the effectiveness of the scleral 
implant procedure in the randomized surgery group compared to effectiveness in the randomized 
control group at 6 months postoperatively. 
 
The effectiveness endpoint, hypotheses, sample size calculations, analysis population, handling 
of missing data, analysis methods, and analysis of safety data are as follows. 
 
11.1 
Effectiveness Endpoint 
The effectiveness endpoint is: 
 
Achievement of distance corrected near visual acuity (DCNVA) of Snellen equivalent 20/40 
or better (at 40 cm) and at least 10 letters (ETDRS) improvement in DCNVA in the primary 
eye.  
 
11.2 
Statistical Hypotheses 
For the effectiveness endpoint, two objectives must be met. 
 
Objective #1: 
The scleral implant procedure is defined as successful if 75% or more of primary eyes 
achieve the effectiveness endpoint at 12 months postoperative. The corresponding 
statistical hypothesis is as follows: 
 
H0 (null hypothesis):   
p < 0.75  
Ha (alternative hypothesis):  p  0.75 
Where, p is the probability that subjects achieve the effectiveness endpoint at 12 
months postoperative (12-month responder rate). 
 
Objective #2: 
An analysis of the randomized surgery group and randomized control group will be 
conducted.  The randomized surgery group is defined as successful if the percentage of 
primary eyes achieving the effectiveness endpoint at 6 months postoperative (6-month 
responder rate) is higher than the percentage in the randomized control group.  The 
corresponding null and alternative hypotheses are as follows: 
 
H0 (null hypothesis):   
p1 ≤  p2   
Ha (alternative hypothesis):  p1 > p2  
Where:  

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▪ 
p1 is the percentage of primary eyes in the randomized surgery group 
who achieve the effectiveness endpoint at 6 months. 
▪ 
p2 is the percentage of primary eyes in the randomized control group 
who achieve the effectiveness endpoint at 6 months. 
 
The primary eye is defined as the subject’s dominant eye and the eye that will undergo 
surgery first.  It is intended that all subjects will also undergo surgery in the fellow eye at 
a subsequent date as specified in the protocol.  
 
11.3  Sample Sizes 
Both Objective #1 and #2 will need to be statistically significant in order to determine the 
effectiveness of the study device.  Therefore the two-sided significance level of 0.05 is not 
adjusted for the multiplicity.  
 
Full Study Cohort Effectiveness Endpoint 
The sample size calculation for the statistical hypotheses described for Objective #1 in Section 
11.2 is based on the following criteria: 
 
• 
The two-sided significance level = 0.05 (or one-sided significance level = 0.025). 
• 
The statistical power = 90% at p = 0.825.  The assumption of true responder rate 
of 0.825 is based on the simple average of success rate observed in previous 
Refocus clinical study data, as follows: 
• Disposable Scleratome group had an observed success rate of 88%. 
• Re-usable Scleratome group had an observed success rate of 77%. 
• Simple average of 88% and 77% is 82.5%. 
• 
Binomial distribution is used for sample size calculation. 
Based on the criteria above for Objective #1, 330 treated primary eyes should be available 
for analysis at 12 months. If a dropout rate of 10% of subjects by 12 months is considered, 
then the surgery cohort should include approximately 360 treated primary eyes.   
 
For safety analysis, in order to detect an Adverse Event (AE) with a true probability of 
occurrence among subjects of 1% with 95% probability, based on the binomial distribution, 
a sample of at least 299 eyes would be required (in accordance with ANSI Z80 29 
18Nov2013 AIOL [rev20]).  Assuming a drop-out rate of approximately 10% of subjects by 
12 months, the surgery cohort should include a minimum of 333 treated primary eyes. 
 
A sample size of 333 treated primary eyes will meet the sample size requirements for both 
safety and effectiveness. The study cohort is planned for 360 surgery subjects at up to 14 
study sites.  However, no site may enroll and determine to be eligible more than 20% of 
the subject surgery cohort. 
 
 
Randomized Sub-study 
The sample size for Objective #2 in Section 11.2 is based on the following criteria: 
 
• 
The two-sided significance level = 0.05 (or one-sided significance level = 0.025). 

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• 
Based on the randomized control group data collected in IDE G970152, the 6-
month responder rate is estimated as 10% for the control group. 
• 
Based on the surgery group data collected in IDE G970152, the 6-month 
responder rate was lower than the 12-month responder rate.  Therefore, it is 
assumed that the 6-month responder rate of the randomized surgery group in this 
study will be approximately 0.75.   
• 
The statistical power = 90%. 
• 
Fisher’s exact test is used for sample size calculation. 
 
Based on the criteria above, a sample of 14 randomized surgery group primary eyes and 
14 randomized control group primary eyes at 6 months will ensure a power greater than 
90% for Objective #2, using a one-sided alpha of 0.025.   
 
A sample size of 30 randomized surgery group subjects and 30 randomized control group 
subjects has been selected which will account for a possible 10% subject drop-out rate 
and allow for greater accuracy in point estimates for both groups.  This randomized sub-
study will be conducted at 3 clinical sites.  Sites will be chosen based on availability of 
equipment for additional sub-study measures, such as availability of an iTrace unit (Tracey 
Technologies, Houston, TX), and the ability and willingness of the site to participate in the 
additional sub-study.  The target enrollment at each of the 3 sites in the randomized sub-
study will be 20 eligible subjects to provide an even distribution.  However, no site may 
enroll and determine eligible more than half of the randomized sub-study cohort or 30 
subjects.      
 
11.4 
Cohort Population 
Potential subjects will sign a screening consent to undergo preliminary screening for eligibility that 
consists of standard of care eye examinations.  Subjects who may be eligible based on the 
preliminary screening criteria and are willing to participate in the study will sign a full informed 
consent and are considered enrolled. At that time, the study specific examinations required to 
complete the baseline examination will be administered to determine eligibility for the 
study.  Subjects who have signed the full informed consent but do not meet all of the inclusion 
and exclusion criteria will be considered enrolled but ineligible for the study.  The reason for the 
disqualification will be recorded and reported.  
  
Safety Cohort: All eyes (both primary and fellow eyes) that have undergone surgical preparation 
of the ocular surface. 
 
Effectiveness Cohort:  All primary eyes that have been implanted with at least one implant 
segment and primary eyes of subjects that have been enrolled and determined eligible in the 
randomized control group.   
 
Figure 9, below, summarizes the status of enrolled subjects and the cohort populations for the 
study, except that the randomized control group is not shown.   
 
 
 
 
 
 

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FIGURE 9 – ILLUSTRATION OF STUDY POPULATION AND ACCOUNTABILITY 
 
 
 

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11.5 
Subject Accountability 
 
The following terms and definitions will be used for the accountability of the study population and are 
based on the definitions found in ANSI Z80.29 Rev 018, section B.5.3 as modified and explained 
below.  
• 
Enrolled – the total number of subjects that have signed the full informed consent. 
• 
Enrolled but ineligible – the total number of subjects that have signed the full 
informed consent but do NOT meet all of the inclusion/exclusion criteria. 
 
• 
Enrolled and eligible – the total number of subjects that have signed the full 
informed consent and meet all of the inclusion/exclusion criteria. 
• 
Surgical Withdrawal – Subjects (eyes) that have been enrolled and determined eligible but 
do not undergo surgical preparation of the ocular surface for any reason. 
 
• 
Discontinued– Subjects (eyes) that have discontinued treatment prior to the visit window 
associated with the form as a result of death, the removal of all 4 implant segments 
(explant), or any other reason except lost to follow-up.  
• 
Explanted Eye – Eyes that underwent implantation surgery, but have had all 
implanted segments removed.   
 
• 
Lost to Follow-up – Subjects that have withdrawn from the study after initial eye surgery or 
subjects that have missed the visit window associated with the form and all subsequent 
scheduled visits despite documented efforts by the Investigator to schedule the subject for 
follow-up.  
 
• 
Missed Visit – Data for subjects (primary eyes) that is not available for a follow-up visit 
within the specified visit window associated with the form, but data is available for a 
subsequent follow-up visit for such subject.   
 
11.6 
Analysis of Effectiveness Cohorts 
For the primary analysis of Objective #1, all observed 12-month data of the surgical primary eyes 
will be included in the effectiveness analysis.   Missing data will not be imputed except that 
explanted primary eyes will be imputed as failures. 
 
For the primary analysis of Objective #2, all reported 6-month data of the randomized primary 
eyes will be included in the analysis.  Missing data will be imputed as follows: 
 
• 
Randomized Control Group:  In the absence of 6 month visit data, the nearest available 
data recorded between and including the 3 month visit up to the 6 month visit will be 
utilized.  Since this randomized control group does not receive the benefit of the surgery 
during this 6 month observation period, the lost to follow-up and missed visit rate could be 
higher and since no intervention occurs during the 6 month period, this imputation of 
missing data is warranted.  In the absence of any observed data between the 3 month visit 

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and 6 month visit, this missing data will not be imputed since failure to achieve the 
effectiveness endpoint is expected.  
• 
Randomized Surgery Group:   
• 
Explanted primary eyes will be imputed as failures. 
• 
In the absence of 6 month visit data, the nearest recorded data after 6 months up 
to and including 12-month visit data will be used.  This imputation is warranted as 
the visit data between 6 and 12 months provides a predictive indicator of 6 month 
results. In the absence of any observed data between 6 and including 12 months, 
this other missing data will not be imputed.   
 
11.7  Baseline Demographic Characteristics 
Demographic data including, but not limited to, age, race, sex and ethnicity and baseline 
characteristics including, but not limited to, DCNVA, UCNVA, UCDVA, BCDVA, manifest 
refraction spherical equivalent (MRSE), cycloplegic refraction spherical equivalent (CRSE), will 
be reported for each subject.  Baseline characteristics such as age, sex, race, and near visual 
acuity will be summarized. 
 
11.8 
Analysis of Effectiveness Data 
As noted previously, both Objective #1 and Objective #2 of the primary effectiveness endpoint 
must be satisfied in order for the study to be considered a success. 
 
 
Analysis of Objective #1:  
The one-sided 97.5% lower confidence limit of the 12-month responder rate will be 
calculated based on the exact binomial distribution.  This goal is met if the one-sided 
97.5% lower confidence limit of the 12-month responder rate is at least 75%.  
 
The percentage of primary eyes achieving the Effectiveness Endpoint at 12 months will 
be compared among the study sites.  The Fisher’s exact test will be used to evaluate the 
possible study site effect. If the site effect is significant, i.e., p-value ≤ 0.15, then  
12-month responder rates stratified by study site will be provided and the average of the 
site 12-month responder rates will be calculated. The normal distribution approximation 
will be used to estimate the one-sided lower 97.5% confidence limit for the average  
12-month responder rate. 
 
Fisher’s exact test will also be used to assess the effects of subject sex, race and age 
category at surgery on the 12-month responder rates for primary eyes using a p-value of 
0.15.  For this analysis, age will be categorized into 3 interval groups (i.e., 45-49, 50-54, 
and 55-60).   
 
 
 
Analysis of Objective #2: 
The number and percentage of primary eyes achieving the Effectiveness Endpoint at  
6 months will be summarized for the randomized surgery group and randomized control 
group separately.  The two-sided Fisher’s exact test will be used to compare the difference 
between 6-month responder rates of the two randomized groups.   
 

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In order to assess potential differences of randomized group allocation and/or site  
6-month responder rates, a logistic regression analysis examining with the following will 
be performed:  
 
• 
treatment effect (the randomized surgery group and the randomized control 
group at that same site),  
• 
study site effect (site by site success rate comparison), and 
• 
site by treatment interaction 
 
If there is a significant difference (p ≤ 0.15) in treatment effect, study site effect, or a 
significant interaction effect between study site effect and treatment effect (p ≤ 0.15), then 
the 6-month responder rate for each study group and the difference in the 6-month 
responder rate between the two randomized groups (ptreatment - pdeferred) will be summarized 
by each study site. 
 
 
Sensitivity Analysis of Objective #1:  
Sensitivity analysis will be performed for Objective #1 using the following imputation 
methods for missing 12-month data: 
 
• 
Best Case Analysis: All discontinued primary eyes will be imputed as effectiveness 
failures. For primary eyes lost to follow-up or for primary eyes missing 12-month visit 
data, the best value from any protocol scheduled visit at 1 month or later (1 month, 3 
month or 6 month visit) will be used. If such visit data does not exist for a primary eye, 
the effectiveness will be imputed as a success.    
    
• 
Worst Case Analysis: All discontinued primary eyes will be imputed as effectiveness 
failures.  For primary eyes lost to follow-up or missing 12 month visit data, the worst 
value from any protocol scheduled visit at 1 month or later (1 month, 3 month or 6 
month visit) will be used.  If such visit data does not exist for a primary eye, the 
effectiveness will be imputed as a failure.    
 
• 
Tipping Point Analysis:  All discontinued primary eyes will be imputed as effectiveness 
failures.  For primary eyes missing 12-month visit data for reasons other than 
discontinued, effectiveness will be initially be set to success.  At this step, the lower 
limit of the one-sided 97.5% confidence intervals (CI) will be calculated.  Serial 
calculations will then be performed using a decreasing number (i.e., n-1, n-2, …1) of 
successes to determine the maximum number of additional failures allowed for the 
lower bound one-sided  97.5% CI of the effectiveness endpoint percent estimate to 
achieve or exceed 75% success.   
 
Sensitivity Analysis of Objective #2:  
• 
Tipping Point Analysis:  All discontinued primary eyes will be iteratively imputed as 
effectiveness success or failures.  Let n1 and n2 be the number of discontinued primary 
eyes for the randomized surgery group and the randomized control group, 
respectively.  For the n1 discontinued randomized surgery group primary eyes, they 
can be imputed as 0 failures, 1 failure, 2 failures, and up to n1 failures, for a total of 
(n1+1) possible imputations.  For the n2 discontinued randomized control group primary 
eyes, there are (n2+1) possible imputations.  Therefore, there are (n1+1) × (n2+1) 
possible combinations of success and failure imputations for these discontinued 

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primary eyes.  For each of these possible imputations, the lower limit of the one-sided 
97.5% confidence intervals (CI) will be calculated.  The imputations that have the lower 
one-sided 97.5% CI < 75% will be identified.    
11.9 
Analysis of Safety Data 
Safety data such as BCDVA, slit lamp findings, and fundus findings will be summarized 
descriptively (mean, standard deviation, minimum, and maximum for continuous outcomes, and 
counts and percentages for categorical outcomes) for primary and all eyes. 
 
For IOP at each visit, the mean, standard deviation, minimum and maximum and change from 
baseline will be summarized for all implanted eyes.  Additionally, number and percentage of eyes 
with a IOP change from baseline of “decrease > 10 mmHg”, “decrease ³ 5 mmHg to ≤ 10 mmHg”, 
“change within ± 4 mmHg”, “increase³ 5 mmHg to ≤ 10 mmHg”, and “increase > 10 mmHg” will 
be prepared for each study visits. 
 
Manifest spherical equivalence (MRSE) will be summarized descriptively with the 95% 
confidence interval for the mean for primary eyes and all eyes at each visit.  Additionally, the 
same analyses will be performed on the MRSE adjusted by normal aging (i.e., minus 0.082 D 
per year1,2,3,4). 
 
11.10 Analysis of Other Clinical Parameters 
Means, standard deviations, and ranges will be derived from the continuous measurements; 
numbers and percentages will be used for summarizing the categorical outcomes.  No specific 
claims will be made based on outcomes not pre-specified as an endpoint and no p-values will be 
presented for analyses without a pre-specified hypothesis. 
 
11.11 Analysis of Patient Reported Outcomes (NAVQ)  
The NAVQ instrument will be scored using Rasch analyses consistent with the analytic framework 
used during development.  An interval score for near visual function will be produced for each 
participant at each assessment.  This score will plotted against binocular DCNVA and correlations 
explored. 
 
The pre- and post-surgery comparison will be made using data from the 12 month visit and paired 
t-tests.  The NAVQ score will also be evaluated across visits, with adjustments for correlated data 
within patients being assessed on multiple occasions using Generalized Estimating Equations.  
 
There is an option of ‘Not applicable’ within the response categories and these responses will be 
scored as 0.  This is necessary as not all study subjects may engage in the activity described and 
may therefore be unable to comment on their vision during the named activity.  Rasch analyses 
can still be completed with missing data, although some precision in the estimate of the score for 
                                                          
1Grosvenor T and Skeates PD. Is there a hyperopic shift in myopic eyes during the presbyopic years? 
Clin Exper Optom 1999;82:236-243 
2Charman WN. Developments in the correction of presbyopia I: spectacle and contact lenses. Ophthalmic 
Physiol Opt 2014;34:8–29 
3Saunders H. A longitudinal study of the age-dependence of human ocular refraction – I. Age-
dependent changes in the equivalent sphere. Ophthalmic Physiol Opt 1986;6:39 
4 Gudmundsdottir E, Arnarsson A, Jonasson F. Five-Year Refractive Changes in an Adult Population: 
Reykjavik Eye Study. Ophthalmology 2005;112:672-677 

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near visual function will be lost.  Subjects will be encouraged to complete all questions and 
missing data will not be imputed.   
 
The PRO data will not be used to support specific labeling claims, thus this assessment is not a 
formal study endpoint.  The PRO data will be described in the product labeling using descriptive 
statistics only. The difference between the baseline and 12 month NAVQ scores will be calculated 
for each participant to determine if there is a measurable improvement in subjective report of near 
visual function.   Correlations between the change in near visual function (NAVQ score) and 
overall satisfaction (0=completely satisfied; 4= completely unsatisfied) and changes in objective 
measures of monocular and binocular DCNVA will be investigated using correlation coefficients 
in linear regression models.  It is hypothesized that there would be a moderate positive correlation 
between DCNVA and NAVQ score based on previous associations found between this instrument 
and visual acuity5.  
  
The stability of any improvement in near visual function (NAVQ score) will be assessed by 
evaluating the change in scores across the post-operative follow-up visits (6, 12, 18 and 24 
months) using Generalized Estimating Equations (GEE) models.   
 
Responses to the NAVQ questions will be used to develop an initial raw score based on the scale 
shown on the NAVQ. The NAVQ was developed using the Rasch model and is recommended to 
be scored using item response theory.[1]  As the NAVQ will be administered before and after 
surgery, all response data will be scored using the Andrich Rating Scale model for polytomous 
data in WinSteps (Version 3.80.1 Chicago, IL).  Interval scores will be produced for each 
participant based on their responses to the 10-item NAVQ before surgery and at each follow-up 
visit and rescored onto a 0-100 scale for ease of interpretation.  Rasch analysis weights the items 
and the scales for the responses to adjust for the varying level of difficulty for the tasks described 
in each item. 
 
11.12 Additional Sub-studies 
For sub-studies, only observed data will be used for analysis and only descriptive statistics will 
be performed.  All statistical analyses for sub-studies will be exploratory, since no formal 
secondary objective is specified in this statistical methods section.  
 
 
 
                                                          
5 Buckhurst, P.J., et al., Development of a questionnaire to assess the relative subjective benefits of 
presbyopia correction. J Cataract Refract Surg, 2012. 38(1): p. 74-9 

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12.0 STUDY MONITORING 
Sponsor or CRO personnel will monitor all clinical studies in accordance with FDA guidelines. 
Study monitoring will involve the following elements: 
• 
Sponsor or CRO personnel will meet with Investigators prior to the initiation of the study in 
order to review the adequacy of the facility, equipment and clinical personnel with respect to 
the needs of the study and to familiarize the Investigator and clinic staff with the protocol. 
 
• 
Sponsor or CRO personnel will meet with Investigators and clinic staff at initiation of the time 
of study to ensure that subjects are being properly consented, the protocol examination 
methods are being complied with and that study data is being properly recorded. 
 
• 
Sponsor or CRO personnel will meet with the Investigator and clinic staff at any time during 
the study regarding study conduct to ensure ongoing compliance with the protocol and data 
recording requirements.  
 
• 
Sponsor or CRO personnel will maintain ongoing email and telephone communication with 
the Investigator and clinic staff regarding study conduct. 
 
• 
The CRO shall select, train and manage qualified contract personnel to visit each 
Investigational site to review and monitor source documents and electronic data in 
accordance with FDA guidance.  
 
 

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13.0 REFERENCES 
1. von Helmholtz H. Uber die akkommodation des auges. Albrecht Von Graefe Arch Opthalmol 
1855;1:1-89. 
2. Coleman DJ. Unified model for the accommodative mechanism. Am J Ophthalmol 
1970;69:1063-1079. 
3. Coleman DJ. On the hydraulic suspension theory of accommodation. Trans Am Ophthalmol 
Soc 1986;84:846-868. 
4. Coleman DJ, Fish SK. Presbyopia, accommodation, and the mature catenary.  
Ophthalmolgy. 2001;108(9):1544-1551. 
5. Buckhurst, P.J., et al., Development of a questionnaire to assess the relative subjective 
benefits of presbyopia correction. J Cataract Refract Surg, 2012. 38(1): p. 74-9. 
6. Glasser A, Kaufman PL. The mechanism of accommodation in primates. Ophthalmology 
1999;106:863-872. 
7. Glasser A, Campbell MCW. Presbyopia and the optical changes in the human crystalline 
lens with age. Vision Res 1998;38:209-229. 
8. Koretz JF, Cook CA, Kaufman PL. Accommodation and presbyopia in the human eye. 
Changes in the anterior segment and crystalline lens with focus. Invest Ophthalmol Vis Sci 
1997;38:569-578. 
9. Rafferty, NS. Lens Morphology. In: The Ocular Lens, edited by: H. Maisel. New York: 
Dekker, 1985;2-6. 
10. Duke-Elder S and Wybar KC.  The anatomy of the visual system. In: System of 
Ophthalmology, edited by Duke-Elder S.  London: Henry Kimpton, 1961;2:80-81. 
11. Goldberg, DB.  Understanding Accommodation.  Cataract & Refractive Surgery Today 
Europe 2014 ; 20-22 

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APPENDIX 1: EXAMINATION METHODS 
Refractions and acuity measurements shall be obtained by an ophthalmologist, optometrist or 
trained technician (who is supervised directly by the ophthalmologist or optometrist).   
Manifest Refraction 
Manifest refraction will be performed pre and post-operatively using ETDRS acuity charts and 
standard phoropters. All systems will employ actual or equivalent optical distances of at least 4 
meters (13 feet) and ambient lighting will be adjusted based on chart specifications.  Chart 
luminance will fall within the ANSI required range of 80-160cd/m2 and chart contrast will be a 
minimum of 85%. 
Cycloplegic Refraction 
Cycloplegic refraction will be performed ~ 20 minutes after application of 1 drop of tropicamide 1% 
at select pre and post-operative visits using the same systems as for manifest refraction. 
Instrument for Measuring Visual Acuities 
All visual acuities will be measured via the OPTEC 6500 (Stereo Optical, 8623 W. Bryn Mawr Ave., 
Suite 502, Chicago, IL 60631 USA 1.773.867.0380 or 1.800.344.9500).  This system utilizes a lens 
system to simulate various test distances for distance, intermediate and near.   The Optec 6500 
has a microprocessor controlled internal illumination system that results in constant luminance of 
85cd/m2; therefore, normal ambient lighting may be used as lighting conditions are not a factor in 
the testing set up.  The manufacturer’s instructions for use will be provided to each Investigational 
site. 
Distance Visual Acuity 
Distance visual acuity will be measured at a simulated (optical) distance of 20 feet.     
Intermediate Visual Acuity  
Intermediate visual acuity will be measured at a simulated (optical) distance of 66cm.      
Near Visual Acuity  
Near visual acuity will be measured at a simulated (ocular) distance of 40cm. 
Determination of Near Add 
The add power will be determined by adding plus lenses, using the Optec 6500 at a 
simulated distance of 40cm. 
Determination of Dominant Eye 
The subject will be advised to perform the following steps for determination of the dominant eye. 
 
1. Hold your hands at arm's length out in front of you. Your palms should be pointing forward - 
in other words, you should be looking at the backs of your hands. 
2. Make a "triangle." Extend both of your thumbs so that they're roughly perpendicular to the 
rest of the hand. Overlap your hands so that the space between makes a triangle. Your two 
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thumbs should be at the bottom of the triangle, while the edge and index finger of each hand 
form the two remaining sides. 
 
3. The triangle space between your hands acts as a viewing window - you should be able to 
clearly see objects through it. 
 
4. Look at an object through the triangle hole made by your hands with both eyes open. Find 
a nearby object that's small enough (or far enough away) that you can see the whole object 
through the viewing window between your hands. This can be anything - a door knob, a 
coffee mug, or even a letter on a faraway billboard. 
 
5. Focus on the object. Try to focus your eyes on the object between your hands - not your 
hands themselves. Your hands should become somewhat blurry, while the object remains 
clear and in-focus. It's important to line this object up directly in front of you and to stare 
straight at it - turning your head to either side can distort your results. 
 
6. For best results, at this point, make minor adjustments to your hands so that the object 
you're looking at fits almost exactly within the edges your viewing window. In other words, if 
your triangle is bigger than the object you're looking at, move your hands together to make 
it smaller, and vice versa. 
 
7. Alternate closing each eye to see which gives better vision. Close one eye, then open it and 
close the other. Each time you switch eyes, the object you're looking at should do one of 
two things. It should either become obscured behind one of your hands or remain visible. 
Next, try your other eye. Your dominant eye is the one that allows you to see the object 
while it remains open. 
 
Scleral Thickness Measurement 
Scleral thickness will be measured and printed using the Sonomed Ultrasonic Biomicroscope 
(UBM). The manufacturer’s instructions for use will be provided to each Investigational site.  
Pupil size, shape and reaction 
The NeurOptics Pupillometer is a portable, battery-operated, hand-held device used to measure 
the iris’ reaction to a standardized level and duration of light.   The manufacturer’s instructions for 
use will be provided to each Investigational site. 
The pupils of both eyes will be assessed at each and every visit as follows: 
• 
Round 
• 
Elliptical 
• 
Irregular 
 
 
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Slit Lamp Evaluation – Grading 
Lids / Lashes 
Blepharitis (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked / severe (4) 
 
Meibomian Gland Dysfunction (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked / severe (4) 
Cornea 
Superficial punctate keratitis (using the Efron Grading scale and reference drawings): 
o None 
o Mild 
o Moderate 
o Marked or Severe 
 
Corneal abrasion: 
o None 
o Tiny 
o 1-2mm 
o 2-3mm 
o > 3mm 
Corneal edema (using the Efron Grading scale and reference drawings): 
o 0 = no evidence of corneal edema 
o 1 = trace corneal edema (edema involves 0% to 5% of the cornea) 
o 2 = mild corneal edema (edema involves 5% to 25% of the cornea) 
o 3 = moderate corneal edema (edema involves 26% to 50% of the cornea) 
o 4 = marked/severe corneal edema (edema involves > 50% of the cornea) 
 
Corneal endothelial gutatta: 
o 0 = no corneal gutatta 
o 1 = rare corneal gutatta 
o 2 = few corneal gutatta 
o 3 = many corneal gutatta 
o 4 = marked/severe corneal gutatta with stromal edema and bullous lesions 
o Other abnormal corneal findings (specify) 
 
 
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Conjunctiva 
Conjunctiva injection (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked/severe (4) 
 
Subconjunctival hemorrhage: 
o 0 = none 
o 1 = less than or equal to 1 quadrant 
o 2 = 2 quadrants 
o 3 = 3-4 quadrants 
 
Conjunctiva edema: 
o 0 = none 
o 1 = trace 
o 2 = mild 
o 3 = moderate 
o 4 = marked/severe 
Other abnormal conjunctival findings (specify) 
Crystalline Lens 
Crystalline lens pathology using the LOCSII scale (with reference photos as published 
in Archives of Ophthalmology July 1989) as follows: 
o Normal 
o Lens Opacity 
o Other Abnormal Findings (specify) 
If lens opacity, please complete the following: 
o 
Nuclear/Color Opalescence:   □ N0     □ N1    □ N2    □ N3  
o 
Cortical:           
 
□ C0        □ C1     □ C2     □ C3      □ C4  
o 
Posterior Subcapsular:    
□ P0        □ P1     □ P2     □ P3  
o 
Anterior Subcapsular:     
□ A0        □ A1     □ A2     □ A3 
 
 
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Anterior Chamber 
Cell and flare will be graded according to the SUN grading scheme (using a 1x1 mm slit 
lamp beam): 
SUN Grading for AC Cells 
GRADE 
CELLS IN 1x1mm Field 
0 
<1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
50+ 
 
SUN Grading for AC Flare 
GRADE 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris/lens details clear) 
3+ 
Marked (iris/lens details hazy) 
4+ 
Intense (fibrin/plastic aqueous) 
 
Iris appearance 
o 1 = Normal 
o 2 = Abnormal (if abnormal, please describe) 
 
 
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Intraocular Pressure 
Intraocular pressure will be measured using Goldmann applanation tonometry.  Measurements will 
be taken according to the published guidelines set forth by Michael A. Kass [Kass MA. 
Standardizing the measurement of intraocular pressure for clinical research. Guidelines from the 
Eye Care Technology Forum. Ophthalmology. 1996 Jan;103 (1):183-5]. Copies of this guideline will 
be provided to all sites. 
Gonioscopy 
 The angle will be evaluated using a 3 or 4 mirror lens and the following grading scheme: 
o Grade 3 – 4 (Wide Open: Angle > 20 degrees < 45 degrees) 
o Grade 2 (Moderately Narrow: Angle = 20 degrees) 
o Grade 1 (Extremely narrow: Angle = 10 degrees) 
o Grade 0 (Angles Closure: Angle + 0 degrees 
o Other:  (Specify) 
A-Scan 
Axial length and ACD will be measured and recorded.  
Internal Examination 
Peripheral Fundus Examination 
o Normal 
o Abnormal (if abnormal, please describe) 
Cup to Disc Ratio will be assessed by means of a dilated fundus exam using condensing 
lenses and the slit lamp biomicroscope.     
Other Observations: 
Photographs, drawings and / or standard descriptive ophthalmic terms may be used as needed to 
describe any other ocular findings. 
Randomized Sub-Study – Additional Examinations 
 
All subjects enrolled and eligible in the randomized sub-study, i.e., both the randomized surgery 
group and the randomized control group, will undergo the following additional testing: 
 
• 
Wavefront measurements 
• 
Defocus curves 
Wavefront Measurements 
 
Wavefront measurements will be recorded for each eye will be tested individually with a target at 6 
m (distance), 66 cm (intermediate or 1.50 dpt), 40 cm (near or 2.5 dpt), and at the preferred reading 
distance (PRD) which will be recorded in centimeters and diopters. Three wavefront scans will be 
captured at each target distance. 
Each of the wavefront scans will be analyzed by the iTrace software (version 5.3.1) for the following 
parameters:   
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1. Refraction (sphere and cylinder) over a calculated 4 mm entry pupil,  
2. Zernike polynomials up to the eighth order, 
3. RMS of higher order aberrations (HOA) 
4. Total depth of focus (DoF). 
Defocus Curves 
Defocus curve testing will be performed to subjectively measure the effectiveness of presbyopia 
correction by using minus and plus lenses.  Testing will be performed using phoropter with a 
computer-controlled LCD distance chart with ETDRS letters at 6m/20ft.  The phoropter will contain 
the subject’s best manifest distance refraction. 
A range of lens powers from -4.00 D to +2.00 D will be used over the best distance refraction for 
this testing. The lens power in the phoropter will be progressively reduced in +0.50 D steps, starting 
at -4.00 D and moving towards +2.00 D.  After each lens power change, the letters should be 
changed to a new set of letters of the same size or smaller and the letters read per line should be 
recorded.  The testing should proceed as follows:  
1. The subject should be seated and looking through a phoropter with the contralateral eye 
occluded. 
 
2. The computer-controlled ETDRS letter chart should be used at a 6 m/20ft distance from 
the patient.  
 
3. The patient's best distance correction should be dialed in to the phoropter. 
 
4. With the patient viewing the smallest letters corresponding to the patients BCDVA, a –
4.00D lens should be added to the patient’s distance correction.  (If the subject cannot 
read any of the letters, the letter size should be increased by 1 line until the acuity can 
be measured.)  As the letters are read, the correct letters should be circled and the visual 
acuity should be recorded with the corresponding lens power.  To prevent memorization, 
the letters should be changed to a new set of letters between each lens change and 
reading attempt. 
 
**If the patient reads all the letters on the line correctly, then switch to the next smallest 
line of letters and instruct that patient "Can you read any letters on this next smallest 
line?" If the patient again reads all letters correctly, repeat until either some or all letters 
in the next smallest line are missed.  Once the subject has missed letters, do not proceed 
to the next line and only record the letters that the subject got correct. (If 5 letters on the 
line are read plus 2 letters on the next line down, the total is 7 letters). In addition, record 
the corresponding acuity for the previous line, where the all the letters were read 
correctly.  
 
 
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5. Repeat the testing sequence on the fellow eye with the other eye occluded. 
 
The above defocus testing protocol is based on the following publication with associated 
graphs: 
 
Win-Hall DM, Glasser A.: Objective accommodation measurements in pseudophakic 
subjects using an autorefractor and an aberrometer.  J Cataract Refract Surg. 2009 Feb;35 
(2):282-90. 
  
 
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APPENDIX 2: VISABILITY IMPLANT SYSTEM SURGICAL PROCEDURE 
The VisAbility Implant System surgical procedure is performed as an outpatient procedure by 
the Investigator as described and categorized in eight major steps below. 
1. 
Marking 
Approximately ten minutes prior to the procedure, a topical anesthetic such as proparacaine 
ophthalmic solution or equivalent is instilled in the eye(s).  With the patient in the standing or seated 
position and fixating on an object straight ahead, mark the limbus at 12:00 and 6:00 o’clock with a 
sterile gentian violet marker.  Reinforce these marks as needed and place on drop of Brimonidine 
0.1% or 0.15% or equivalent on the patient’s operative eye.  Have the patient close their eyes for 
two minutes. 
In the operating room, with the patient’s vital signs monitored, use systemic relaxation as needed 
(e.g. Valium, Fentanyl, and/or Versed). 
Clean the eye and the skin around the eye in the usual manner for sterile intraocular surgery and 
drape the patient and their lids and lashes from the surgical field. 
Use a locking eyelid speculum that will hold the eyelids widely open. 
Instill sterile 2% xylocaine drops without epinephrine or equivalent topically to the cornea and 
conjunctiva, drying off any excess. 
Positively identify the superior and inferior rectus muscle insertions and the anterior ciliary arteries 
accompanying them such as by gently blanching the area with a flat spatula or the flat handle of a 
forceps or other alternative method.  Confirm that the previously placed 6:00 and 12:00 o’clock 
limbal marks correspond to the axis of the center of the respective rectus muscle insertion or correct 
their position to this axis as needed. 
On a relatively dry limbus, align the positioning barrel to the geometric limbus and rotate it to align 
the internal grooves with previously placed limbal marks.  Place the barrel marker in its positioning 
slits and mark the eye. 
2. 
Peritomy 
Re-instill sterile 2% xylocaine drops without epinephrine or equivalent topically to maintain good 
anesthesia. 
Make two 3mm or longer vertical conjunctival incisions approximately 0.5mm from the limbus at 3 
and 9 o’clock using a 0.3 forceps and blunt Westcott scissors. 
Taking care not to tear the conjunctive, utilize blunt Westcott scissors to bluntly dissect posteriorly 
into sub-Tenon’s space at an angle to avoid the horizontal plane of the medial and lateral recti 
muscles. 
 
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With a blunt cannula on a syringe containing sterile 2% xylocaine solution without epinephrine or 
equivalent, enter the sub-Tenon’s space posteriorly.  Advance the cannula and then sweep the 
cannula toward the limbus. Inject about 0.25 cc of the sterile 2% xylocaine solution without 
epinephrine or equivalent in each of the 4 quadrants. 
After the sub-Tenon’s injection of anesthetic has been completed, perform a 360 degree limbal 
peritomy of the conjunctiva and Tenon’s capsule. 
Upon completion of the peritomy inspect the sclera at 3, 6, 9 and 12 o’clock for bare sclera in 
preparation for placement of the VIS Docking Station. Utilize an absorbent stick, forceps if additional 
blunt dissection of the sclera is required. 
CAUTION: 
If after completing the conjunctival peritomy, the surgeon observes the insertions of the rectus 
muscles nearer than 4.5mm posterior to the limbus, aborting the procedure and closing the 
conjunctiva must be considered. This is done to avoid the risk of impinging upon the vasculature 
supplying the anterior segment, thus decreasing the risk of Anterior Segment Ischemia. 
CAUTION: 
Due to the potential of a detrimental effect on perfusion and / or scleral thickness, bipolar 
and / or thermal cautery should not be used during surgery.  
 
 3. 
VIS Docking Station Placement 
Place the VIS Docking Station on the eye by holding the unit slightly above the eye. Carefully drape 
the conjunctiva over the four corners and perimeter of the VIS Docking Station to avoid engaging 
any conjunctiva in the helical twists. 
Center the VIS Docking Station on the geometric limbus by keeping the inside diameter of the unit 
concentric with the limbus. Maintain the desired rotational position by aligning the 6 and 12 o’clock 
internal arrow points on the unit with the 6 and 12 o’clock limbal marks and the docking channels 
on the unit with the oblique line marks from the VIS Barrel Marker. 
Once concentricity and rotational position have been satisfactorily achieved, use the VIS Actuation 
Tool to rotate each of the four fixation points clockwise 180˚ to the stop while pressing down on the 
VIS Docking Station to engage the helical twists into the limbal sclera. 
After fixation, visually confirm satisfactory x/y and rotational positioning and verify sufficient four 
point fixation of the VIS Docking Station by lightly proptosing the eye with gently lifting of the unit. 
Reposition if necessary. 
 
 
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4. 
Lamellar Scleral Tunnel Creation 
Each of four tunnels will be created solely with the VIS Scleratome positioned by the VIS Docking 
Station.  USE OF A MANUAL LAMELLAR BLADE IS NOT ALLOWED FOR USE IN CREATING 
OR AUGMENTING ANY SCLERAL TUNNEL. 
Tunnels should be created in the following sequence to facilitate hand positioning and ensure the 
superior temporal quadrant tunnel is created last, due to the sclera in that quadrant being the 
thinnest on the eye: 
1. Inferior Nasal   (IN) 
2. Superior Nasal (SN) 
3. Inferior Temporal  (IT) 
4. Superior Temporal  (ST) 
Beginning with the inferior nasal quadrant, rotate and proptose the eye to provide adequate 
exposure of the sclera. Confirm the sclera near the VIS Docking Station is bare. Perform additional 
blunt dissection if required. 
Prior to placing the VIS Scleratome, verify the winding knob has been fully actuated. 
Dock the VIS Scleratome locating ridge to the corresponding channel in the VIS Docking Station 
and line up the blade guard with the surrounding edge.  While maintaining this docked position, 
bring the VIS Scleratome perpendicular to the sclera such that the footplate is flat to bare sclera.  
With a balance of pressure with the VIS Scleratome and proptosis with the VIS Docking Station, 
activate the VIS Scleratome by advancing the slide button toward the eye. 
Confirm the length of each lamellar scleral tunnel created using the VIS Spatula. 
CAUTION: 
When advancing the VIS Spatula thru the scleral tunnel, the leading tip must be directed 
outwards (anteriorly) along the roof of the tunnel to facilitate exiting from the tunnel and to avoid 
unintentional scleral perforation. 
To minimize manipulation of the eye, a VIS Implant Segment should be placed in each Lamellar 
Scleral Tunnel made prior to proceeding to the creation of the next Lamellar Scleral tunnel.  If for 
any reason, only one or two Lamellar Scleral Tunnels are able to be implanted with VIS Implant 
Segments, these segments will be removed from the eye.  
The VIS Scleratome requires winding of the knob prior to creation of the next scleral tunnel.  
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5. 
Implantation of the VisAbility Implant Segment 
To facilitate hand positioning, inferior quadrant tunnels (IN and IT) should be entered forehand from 
the inferior end of the tunnel. Superior quadrant tunnels (SN and ST) should be entered backhand 
from the superior end of the tunnel. 
While continuing to maintain fixation of the eye with the VIS Docking Station, immediately after the 
creation and verification of each tunnel, grasp the Shuttle / Implant segment assembly 
approximately 12mm from its leading edge and insert the front end of the shuttle into the tunnel and 
advance the VIS Shuttle / Implant segment assembly into the tunnel. 
CAUTION: 
When advancing the VIS Shuttle / Implant segment assembly thru the scleral tunnel, the leading 
tip must be directed outwards (anteriorly) along the roof of the tunnel to facilitate exiting from 
the tunnel and to avoid unintentional scleral perforation. 
After 3mm or more of the VIS feeder tube has exited the tunnel, grasp the exited VIS feeder 
tube and pull the assembly until the feet of the VIS implant segment have exited the tunnel.  
CAUTION: 
While pulling the VIS feeder tube thru the scleral tunnel, pay close attention that the Feeder 
tube does not begin to disinsert from the VIS implant segment prematurely. 
After the feet of the VIS implant segment have exited the tunnel, continued pulling of the VIS feeder 
tubing will disinsert it from the VIS Main Body Implant allowing the compressed feet to open, 
effectively locking the VIS Main Body Implant into the tunnel. 
Using the VIS Center insert implant loading forceps, grasp the top edges of the VIS Center Insert 
implant at the midpoint and guide it into the receiving slot of the VIS Main Body Implant. Use the 
VIS Center Insert implant loading forceps to then clasp the VIS center insert implant fully into the 
VIS main body Implant. A snap-like action will be apparent when the VIS center insert implant has 
been properly placed, In addition, the outer edge of the assembled VIS Implant Segment will line 
up flush and smooth. 
Repeat tunnel creation and implantation for each of the four quadrants. If for any reason, only one 
or two Lamellar Scleral Tunnels are able to be implanted with VIS Implant Segments, these 
segments will be removed from the eye. 
 
 
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6. 
VIS Docking Station Removal 
Use the Actuation Tool to rotate each of the four fixation points of the VIS Docking Station 
counterclockwise 180 ˚ to the stop, to disengage the helical twists from the limbal sclera and 
completely unlock the device from the eye.  Once free of fixation, carefully lift the VIS Docking 
Station from the eye to avoid causing any corneal abrasion with the underside helical twists. 
After lifting the unit from the eye, rinse away any excess clotted blood in the field. Reapply sterile 
2% xylocaine drops without epinephrine or equivalent topically to maintain good anesthesia as 
needed.  Check the implant location by measuring from the anterior center of the implant to the 
limbus. 
7. 
Conjunctival Closure 
Ensure adequate hemostasis is obtained prior to closing the conjunctiva 
CAUTION: 
Due to the potential of a detrimental effect on perfusion and / or scleral thickness, bipolar 
and / or thermal cautery should not be used during surgery.  Should hemostasis be 
required, Evicel fibrin sealant (Omrix Biopharmaceuticals, Ltd., Kiryat Ono, Israel) or 
TISSEEL fibrin sealant (Baxter International, Inc., Deerfield, IL) may be used. 
 
Bring the conjunctiva into position to approximate where it will need to be located when closed. 
Starting nasally, use a 9-0 braided Vicryl suture or equivalent with a modified mattress technique, 
starting nasally, close 3 and 9 o’clock as needed such as using a 3mm scleral bite tangential to the 
limbus and a 4-5mm conjunctival bite then at 6 and 12 o’clock as needed. 
Care must be taken to ensure a smooth, uniform, minimally wrinkled conjunctival closure. 
8. 
After Conjunctival Closure 
At the completion of the surgery, a removable punctual plug should be placed in the inferior 
punctum and an initial dose of antibiotic drops such as moxifloxacin ophthalmic solution or 
equivalent and steroid drops such as prednisolone acetate 1% ophthalmic suspension or 
equivalent should be instilled in the eye. Instruct the patient to keep their eyes closed, and use 
ice compresses to decrease swelling. 
 
 
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9.  
Post-Operative Care  
Following surgery, physicians should adhere to the following guidelines of topical ophthalmic 
medications and care: 
• 
To help control pain postoperatively, an icepack should be applied to the eye at intervals for 
approximately 30 minutes or longer as needed.  A topical non-steroidal anti-inflammatory drug 
(NSAID) such as nepafenac ophthalmic suspension or equivalent may also be instilled immediately 
postoperatively.  Chilled BSS may be instilled every 15 minutes and topical steroid drops such as 
prednisolone acetate 1% ophthalmic suspension or equivalent may be used every 15 to 30 
minutes until the pupil reaction is greater than 25% as described in the next step.  Prior to discharge 
the patient should be given Diamox 500mg Sequel PO or equivalent. 
• 
Pupil functionality will be evaluated postoperatively using a NeurOptics Pupillometer every 
15 to 30 minutes until the percent pupil constriction reading is at least 25%.  A second, confirmatory 
reading of 25% or greater may be taken as soon as 5 minutes after the first.  If two pupil constriction 
readings of at least 25% are not achieved within the first 4 hours after surgery, preparation for 
removal of the implant segments will commence.  The Investigator must remove all four implant 
segments no later than 6 hours after the implantation surgery if the two pupil constriction readings 
of at least 25% are not achieved within 6 hours postoperatively.  
• 
During the first week after the surgery, antibiotic drops such as moxifloxacin ophthalmic 
solution or equivalent and topical steroid drops such as Lotemax gel or equivalent should be 
instilled in the eye.  Additionally, NSAIDs such as topical nepafenac ophthalmic suspension or 
equivalent and / or oral medications such as naproxen or equivalent or acetaminophen with codeine 
or equivalent may be given as needed for pain during this time. 
Procedure to Surgically Remove VIS Implant Segments 
Subjects may request to have the VIS implant segments removed at any time. The VIS Implant 
segment removal procedure, if requested and deemed safe to do so by the Investigator will be 
performed by the Investigator as described below.  
Magnification of the surgical area at a surgical microscope is advised. 
Preoperative sterile prep and drape is required. 
Topical anesthesia with sterile 2% xylocaine drops without epinephrine or equivalent should be 
applied to the operative eye requiring Implant segment removal.  A drop of Brimonidine 0.1% or 
0.15% or equivalent may also be used to decrease bleeding. 
Using a sterile sharp blade such as a 15 degree ophthalmic sharp, 18 to 21 gauge hollow injection 
needle, or equivalent, a small (2mm) scratch down incision of the conjunctiva is made over both 
exposed ends of the VIS Implant segment. 
Use a forceps such as a .12 forceps to further expose the ends of the VIS Implant Segment from 
the overlying conjunctiva. 
 
 
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Once the ends of the VIS Implant segment are un-encapsulated, grip the solid end of the VIS Main 
Body implant with the jaws of the VIS Cutter (966-0030) with the tips perpendicular to the length of 
the implant and one tip flat to the sclera. Ensure that the full portion of the widened extra lamellar 
scleral tunnel portion of the VIS Main Body implant is fully enclosed within the VIS Cutter. Close the 
VIS cutter to sever the complete solid, wide end of the VIS Main Body Implant.  
Carefully remove the severed piece(s) of the VIS Main Body Implant segment from the Cutter and 
inspect the cut end for any barb that might remain and carefully sever it. 
Using the VIS Implant Loading Forceps, the distal end of the Shuttle forceps or other toothed 
forceps grasp the uncut end of the VIS Implant segment, and pull it through the tunnel with a slight 
twisting motion to remove it from the eye. 
Repeat for each Implant segment requiring removal. 
After completing removal of all required VIS implant segments, the scleral and conjunctival areas 
that have been opened should be assessed to see if they will heal primarily, if they need inflated 
with an intra tenon’s injection of BSS or need to be sutured with an appropriate gauge suture. 
An initial dose of antibiotic drops such as moxifloxacin ophthalmic solution or equivalent and 
steroid drops such as prednisolone acetate 1% ophthalmic suspension or equivalent should 
be instilled in the eye. 
A light dressing may be applied to keep the eyes closed overnight for patient comfort. 
During the first week after the surgery, antibiotic drops such as moxifloxacin ophthalmic solution 
or equivalent and topical steroid drops such as prednisolone acetate 1% ophthalmic 
suspension or equivalent should be instilled in the eye.  Additionally, NSAIDs such as topical 
nepafenac ophthalmic suspension or equivalent and / or oral naproxen or equivalent may be 
given as needed for pain during this time. 
 
 
 
 
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APPENDIX 3: PATIENT-REPORTED OUTCOME (PRO) INSTRUMENT 
FOR USE IN PROTOCOL VIS-2014 
 
I. Introduction 
The Near Activity Visual Questionnaire (NAVQ) is a PRO instrument designed for use in study 
subjects receiving presbyopia correcting devices and is currently being used in an ongoing IDE 
study. The Near Activity Visual Questionnaire (NAVQ) consists of 10 items which are combined to 
produce a single score for near visual function and an 11th item which is a global satisfaction 
question.  
In Protocol VIS-2014 the NAVQ will be administered at the pre-operative visit and at 6, 12, 18 and 
24 months. The repeated assessments over the post-operative period will provide an indication of 
the stability of the near visual function. This schedule is appropriate for the purpose of assessing 
near vision before surgery and at a minimum of 6 months after surgery since it allows for recovery 
and adaptation to the bilateral surgery.  The full questionnaire to be used in the IDE study of the 
VisAbility Implant System is provided in Exhibit A.   
The NAVQ is uni-dimensional and produces a single score related to difficulty with near vision tasks.  
The global satisfaction question will be considered on its own and is not scored with the first 10 
items. 
II. Instructions for NAVQ Use 
The NAVQ instrument should be self-administered to avoid bias in reporting, as recommended by 
the authors of the NAVQ.[1]   It is anticipated that completion of the NAVQ will be a modest burden 
on the trial subjects.  The layout and font size were optimized by the instrument developers for good 
legibility and self-administration, and it is being used as published. 
At designated visits, the questionnaire will be completed by each study subject in the clinic, prior to 
any clinical assessments of vision.  Study subjects will be instructed to answer each question about 
their recent everyday experience with near vision without any spectacle correction.  All responses 
will be documented by the study subjects on a paper case report form.  Subjects will be encouraged 
to complete the full questionnaire and completed questionnaires will be checked by clinic staff to 
ensure all questions were answered.  The script to be used by clinic staff in instructing subjects on 
how to complete the PRO instrument is provided in Exhibit C.  
It is critical that study subjects understand that they are reporting on their near visual function 
without the use of reading glasses.  It is expected that study participants will be close to emmetropic 
with a need for some add power for certain near tasks.  As a result, subjects will be instructed to 
answer the questions about their near vision when they are not using their reading glasses or any 
other corrective lenses.  
Testing of the NAVQ has been associated with minimal missing data, indicating that the content of 
the questions is generally relevant and acceptable to patients who have had surgical correction of 
presbyopia.[1, 3]. 
 
 
 
 
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III. The PRO Instrument’s Conceptual Framework 
 
The sections below describe the NAVQ and its validation using the principles described in FDA’s 
Guidance, “Patient-Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims”. 
The NAVQ was designed with the stated purpose of creating a standardized questionnaire to 
subjectively assess near visual function and satisfaction with a variety of presbyopia-correction 
techniques.[1, 2]   The NAVQ is a 10-item questionnaire with an additional global question about 
satisfaction.  The 10-items are combined into a single score where high scores indicate greater 
difficulty with near vision tasks (Table 1). The NAVQ therefore measures the construct of difficulty 
with near visual tasks using 10 items and the concept of ‘satisfaction with near vision’ is assessed 
separately with a single global question (Figure 1).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIGURE 1: CONCEPTUAL FRAMEWORK FOR THE NAVQ[1] 
 
IV. Content Validity Documentation 
 
A. Literature review and documentation of expert input: 
 
The patient perspective on the outcome of a medical intervention is helpful because such a 
perspective may provide supplemental information both to patients and physicians regarding the 
performance of the intervention.  The VisAbility Implant Procedure is designed to improve near 
vision in presbyopic patients.  The primary outcome of the proposed trial is the improvement in 
distance corrected near visual acuity (DCNVA) at a distance of 40cm in the primary eye at 12 
months.  However, the VisAbility Implant Procedure is a bilateral procedure and the NAVQ may 
provide additional patient perspective on reduction in limitations in vision due to presbyopia.  
 
 
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A review of the literature has been completed to identify a suitable PRO instrument.  Cochener 
published a meta-analysis of outcome data for clinical trials of multifocal intra-ocular lenses in 2011 
which included literature up until June 2009.  Like the VisAbility Implant System, multifocal IOLs are 
designed to correct presbyopia.   While there was uniformity in the collection of visual acuity data, 
there was no consistency in the questionnaires used for Patient Reported Outcomes (PRO).   
Patient satisfaction and spectacle independence have mostly been collected as individual items, 
usually on a Likert scale (14/20 trials).  One trial used the VF-14 index, a questionnaire designed to 
assess the impact of cataract on visual function. 
 
Although there are a number of PRO questionnaires related to visual function that have undergone 
extensive validation, only one was specifically conceptualized, designed and validated for the 
assessment of the correction or reduction of presbyopia.  That questionnaire is the Near Activity 
Visual Questionnaire (NAVQ).[1-3]   
 
B. Qualitative study protocols 
The NAVQ was developed with the aim to be able to assess near visual function and satisfaction 
with a variety of presbyopia-correction techniques.[1, 2]  As the VisAbility Implant Procedure is a 
surgical correction for presbyopia, the application of the NAVQ falls within the scope of the intended 
population for this instrument.  Because NAVQ is a published instrument for which content validity 
has already been demonstrated as described herein, Refocus Group, Inc. has not performed 
additional qualitative studies to investigate content validity.   
 
C. Origin and derivation of items with chronology of events for item generation, 
modification and finalization: 
 
The development of the NAVQ has been described in a publication by Gupta, et al (n=22) [2]  and 
in a second larger study by Buckhurst, et al (n=150).[1]  The process of item generation involved a 
review of published vision-related quality of life (VR-QOL) questionnaires to identify any items 
relating to near vision tasks.  This search found 374 candidate items.[2]  This bank of items was 
reduced by combining duplicate items and through review by ophthalmic professionals (5 
ophthalmologists and 3 optometrists) and 10 lay-people with presbyopia [2] at which time it was 
possible to add questions to cover any new areas identified.  This review process resulted in 19 
candidate items which was reduced to a 9-item questionnaire plus a global question about 
satisfaction using the Rasch Model.[2]   
 
Though this questionnaire was considered to be internally consistent, reliable and a valid instrument 
for assessing accommodating IOLs, the authors suggested the addition of items to better target 
patients with good near vision and to allow assessment of other types of presbyopic correction.[2]  
Subsequently, Buckhurst  expanded the instrument to 26 items and revisited the psychometric 
properties in a population of 150 patients with varying types of corrections for presbyopia.[1]   
  
 
 
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The Rasch model was used to reduce the 26 items to those relevant to near visual function, the 
concept being measured.[1]  The number of items was reduced by considering in priority order: 
item fit statistics, item targeting, frequency of endorsement and skew and kurtosis.  The outfit mean 
square was required to fall within the range of 0.6 to 1.4 where items below 0.6 were considered 
too predictable and those above 1.4 were considered too variable.  The targeting was evaluated 
using a person map of items.[4]  Frequency of endorsement was kept in the range of 65 to 85% to 
ensure the questions were relevant.  Skew indicates the symmetry of the frequency distribution of 
responses and kurtosis the height of the peak of the distribution.  Items with skew or kurtosis >2 
were excluded.  Items were removed one at a time and item statistics recalculated each time until 
all of the items fitted the Rasch model.[1]  This final NAVQ had 10 items and a global item about 
satisfaction. 
 
D. Summary that supports content validity: 
 
Item content: The involvement of patients in review of the candidate items is recommended in 
the FDA guidance document regarding the use of PRO’s in clinical studies. [5]  .Patient input 
was part of the development of the NAVQ instrument as described above [2].   
 
Additionally, Refocus Group, Inc. has conducted a pilot study to confirm whether patients who 
have undergone the VisAbility Implant Procedure understand the NAVQ and are able to answer 
the questions.  The NAVQ was administered over the telephone to 11 post-operative subjects 
in the IDE G970152 clinical trial so their understanding could be ascertained.  The subjects were 
able to understand and answer all of the questions. 
   
Response Options: During development, items were required to have frequency of 
endorsement in the range of 65 to 85% to ensure the questions were relevant but not 
redundantly predictable.[1]  All items were originally assigned a 6-point Likert scale, however 
the rating scale was scrutinized using category function statistics to refine the response scale 
and a 4-point scale was recommended.[1]  With the 4-point scale, respondents were able to 
use the scale to reliably represent their level of difficulty with the task.  For the satisfaction scale 
the 6-point Likert scale was retained. All items are consistent in that higher scores represent 
greater difficulty or greater dissatisfaction. 
 
Recall period:  The questionnaire does not specify a recall period and refers to the patient’s 
current vision status.  As the tasks are commonly encountered in everyday life , the subject 
should be able to reference a recent experience within the past few days relevant to all 
questions in the NAVQ. If a subject does not perform an activity or has stopped doing the activity 
for a reason other than because of their vision, they will be asked to answer “0”, for “Not 
Applicable”.  As the instrument is scored using the Rasch model rather than a raw score, the 
person score can be created despite any missing data for individual items. 
 
Scoring:  The instrument is recommended to be scored using the Rasch Model to enable 
generation of an interval score.[1]    Buckhurst validated the scoring in a clinical population 
comprised of 150 subjects including patients with a range of corrections for presbyopia:  
monofocal, accommodating, and multifocal intraocular lenses, multifocal contact lenses and 
varifocal spectacles. The questionnaires were administered 3 months after any surgeries, 1 
month after contact lens fitting and 3 to 8 months after varifocal spectacles were dispensed.   
 
 
 
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Table 1 summarizes the patient characteristics in the validation study[1] and Table 2 shows the 
NAVQ scores stratified by type of correction.  In the table, a lower score represents better near 
visual function. 
 
TABLE 1: CHARACTERISTICS OF PATIENTS RECRUITED FOR VALIDATION OF NAVQ[1] 
 
Type of Correction 
 
N=20 (13%) Monofocal IOL 
N=60 (40%) Multifocal IOL 
N=30 (20%) Accommodating IOL 
N=20 (13%) Multifocal spectacles 
N=20 (13%) Varifocal spectacles 
 
Age, mean±standard deviation [range] 
 
63 years±11 [30-82] 
 
Sex, male:female 
 
N=66:n=84 
 
 
TABLE 2: NAVQ SCORES RESCALED TO 1-100 FOR EACH TYPE OF PRESBYOPIA CORRECTION[1] 
 
Type of correction 
 
Mean NAVQ score  ± SD 
 
Monofocal IOL 
 
59.0 ±  10.5 
 
Multifocal IOL 
 
18.9 ±  13.2 
 
Accommodating IOL 
 
34.2  ±  12.1 
 
Multifocal spectacles 
 
24.0  ±  11.6 
 
Varifocal spectacles 
 
17.9  ±  11.6 
 
V. Assessment of Other Measurement Properties 
 
The attributes of reliability, validity and ability to detect change have been assessed during 
instrument development and these reports have been published.[1, 2] and are summarized as 
follows.   
 
A. Reliability:  It is important that a PRO can yield a consistent, reproducible estimate of effect.  
The repeatability of the NAVQ score has been assessed by calculating its intra-class 
correlation coefficient (ICC) in a sub-set of 90 patients who repeated the NAVQ two weeks 
after the first administration.  The 2 way random effects intraclass correlation coefficient 
(ICC) for test-retest reliability was estimated as 0.72.  This can be interpreted as high 
reliability.  Internal consistency was also investigated and the Cronbach α coefficient was 
0.945 showing good construct validity.[1]  The instructions for completing the questionnaire 
will be scripted to ensure no variability between administrations such that the reliability of 
the instrument will be maintained during the IDE study. 
 
 
 
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B. Construct validity:  Buckhurst investigated the relationship between the NAVQ and 
objectively measured distance corrected near visual acuity (DCNVA, logMAR) and critical 
print size (CPS).  CPS was the smallest print size on the Minnesota Low Vision Reading 
Test (MN-Read) chart that could be read at the patient’s maximum reading speed.  The 
correlation coefficient was 0.543 for DCNVA and 0.526 for CPS representing moderate 
correlations.[1]  The moderate correlation to reading is not surprising, since reading speed 
can also be affected by motivation, education and intelligence; and DCNVA at a 
standardized distance by no means captures the variability in near tasks and preferred 
working distances among patients.    
 
C. Ability to detect change:  The person separation index (PSI) is the ratio of the true variance 
in the estimated measures to the observed variance and indicates the number of distinct 
person strata that can be distinguished by the PRO.[6]  The NAVQ was reported to have a 
PSI of 2.92 which indicates excellent discriminant ability.[1]  Further, the NAVQ 
demonstrated the ability to distinguish between different types of presbyopia correction.[1]  
It is anticipated that the NAVQ will be able to measure a change in near visual function from 
before to after surgery and determine if the near visual function is relatively stable across 
visits. 
 
VI. Interpretation of scores 
 
The NAVQ provides a score for patient reported near visual function and satisfaction with 
presbyopia correction.  It was found to be reliable and valid, using standard, current psychometric 
techniques.[1]  The NAVQ was also able to discriminate between those with and without near vision 
difficulties as shown by the difference in mean scores by type of refractive correction (Table 3) and 
as shown by the separation index (2.92).[1]   Therefore, NAVQ interval scores provide a relative 
measure of difficulty with near visual tasks and can be compared between subjects and across 
different time points.   
 
VII. Language and cultural adaptation 
 
The NAVQ was developed and validated in the United Kingdom in an English speaking population.  
The questionnaire has been pilot tested with 11 patients who have undergone the VisAbility Implant 
Procedure.  All questions were understood and there was no missing data.  Because the instrument 
has been successfully self-administered to 150 patients in the UK during development[1] and in an 
evaluation of 15 patients in the UK with a diffractive trifocal IOL[3], it is likely that the readability is 
sufficient for an English speaking U.S. study population. As a result, the instrument will be 
administered in its original form in English without cultural adaptation.  
 
VIII. 
Modifications 
 
A comparison of the original NAVQ instrument provided in Exhibit B and the PRO instrument to be 
used in the IDE clinical study, Exhibit A, shows that they are virtually identical.  The instructions, 
which have been adapted for the context of this trial, are also virtually the same as the original 
NAVQ instrument.  Since there is only one presbyopic correction being considered, the field where 
type of presbyopic correction is indicated has been replaced with a single option. A subject identity 
field has been added at the top for completion by the clinical staff to ensure proper recordkeeping.  
 
 
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IX. Conclusion 
 
Although the PRO outcomes are not intended to support specific labeling claims, the NAVQ 
questionnaire’s characteristics, conceptual framework, content validity, and other measurement 
properties (i.e. reliability, construct validity, and ability to detect change) are adequate for the 
instrument to serve as an additional evaluation in the IDE investigation of the VisAbility Implant 
System.  
 
X. Key references 
 
1. 
Buckhurst, P.J., et al., Development of a questionnaire to assess the relative subjective 
benefits of presbyopia correction. J Cataract Refract Surg, 2012. 38(1): p. 74-9. 
2. 
Gupta, N., et al., Development of a near activity visual questionnaire to assess 
accommodating intraocular lenses. Cont Lens Anterior Eye, 2007. 30(2): p. 134-43. 
3. 
Sheppard, A.L., et al., Visual outcomes and subjective experience after bilateral 
implantation of a new diffractive trifocal intraocular lens. J Cataract Refract Surg, 2013. 
39(3): p. 343-9. 
4. 
Stelmack, J., et al., Use of Rasch person-item map in exploratory data analysis: a clinical 
perspective. J Rehabil Res Dev, 2004. 41: p. 233-244. 
5. 
Food and Drug Administration, Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims, in Guidance for Industry2009, US 
Department of Health and Human Services,: Washington. 
6. 
Pesudovs, K.P., et al., The Development, Assessment, and Selection of Questionnaires. 
[Article]. Optometry & Vision Science, 2007. 84(8): p. 663-674. 
 
 
 
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EXHIBIT A 
Near Activity Visual Questionnaire (NAVQ) to be used in the IDE study of the VisAbility Implant 
System 
 
 
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EXHIBIT B 
Original Published Near Activity Visual Questionnaire (NAVQ)  
 
 
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EXHIBIT C 
Manual for NAVQ Administration 
The Sponsor shall provide training regarding the administration of the NAVQ questionnaire used in 
the clinical trial of the VisAbility Implant System.  This administrative manual is the training to be 
used by the staff at the clinical sites.  
This guidance includes instructions on WHEN the NAVQ is to be administered, WHERE the 
administration should take place, HOW it is to be given to the subject, HOW questions are to be 
answered and WHAT the plan is for the scoring process. 
Clinic staff is to use the script provided in Section C below each time a subject is asked to complete 
the NAVQ questionnaire.   
A.  WHEN and WHERE to give the NAVQ: 
The NAVQ should be given either in the waiting room or in the examination room BEFORE the 
patient has any examination of their vision by the doctor or study staff. It is not necessary for the 
subject to be in complete privacy while taking the short questionnaire, but study staff will be 
instructed to insure the subject completes the questionnaire independently.  
B.  HOW to give the NAVQ and HOW to answer questions:   
1. Give the subject a pen and the paper copy of the NAVQ on a clipboard. 
 
2. It is important that the patient is instructed to answer about their experience when not 
wearing reading glasses, magnifiers or corrective lenses of any type.  Ask the subject if 
they understand what is meant by “reading glasses, magnifiers or corrective lenses.    
 
3. Verbally give the subject the scripted instructions, visually checking after each 
instruction to see if the subject apparently understood the instruction.  
  
4. If subjects have questions, emphasize that there is no right or wrong answer and that if 
they no longer perform some tasks due to non-visual reasons that they should mark “X” 
in the first column.  If they have stopped doing a task because of vision, they should 
mark “3” for Extreme Difficulty.   
C.  Script for Administration of NAVQ: 
1. ‘Please fill out this short questionnaire before we get started with the examination. You 
will need to write in your name, date of birth and today’s date.  Circle the answer that 
most closely reflects your amount of difficulty with near vision tasks.  There is no right or 
wrong answer.  I will check that you have completed all questions but will not pay 
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2. ‘You should answer the questions about your near vision when you are not wearing 
reading glasses or using magnifiers or corrective lenses of any type. Please let me know 
that you understand.’  
 
3. ‘The questions are about different activities where you need to see up close.  Again, you 
should respond based on your experience with these activities when you are not wearing 
reading glasses.’ 
 
4. ‘If you don’t do or have stopped doing the activity for a reason other than because of 
your vision – please circle ‘X’ in the first column for ‘not applicable.’  We would like you 
to complete all of the questions.’   
 
5. 'Please answer the questions by writing on the paper form.  Please answer the questions 
independently without advice or input of clinic staff or family members.’   
 
Clinic staff is to check to determine that all questions have been answered and to ask the subject 
to complete any unanswered questions.  Make sure that all fields are completed and that the Subject 
ID# is correct.  Place the completed form without scoring in the subjects’ study file. 
WHAT the plan is for the scoring process.  Scoring of the questionnaire results will not be conducted 
at the clinical sites.  The Sponsor will handle the statistical scoring process for each NAVQ 
questionnaire at a later time.   
 
 
 
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APPENDIX 5: DATA SAFETY MONITORING BOARD CHARTER 
 
 
 
Refocus Group, Inc. 
 
DATA SAFETY MONITORING BOARD (DSMB) CHARTER 
 
A PROSPECTIVE, MULTICENTER CLINICAL TRIAL OF  
THE VISABIITY IMPLANT SYSTEM (VIS) 
 FOR THE IMPROVEMENT OF NEAR VISUAL ACUITY IN PRESBYOPIC 
PATIENTS 
 
Protocol: VSI-2014 
 
Date of Protocol: October 13, 2014 
Date of Protocol Amendment 1: January 10, 2015 
 

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1. INTRODUCTION 
This charter governs the Data Safety Monitoring Board (the “DSMB”) established by 
Refocus Group, Inc. (the “Sponsor”) for the prospective, multicenter clinical trial of the 
VisAbility Implant System for the improvement of near visual acuity in Presbyopic patients 
under Protocol VIS-2014 (the “Clinical Trial”).  The charter describes; the role and 
responsibilities of the DSMB, its members, conduct of meetings, its access to data and the 
manner of communication with the Sponsor. 
2. ROLE OF THE DSMB: RESPONSIBILITIES & FUNCTION 
The primary role of the DSMB will be to ensure subject safety during the conduct of the 
Clinical Trial. 
The DSMB will periodically evaluate the conduct of the Clinical Trial, adverse events and 
related safety data, and efficacy data from the perspective of relative benefit.  The DSMB 
will make recommendations to the Sponsor as follows. 
The recommendations of the DSMB to the Sponsor may include: 
Modification of the study protocol, subject to approval of FDA or the IRB as applicable. 
Continuation of the study according to the protocol and any related amendments. 
Modification of the manner of study conduct. 
Discontinuation of the study (with provisions for orderly discontinuation in accord with good 
medical practice). 
Discontinuation of enrollment into the study. 
3. DSMB MEMBERSHIP 
3.1       Members 
The DSMB will consist of three members with at least two members being licensed 
ophthalmologists or optometrists.  The names and contact information of the DSMB 
members are as shown in the Appendix and will be updated periodically as needed 
should changes in DSMB membership occur. A copy of each DSMB member's 
curriculum vitae, updated at least annually, will be maintained by the Sponsor and 
available upon request. DSMB members will not act as investigators or sub-
investigators for the Clinical Trial and will have no involvement in the Clinical Trial 
outside their role on the DSMB. DSMB members may not participate in any other 
IDE clinical study of a presbyopia correcting surgical device or technique, other than 
studies of presbyopia correcting intraocular lenses, nor may DSMB members serve 
as a personal physician to any subject enrolled in the Clinical Trial. 
 
 
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3.2  
Financial Disclosure and Conflict of Interest 
Each DSMB member must disclose any financial or other material interests which 
may create a potential conflict with respect to their role on the DSMB including, but 
not limited to, equity interests in the Sponsor. Members of the DSMB will be 
responsible for advising the Sponsor of any change in related financial interests. 
The Sponsor will be responsible for deciding whether financial or material interests 
may impact a member's objectivity, and may ask a member to resign from the DSMB. 
3.3  
Duration of DSMB Membership and Replacement of Members 
The DSMB membership will cover the duration of the Clinical Trial, including any 
extension of the follow-up period of the subjects.  
3.4 
Replacement of Members 
If a member cannot continue to serve on the DSMB, the reason must be 
communicated in writing to the DSMB Chairperson and the Sponsor. If a member or 
the Chairperson leaves the DSMB, the Sponsor will select an appropriate 
replacement. If a member cannot reasonably be available for meetings of the DSMB, 
the Chairperson may request the member be replaced and the Sponsor may remove 
such member with the recommendation of the Chairperson. The Sponsor will be 
responsible for providing any new DSMB member with necessary study related 
materials. 
 
4 DSMB MEETINGS 
The DSMB will meet in person or by conference call according to the following schedule. 
4.1  
Initial Organizational Meeting 
The initial meeting of the DSMB will be to acquaint the DSMB members with Protocol 
VIS-2014, Sponsor personnel, Sponsor communication, planned study conduct as 
well as other pertinent information. The DSMB may also recommend changes to this 
charter during this organizational meeting. Invited attendees include the DSMB 
members, the Medical Monitor and the Sponsor’s representatives. 
4.2  
Scheduled Meetings 
Meetings will be held by phone or in person twice per year during the Clinical Trial. 
The frequency of scheduled meetings may change at the discretion of the DSMB 
Chairperson depending on subject enrollment and safety event rates. Meetings will 
also be held upon the occurrence of a device-related SAE or UADE, or at the request 
of the Medical Monitor.   
 
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4.3 
 
Quorum and Voting 
A quorum of two of the three DSMB members is required to hold any teleconference 
or in-person meeting. All three DSMB members must participate for a vote on any 
recommendation to the Sponsor other than normal continuance of the Clinical Trial. 
4.4  
Meeting Format 
The meeting will begin with an open session to review enrollment, study conduct and 
safety information generated in the Clinical Trial. Representatives from the Sponsor 
and the Medical Monitor will present the information and answer any questions from 
the DSMB.  
A closed session will follow to discuss safety data and any actions required by the 
DSMB regarding the available safety information. This session will be attended by 
only the DSMB members and, if requested with reasonable advance notice, an 
independent statistician retained by the Sponsor with access to the Clinical Trial 
database. The DSMB members will discuss the safety data, formulate any 
recommendations, and conduct their voting. 
A final session will then convene to be attended by the DSMB members and 
representatives from the Sponsor and the Medical Monitor. The DSMB will verbally 
convey its recommendations to the Sponsor's representatives. The DSMB 
Chairperson will convey written DSMB recommendations within a timely fashion 
(within three weeks after the meeting) to the Sponsor. 
 
5       COMMUNICATION 
5.1  
Data Reports 
The Sponsor will prepare and provide safety data to the DSMB in advance of each 
meeting. All available data will be used to create a summary report and summary 
tables of safety data, listings of adverse events and specific case histories for 
selected AEs, SAEs or UADEs. The data in these tables will be drawn from active 
study databases. The Sponsor and Medical Monitor shall present and explain the 
data in the open session to the DSMB and answer any questions. The DSMB 
Chairperson may, on behalf of the DSMB, communicate in advance to the Sponsor 
a request for additional information and the Sponsor shall make reasonable efforts 
to comply.  
If requested, the Sponsor will designate an independent statistician with access to 
the Clinical Trial database to be available to prepare and provide data directly to the 
DSMB regarding the Clinical Trial effectiveness outcomes.  
The DSMB chairperson will be notified by the Sponsor or Medical Monitor upon the 
occurrence of a device-related SAE or UADE.  
If the DSMB requests additional information concerning the study data, the DSMB 
Chairperson may contact the Sponsor’s designated independent statisticians directly 
and the statistician shall be instructed by the Sponsor to provide any information 
reasonably requested.  
 
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5.2 
DSMB Minutes 
Following each meeting, summary minutes of both the open and closed meeting 
sessions will be drafted and distributed on a timely basis for approval.  Minutes from 
open session meetings will be compiled by a Sponsor representative and reviewed 
by Sponsor representative(s) as well as DSMB members attending the 
meeting.  Minutes from closed session meetings will be compiled by a DSMB 
member and reviewed only by DSMB members attending the meeting.  Both open 
and closed session meeting minutes will be retained throughout the study by the 
DSMB Chairperson.  The minutes of both open and closed meetings will be 
approved by the DSMB at the subsequent meeting. 
Upon completion of the Clinical Trial follow-up period and the locking of the database 
by the CRO, the DSMB will forward a complete set of both open and the closed 
meeting minutes to the Sponsor. 
5.3 
DSMB Recommendations 
At each DSMB meeting, the DSMB will recommend whether the study should 
continue, stop, or be modified based on study findings. The DSMB will provide 
written recommendations about the trial to the Sponsor within a timely fashion but 
not longer than three weeks after the meeting. In addition, the DSMB will also 
communicate verbally with the Sponsor's representatives immediately regarding any 
safety issues or other findings. 
Upon receipt of the DSMB recommendations, the Sponsor will consider the 
recommendations, review the status of the Clinical Trial, and determine a timely 
course of action. 
The Sponsor may identify expert individuals to review the DSMB Reports. These 
individuals will not have any direct involvement with the Clinical Trial but will have 
the clinical, statistical, and regulatory expertise needed to contribute to any decisions 
on behalf of the Sponsor. The Sponsor may seek input from regulatory agencies and 
make a decision to accept or disregard the recommendation from DSMB. The 
Sponsor and DSMB will assure that confidentiality of the data will be maintained. 
If a DSMB recommendation is implemented, the Chairperson of the DSMB will 
receive written notification of this fact. If the Sponsor does not implement a 
recommendation, the reasons for such a decision will be documented in writing and 
provided to the DSMB Chairperson. The Sponsor will assume the responsibility to 
notify the regulatory agencies of all recommendations of the DSMB. 
If the DSMB recommends stopping the trial and the Sponsor agrees, the Sponsor 
will inform all regulatory agencies of the decision and notify all Investigational sites. 
Public disclosure of the decision to stop the trial is entirely at the Sponsor's 
discretion. 
 
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APPENDIX 
VIS-2014 Clinical Trial DSMB Member List 
XXXXXXXXX, M.D. 
Ophthalmologist/Optometrist 
INSERT ADDRESS & CONTACT INFO 
 
XXXXXXXXX, M.D. 
Ophthalmologist/Optometrist 
INSERT ADDRESS & CONTACT INFO 
 
XXXXXXXXX,  
 
INSERT ADDRESS & CONTACT INFO 
 
 
 
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APPENDIX 6: ANTERIOR SEGMENT ISCHEMIA (ASI):  DETECTION, MITIGATION AND 
REPORTING 
Anterior Segment Ischemia (ASI) is a potentially serious but most often self-limited response to 
decreased perfusion that even in severe cases generally resolves without sequelae or detrimental 
effects on vision.  The rich collateral blood supply of the anterior segment likely explains its 
relatively benign common clinical course. 
Decreased constriction of the pupil in response to light is the earliest physiological indicator of ASI 
and serves as a bellwether indicating diminished perfusion.  Recovery of perfusion, when it occurs 
at this mild stage, avoids potential sequelae such as persistent pupillary abnormalities.  
Monitoring the pupillary reflex in the immediate postoperative period helps prevent progression by 
allowing prompt intervention to restore perfusion while the condition remains completely 
reversible. 
In this clinical study of the VisAbility Implant, Refocus has adopted digital infrared dynamic 
pupillometry as a sensitive indicator of neuromuscular disturbance secondary to decreased iris 
vascular perfusion in the immediate postoperative period.  Pupillometry serves the primary 
purpose of evaluating the impact of surgery on perfusion and allowing for prompt removal of 
scleral implants from eyes that demonstrate compromised perfusion, thus reversing impaired 
pupillary function and preventing progressive damage from ischemia. 
Clinical Syndrome, Natural History and Severity Grading 
ASI represents an acute, generally self-limited response of the anterior segment of the eye to 
decreased vascular perfusion.  While mild cases most often resolve without sequelae, more 
severe cases may develop persistent pupillary abnormalities and iris atrophy.  Though rare, 
cataract and hypotony have been reported in a few isolated, very severe cases.  
The clinical syndrome of ASI was first described in 1954 and has become recognized as an 
uncommon complication of surgery involving the extraocular muscles.1  Risk factors for the 
development of ASI include advanced age, previous extraocular surgery, blood dyscrasias, 
hypercoagulable states, atherosclerosis, carotid artery disease and thyroid related immune 
orbitopathy.  In the setting of strabismus surgery, these risk factors play a larger role in 
determining susceptibility to ASI than the number or combination of muscles operated.2 
Anatomical studies have demonstrated that the anterior ciliary arteries are the source of 70 to 
80% of the circulation of the anterior segment, including the iris and ciliary body.  The long 
posterior ciliary arteries provide the remainder, along with some contribution from the 
conjunctiva.3  The anterior ciliary arteries run along the rectus muscles, dividing into multiple 
branches and forming three levels of collateral anastomoses near the muscles’ scleral insertion 
points.  This rich collateral circulation likely explains the rarity and generally self-limited nature of 
postoperative ASI.  
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Delayed perfusion of the iris as demonstrated by angiography is recognized as Grade 1 ASI.4  
However, iris fluorescein angiography is not a useful tool in predicting which patients are likely to 
progress to higher grades of ASI or develop long-term sequelae postoperatively.9  Acutely 
decreased pupil reactivity represents Grade 2 ASI.  Anterior chamber reaction in addition to 
decreased pupil reactivity constitutes Grade 3.  Striate keratopathy, which is similar to the type of 
corneal edema typically seen following cataract surgery, in addition to anterior chamber reaction 
and decreased pupil reactivity represents the highest level of severity, Grade 4. 
Patients with Grade 4 ASI typically experience pain and reduced visual acuity beginning one or 
two days after surgery.  Without any surgical re-intervention, a period of gradual clinical 
improvement follows, with return of preoperative visual acuity in nine weeks or less.9 It is not 
known whether medical treatment with topical or systemic anti-inflammatory agents has any effect 
on the natural history of ASI.  Patients with severe iris ischemia may develop iris atrophy, 
decreased pupil reactivity and an oval or irregular pupil. 
Case reports and series in the literature reveal the natural history typical of ASI.  For example, 
Forbes reported on a case of Grade 4 ASI occurring after a four muscle operation.  Striate 
keratopathy initially reduced the visual acuity to 20/200.  Over two months the vision improved to 
20/30. Iris atrophy and an irregular pupil were the only sequelae.5 Keech et al described a case of 
Grade 4 ASI following a transposition procedure in a 74 year old woman with hypertension. On 
postoperative day 1, visual acuity was reduced to 20/100.  Slit lamp exam revealed an oval pupil 
with an atonic sphincter, anterior chamber reaction and striate keratopathy.  By 6 weeks all clinical 
signs had resolved except for a sluggishly reactive, oval pupil.6  
 
 
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Saunders et al reported on a series of cases involving surgery on three extraocular muscles.7 Five 
adult patients developed acute ASI, including 3 with pupil signs and anterior chamber reaction 
(Grade 3) and 2 with striate keratopathy (Grade 4).  Treatment consisted of topical and systemic 
steroids.  With the exception of corectopia, there was complete resolution of all signs within 9 
weeks postoperatively. No patient suffered permanent visual loss.  Olver and Lee reported a 
series including 17 eyes with Grade 1, 11 eyes with Grade 2 and 5 eyes with Grade 3 ASI.16 
Recovery of the iris circulation in most patients occurred within 4 weeks of surgery.  Only 2 eyes 
in the entire series demonstrated long-term pupil changes; the remaining eyes had no sequelae.  
To further elucidate the natural history of ASI, Bagheri et al investigated ASI in a rabbit model, 
chosen for its anatomic similarity to the human, including the significant contribution of the 
vasculature of the 4 rectus muscles to nourishment of the anterior segment.8  Performing various 
combinations of surgery involving from 1 to 4 muscles, they found that 51 eyes (30.4%) 
developed signs of ASI, but in most cases inflammation and corneal edema resolved 
spontaneously and histopathology revealed no major permanent ischemic changes.  Long-term 
complications included pupil irregularity and decreased response to light in 12 eyes and cataract 
in 4 eyes. A single case in the 4-muscle group showed neovascularization of the cornea and iris.  
These findings support the clinically recognized natural history of ASI, which involves complete 
resolution without sequelae in most cases. 
Digital Pupillometry  
Because pupillary dysfunction constitutes the earliest functional sign of ASI, sensitive and precise 
measurement of the pupillary response to light in the immediate postoperative period represents a 
useful indicator of the risk of disease progression.  Other methods of detecting changes in anterior 
segment perfusion, including iris angiography and laser Doppler flowmetry, have not been proven 
as useful.  Iris angiography is not a useful tool for predicting which patients may develop clinical 
signs of decreased perfusion; therefore, iris angiography has not been standardized as a means 
of assessing postoperative iris perfusion, nor has it been utilized to assess the risk of sequelae.9 
In addition, iris angiography does not reveal filling of intrastromal vessels in eyes with highly 
pigmented irides.  Further, the dye pattern is different in each individual, with a wide range of 
normal filling times and patterns. Additionally, validated commercial instruments designed 
specifically for iris angiography are not currently available, so iris angiography requires 
modification of existing equipment.10 Lastly, iris angiography adds risk due to potential reactions 
to intravenous fluorescein dye and may also prove difficult due to the status of the ocular surface 
and subjects’ reduced ability to comply with the procedure in the immediate postoperative period 
due to fatigue and residual effects of intraoperative sedation. 
 
 
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While laser Doppler flowmetry has found utility in the study of the retinal and optic nerve head 
circulation, it has had only limited investigational use for the purpose of measuring the blood flow 
of the iris in humans.11,12,13  This technique requires adaptation of a laser delivery system, 
photodetector and target fixation device to a slit lamp, and while it has been used to investigate 
the effects of increased intraocular pressure and increased arterial pressure on perfusion, it has 
not to date been used to investigate the impact of reduced blood flow in the anterior ciliary 
arteries.14 
Therefore, digital infrared dynamic pupillometry is the optimal indicator of iris neuromuscular 
function relative to iris vascular perfusion.  Measurement of the dynamic response of the pupil to 
standardized illumination is the most sensitive means to assess the eye’s recovery from surgery 
because pupillary abnormalities represent the earliest functional sign of anterior segment 
ischemia (ASI).15  The purpose of pupillometry in the immediate postoperative period in this study 
is to allow for timely removal of scleral implants and prevent the development of potential 
sequelae. 
Infrared digital pupillometry consists of an integrated intense light source for pupil stimulation; an 
image capture system with an infrared digital camera capable of obtaining pupil measurements 
throughout the entire examination process (pupil diameter at rest, during light stimulation, and at 
the end of the stimulus), without interfering with pupil response because it provides no visible 
light; and a data processor to perform calculations.16  Using this type of device, i.e., the 
NeurOptics NPi™-200 Pupillometer (Neuroptics, Inc., Irvine, CA)], the mean percent pupil 
constriction in a population of healthy adults has been determined to be 34% according to the 
formula %CH ={[dilated pupil diameter – constricted pupil diameter]/[dilated pupil diameter]} x 
100.17  The authors of this study noted that, “in only one of 2432 measurements was the 
percentage of reduction below 10%.17 Therefore, digital infrared pupillometry offers a non-invasive 
method of obtaining a precise, numerical clinical measurement that serves as an early indicator of 
risk for progressive ASI and provides a clear threshold criterion value, allowing for timely 
intervention. Of note, an enrollment criterion for this study excludes any subject in whom the 
baseline mean percent pupil constriction is less than 30% in either eye, so that any impact of 
surgery on pupillary function can be readily discerned. 
In this protocol we have adopted the following instrumentation, threshold criterion and standard 
operating procedures: 
• 
Measurement of the pupillary reflex in both eyes with the NeurOptics NPi™-200 
Pupillometer (Neuroptics, Inc., Irvine, CA)18 in the immediate post-operative period at 
15-30 minute intervals and recording the pupillary reflex in the eye as a percentage 
constriction based on the following formula: 
Percent Change (%CH) = {[dilated pupil diameter – constricted pupil diameter]/[dilated pupil 
diameter]} x 100 
• 
A threshold criterion value of %CH ≥ 25% constriction in the operative eye at two 
distinct time points at least 5 minutes apart 
• 
Immediate removal of all PSI from any eye which does not achieve the threshold 
criterion within 6 hours postoperatively and before the patient is released from the 
facility; and  
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• 
Mandatory electronic reporting of pupil constriction values to Refocus.  
 
This procedure is shown in the flow chart below. 
 
 
These procedures are designed to allow for timely recognition of persistent reduction in the 
pupillary reflex and to insure removal of all implant segments from any eye at risk of developing 
sequelae of ASI prior to discharge of the subject from the surgical facility on the day of surgery. 
Adverse Event Reporting 
As described above, implant segments are to be removed from any eye with Grade 2 ASI (acutely 
decreased pupil reactivity) or Grade 3 ASI (decreased pupil reactivity plus anterior chamber 
reaction) persisting 6 hours postoperative; therefore, the AE category “Secondary Surgical 
Intervention: Implant segment removal” should be reported for these cases.  At postoperative day 
one or later, the constellation of findings of Grade 4 ASI, i.e., corneal edema, anterior chamber 
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reaction and decreased pupillary reactivity, should be reported with the AE category “Grade 4 
anterior segment ischemia.” Additionally, any persistent pupillary abnormalities due to reduced iris 
vascular perfusion should be reported with the AE category, “Pupil abnormalities persisting after 3 
months.” 
1  Wilson WA, Irvine SR.  Pathologic changes following disruption of blood supply to iris and 
ciliary body. Trans Am Acad Ophthalmol Otolaryngol. 1955 Jul-Aug;59(4):501-2. 
 
2  Hiatt RL. Production of anterior segment ischemia.  Trans Am Ophthalmol Soc. 1977;75:87-
102. 
3  Wilcox LM, Keough EM, Connolly RJ, Hotte CE. The contribution of blood flow by the anterior 
ciliary arteries to the anterior segment in the primate eye. Exp Eye Res. 1980 Feb;30(2):167-
74. 
 
4  Olver JM, Lee JP. The effects of strabismus surgery on anterior segment circulation. Eye 
(Lond). 1989;3 ( Pt 3):318-26. 
 
5   Forbes SB. Muscle Transplantation for External Rectus Paralysis : Report of Case with 
 
Unusual Complications. Am. J. Ophth. 48:248-251 (Aug.) 1959. 
 
6   Keech RV, Morris RJ, Ruben JB, Scott WE. Anterior segment ischernia following vertical 
muscle transpositionand botulinum toxin injection (letter) . Arch Ophthalmol 108:176, 1990. 
 
7   Saunders RA, Phillips MS. Anterior segment ischemia after three rectus muscle surgery. 
Ophthalmology. 1988 Apr;95(4):533-7. 
 
8   Bagheri A, Tavakoli M, Torbati P, Mirdehghan M, Yaseri M, Safarian O, Yazdani S, Silbert D.  
Natural course of anterior segment ischemia after disinsertion of extraocular rectus muscles in 
an animal model. J AAPOS. 2013 Aug;17(4):395-401. 
 
9  Saunders RA, Bluestein EC, Wilson ME, Berland JE. Anterior segment ischemia after 
strabismus surgery.  Surv Ophthalmol. 1994 Mar-Apr;38(5):456-66. 
 
10  Brancato R, Bandello F, Lattanzio R.  Iris fluorescein angiography in clinical practice. Surv 
Ophthalmol. 1997 Jul-Aug;42(1):41-70. 
 
11 Chamot SR, Movaffaghy AM, Petrig BL, Riva CE. Blood flow in the human iris measured by 
laser Doppler flowmetry. Microvasc Res. 1999 Mar;57(2):153-61. 
 
12  Chamot SR, Movaffaghy A, Petrig BL, Riva CE. Iris blood flow response to acute decreases in 
ocular perfusion pressure: a laser Doppler flowmetry study in humans.  Exp Eye Res. 2000 
Jan;70(1):107-12. 
 
13  Michelson G, Groh M, Gründler A. Regulation of ocular blood flow during increases of arterial 
blood pressure. Br J Ophthalmol. 1994 Jun;78(6):461-5. 
 
14  Riva CE, Geiser M, Petrig BL; Beijing 100193, PR China. Ocular Blood Flow Research 
Association. Ocular blood flow assessment using continuous laser Doppler flowmetry. Acta 
Ophthalmol. 2010 Sep;88(6):622-9.  
 
 
 
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15  Olver JM, Lee JP.   Recovery of anterior segment circulation after strabismus surgery in adult 
patients.  Ophthalmology. 1992 Mar;99(3):305-15. 
 
16  Martínez-Ricarte F, Castro A, Poca MA, Sahuquillo J, Expósito L, Arribas M, Aparicio J. 
Infrared pupillometry. Basic principles and their application in the non-invasive monitoring of 
neurocritical patients. Neurologia. 2013 Jan-Feb;28(1):41-51.  
 
17 Taylor WR, Chen JW, Meltzer H, Gennarelli TA, Kelbch C, Knowlton S, Richardson J, Lutch MJ, 
Farin A, Hults KN, Marshall LF. Quantitative pupillometry, a new technology: normative data 
and preliminary observations in patients with acute head injury. Technical note. J Neurosurg. 
2003 Jan;98(1):205-13. 
 
18 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/rl.cfm?lid=83319&lpcd=HLG 
 
 
 
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APPENDIX 7: SPONSOR COMMITMENTS 
Refocus Group, 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. Providing the statistical analysis and study report writing resources necessary to complete 
reporting of the study results. 
 
6. Ensuring equity of consideration among all investigators in multicenter studies in all 
matters of publications, meeting presentations, etc. 
 
7. Certifying that IRB approval of the protocol and Investigator’s Clinical Agreement will be 
completed prior to initiation of study at an investigational site. 
 
 
 

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APPENDIX 8: INVESTIGATOR COMMITMENTS AND RESPONSIBILTIES 
Each Investigator must be a licensed physician who has completed a residency in ophthalmology.  
The investigators have the following responsibilities: 
1. Subject Selection 
The investigator is responsible for assuring that all subjects enrolled and determined eligible for the 
study meet all inclusion and exclusion criteria stated in this protocol. 
2. 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 Study Informed Consent in compliance with 21 CFR 
50 for each subject, prior to performing surgery on a subject.  The original signed Informed Consent 
Form will be maintained in the subject's medical record, and a redacted copy of the signed Informed 
Consent Form will become an integral part of each Case Report file provided to the Sponsor. 
3. Institutional Review Board (IRB) Approval 
The investigator will obtain or verify approval for his/her participation in this study from the IRB for 
the institution at which the procedure will be performed, prior to enrolling any subjects in the study.  
The Informed Consent document to be used must also be approved by the IRB prior to initiation of 
the study.   
4. 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 subject source 
document or case report forms.  The investigator will sign and date each individual form upon its 
completion.  Originals of all case report forms will be retained in the investigator’s office in order to 
be available for monitoring by authorized regulatory bodies. 
The investigator will not deviate from the study protocol without prior approval from the Sponsor 
unless protection of the health, safety or welfare of study subjects requires prompt action. 
5. Record Retention 
The investigator shall maintain all subject records for whichever of the following periods is shortest: 
• 
A period of two years after the date on which the FDA approves the marketing of the device 
for the purpose that was the subject of the study. 
• 
A period of five years after the date on which the results of the study are submitted to the 
FDA in support of the marketing of the device for the purpose that was the subject of the 
study. 
 
 
 
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6. Investigational Material Accountability 
The investigator must maintain accurate records of the receipt, use and return of all investigational 
devices, including the product identification and serial numbers as applicable.    The investigator 
must assure that study supplies be dispensed only to subjects enrolled and eligible to be in the 
study and under the direct supervision of the investigator or co-investigators. 
The principal investigator must keep records of all investigational supplies.  Investigational material 
accounting procedures must be completed before the study is considered completed. 
 
 
 
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APPENDIX 9: DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
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 patients, including those 
who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
 
4. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient'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. 

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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 requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
 
B. 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. 
 
 

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16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients 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. 
 
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 

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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 patients, 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 
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. 
 

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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 patients 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 
patients 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, patients 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 patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in 
the physician's judgement 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.